1. health and fitness
2. disease
3. cancer

Collaborate Explore Discover
2008-2009
Scientific Report
Director’s Letter
Dear Friends and Colleagues:
It is my pleasure to present you with our 2008 – 2009 Scientific Report, which provides an account of the
progress we have made during the last two years. As the report documents, we are building on our strong
tradition of innovative cancer research, expanding our programs, and strengthening our commitment to
population research, epidemiology, and pediatric cancer studies. In 2008, the National Cancer Institute
designated the University of Chicago Cancer Center (UCCRC) as a Comprehensive Cancer Center,
acknowledging the “depth and breadth of research activities in each of three major areas: laboratory, clinical,
and population-based research, with substantial transdisciplinary research that bridges these scientific areas.”
Since 1996, we have grown from 136 to 212 members with peer-reviewed cancer research grants of
approximately $98 million in total costs. Our members also have $25 million in non-peer reviewed
grants and contracts.
As you will see in this report, our members have substantiated accomplishments in our renowned areas of
research, such as early-phase clinical trials, drug development, characterization of hematological malignant
diseases, new treatment paradigms in head and neck cancer, pharmacogenomics, medical imaging, and
tumor immunology.
We are building a world-class program in population research by recruiting key faculty in molecular
epidemiology, environmental epidemiology, behavioral psychology, and chemoprevention trials research.
For example, our new “Epidemiology and Recruitment Core” provides our members with uncommon
expertise and technology. We are enlisting superior faculty in other high priority areas, including systems
biology, and are developing state-of-the-art capabilities in cancer stem cell research, metastasis research,
pediatric sarcoma research, immunotherapy and translational immunology research, lymphoma research,
and GI oncology.
Our growing pediatric oncology program is robust with enhanced resources in its allogeneic transplant
program, solid tumor biology and therapy program, and the expanded Pediatric Cancer Survivorship clinical
and research program. Cancer survivorship research and long-term clinical care of survivors is a chief
priority. Consequently, we have developed the Breast Cancer Survivorship Clinic, opened in January 2008, as
a joint initiative of the UCCRC Women’s Cancer Working Group, the UCCRC Breast Cancer SPORE, and the
Section of Hematology/Oncology.
We are proud of our past, enthusiastic about the present, and optimistic about the future. The dedication our
members and our supporters is the source of this confidence. The UCCRC thrives on ambitious, daunting
goals. We can meet these challenges because of the commitment and generosity of our senior leaders,
members, staff, Foundation, and many donors.
With gratitude,
Michelle M. Le Beau, PhD
Professor of Medicine
Director, University of Chicago Cancer Research Center
Overview &
Administration
Cell Signaling &
Gene Regulation
Molecular Genetics
& Hematopoiesis
Immunology
& Cancer
Clinical & Experimental
Therapeutics
Advanced
Imaging
Table of Contents
Overview and Administration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Cancer Risk
& Prevention
Programs
Cell Signaling and Gene Regulation Program. . . . . . . . . . . . . . . . . 6
Clincal Trials
Activity
Molecular Genetics and Hematopoiesis Program. . . . . . . . . . . . . 28
Immunology and Cancer Program . . . . . . . . . . . . . . . . . . . . . . . . . 44
Clinical and Experimental Therapeutics Program. . . . . . . . . . . . 58
Shared
Resources
Advanced Imaging Program. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
Cancer Risk and Prevention Program. . . . . . . . . . . . . . . . . . . . . . . 98
Other Resources
& Centers
Clinical Trials Activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
Shared Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
Highlights
Other Resources and Centers. . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
Highlights. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
UCCRC SCIEN T IFI C R EPO R T 20 0 9
1
UCCRC senior staff (from left to right): Paul Butera, PhD, Hoyee Leong, PhD, Marcy List, PhD, Michelle Le Beau, PhD,
Umberto Tachinardi, MD, Mary Ellen Connellan, MS, Maria Reyes, BS. Not pictured: Connie Skosey, RN
Overview &
Administration
The mission of the University of Chicago Cancer Research
Center (UCCRC) is to elucidate the determinants of cancer,
to develop cures for cancer, and to prevent cancer.
Overview
The UCCRC, founded in 1973 under the
The UCCRC was designated as a National Cancer
leadership of John E. Ultmann, MD, was
Institute (NCI) Cancer Center in 1974 with the
established as a multidisciplinary, matrix
award of the initial Cancer Center Support
program of basic and clinical research in
Grant (CCSG). The UCCRC was designated as
cancer. Today, our cancer programs emphasize
a Comprehensive Cancer Center by the NCI in
translational and interdisciplinary research,
2008 following its last review, in recognition of
and promote collaboration among a diverse
the “depth and breadth of research activities in
and dedicated team of outstanding basic,
each of three major areas: laboratory, clinical,
translational, clinical, and population
and population-based research, with substantial
researchers, caregivers, and trainees.
transdisciplinary research that bridges these
The UCCRC has integrated 212 members
from 20 academic departments and three
University Divisions (Biological, Physical,
and Social Sciences) into a highly interactive,
collaborative, and interdisciplinary research
environment.
The members are organized into six established
programs and include Cell Signaling and
Gene Regulation, Molecular Genetics and
Hematopoiesis, Immunology and Cancer, Clinical
and Experimental Therapeutics, Advanced
Imaging, and Cancer Risk and Prevention. Clinical
research is a major focus of multidisciplinary
activity at the UCCRC. The UCCRC has
long been recognized for its strength in basic
and clinical research, particularly our major
scientific areas,” as well as demonstrated
proficiency in “professional and public education
and dissemination of clinical and public health
advances into the community it serves.” For
the past 34 years, the CCSG has been strongly
supported by the Biological Science Division
(BSD), continuously funded by the NCI, and
has provided the structure for enhancing and
advancing the UCCRC mission. The research
base of the UCCRC members is approximately
$98 million in total costs, with approximately
$28 million of this sum awarded by the NCI, and
over $25 million in non-peer reviewed grants
and contracts. The current funding base for the
UCCRC includes 8 P01 and Center type grants,
5 U series awards, 3 SPORE/SCOR awards, and
11 T32 awards.
contributions to early-phase clinical trials and drug
development, the characterization of hematological
malignant diseases, the development of new
treatment paradigms in head and neck cancer,
pharmacogenomics, medical imaging, and tumor
immunology.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
3
Administration
UCCRC Executive Committee
Michelle M. Le Beau, PhD
Director
Professor of Medicine
Director, Cancer Cytogenetics Laboratory
Marcy A. L ist, PhD
Associate Director for Administration
Scientific Director, Cancer Clinical
Trials Office
Marsha R. Rosner, PhD
Deputy Director for Basic Sciences
Charles B. Huggins Professor
Director, Ben May Department for
Cancer Research
Professor of Neurobiology, Pharmacology
and Physiology
Everett E. Vokes, MD
Deputy Director for Clinical Sciences
John E. Ultmann Professor
Chairman of Medicine
Habibul Ahsan, MD
Associate Director for Population Research
Professor of Health Studies
Geoffrey L. Greene, PhD
Associate Director for Basic Sciences
and Education
Virginia and D.K. Ludwig Professor
Associate Director, Ben May Department
for Cancer Research
Rick A. Kittles, PhD
Associate Director for Diversity and
Community Outreach
Associate Professor of Medicine
Yves Lussier, MD
Director for Biomedical Informatics
Associate Professor of Medicine
Medicine Director, Center for
Biomedical Informatics
Mark J. Ratain, MD
Associate Director for Clinical Sciences
Leon O. Jaobson Professor of Medicine
Chair, Committee on Clinical
Pharmacology and Pharmacogenomics
Additional UCCRC Senior
Leaders and Members of the
Cancer Advisory Committee
Julie A. Auger, BS
Associate Director for Core Facilities
Executive Director, Office of Shared
Research Facilities
UCCRC Senior Staff
Paul Butera, PhD
Director for Communications
Mary Ellen Connellan, MS
Executive Director,
Cancer Research Foundation
John Cunningham, MD
Hoyee Leong, PhD
Carol S. Giometti, PhD
Maria Reyes, BS
Professor and Section Chief of Pediatric
Hematology/Oncology
Biosciences Director
Argonne National Laboratory
Olufunmilayo Olopade, MBBS
Walter L. Palmer Distinguished Service
Professor of Medicine
Associate Dean for Global Medicine
Mitchell C. Posner, MD
Thomas D. Jones Professor and Chief
of General Surgery
Richard L. Schilsky, MD
Professor of Medicine
Arieh Shalhav, MD
Fritz and Mary Lee Duda Chair,
Professor and Chief of Urology
Gary Steinberg, MD
Professor of Surgery
Michael Vannier, MD
Professor of Radiology
Ralph Weichselbaum, MD
Daniel K. Ludwig Professor and
Chairman of Radiation and
Cellular Oncology
S. Diane Yamada, MD
Associate Professor of Obstetrics
and Gynecology
Chief, Section of Synecological Oncology
Director for Scientific Communications
and Strategic Partnerships
Director for Finance
Connie Skosey, RN
Director for Clinical Operations
Umberto Tachinardi, MD
Director for Informatics
Overview &
Administration
UCCRC –
External Advisory Board
James K. Willson, MD (CHAIR)
Director, Harold Simmons Cancer Center
University of Texas Southwestern
Medical Center at Dallas
Donald Berry, PhD
Professor & Chair, Department
of Biostatistics
M.D. Anderson Cancer Center
Michael A. Caligiuri, MD
Director, The Ohio State University
Comprehensive Cancer Center
Mary B. Daly, MD, PhD
Senior VP for Population Science
Director, Cancer Prevention and
Control Program
Fox Chase Cancer Center
Stephen H. Friend, MD, PhD
Senior Vice President
Merck & Co., Inc.
Stanton L. Gerson, MD
Director
Case Comprehensive Cancer Center
Steven D. Gore, MD
Professor of Oncology
Sidney Kimmel Comprehensive Cancer
Center at Johns Hopkins
H. Kim Lyerly, MD
Director
Duke Comprehensive Cancer Center
Gloria Petersen, PhD
Professor of Epidemiology
Mayo Clinic College of Medicine
Stephen E. Sallan, MD
Chief of Staff – Chief Medical Officer,
Childrens Hospital Cancer Care
Dana-Farber Cancer Institute
Margaret R. Spitz, MD
Professor and Chair
Department of Epidemiology
M D Anderson Cancer Center
Daniel Sullivan, MD
Professor, Department of Radiology
Duke University Medical School
Michael J. Weber, PhD
Director, Cancer Center at the
University of Virginia Health System
Jane Wegenke, BS
Associate Director – Administration
University of Wisconsin Comprehensive
Cancer Center
Michael J. Welch, PhD
Professor of Radiology
Department of Radiology
Washington University School
of Medicine
Philip D. Greenberg, MD
Professor of Medicine and Immunology
University of Washington
Scott J. Leischow, PhD
Professor, Colleges of Medicine and
Public Health
Arizona Cancer Center -The University
of Arizona
C. Clifton Ling, PhD
(Ad Hoc Imaging)
Head, Radiation Biophysics Laboratory
Memorial Sloan-Kettering Cancer Center
UCCRC SCIEN T IFI C R EPO R T 20 0 9
5
P ro g r a m 1
Cell Signaling and Gene Regulation
4T07 metastatic mouse breast cancer cells stained with anti-APC antibody (red) and phalloidin (green). APC
accumulation is particularly associated with the ends of actin-rich cell protrusions. The protrusion-associated
APC is necessary for the mesenchymal morphology of these cells because RNAi-mediated knockdown of APC
results in a more pronounced epithelial phenotype of the cells. (Image by C. Stengel and K. Goss)
The Program fosters collaborations between basic scientists
Cell Signaling &
Gene Regulation
and clinical researchers to ultimately identify potential
therapeutic targets and facilitate the testing of small
molecule inhibitors of such targets.
Overview & Goals
The Cell Signaling and Gene Regulation Program
in cancerous versus normal cells, analysis of
focuses on determining the basic cell signaling
transcription factor biology (including nuclear
and gene expression mechanisms that underlie
hormone receptors), and the structural biology
key events in malignant transformation and
of key proteins involved in cancer etiology. The
development. The Program brings together
Program fosters collaborations between basic
a diverse group of 43 basic and translational
scientists and clinical researchers to ultimately
investigators from 12 departments with a wealth
identify potential therapeutic targets and facilitate
of experience in chemistry, cell signaling,
the testing of small molecule inhibitors of such
systems biology, developmental biology, and drug
targets.
discovery. These investigators are dedicated
to discovering mechanisms of abnormal cell
growth that could lead to innovative anti-cancer
treatments.
The research aims of the Cell Signaling and
Gene Regulation Program are to (1) elucidate
Program Leaders:
the molecular mechanisms of tissue specific and
cell type specific gene expression; (2) elucidate
the cellular mechanisms underlying cell growth/
division and cell survival/death; (3) understand
the multi faceted mechanisms leading to
Marsha R. Rosner, PhD
cancer metastases; (4) use large scale, high
throughput and systems biology approaches,
as well as genetic evolutionary approaches to
understand cancer biology; and (5) discover novel
developmental pathways relevant to cancer cell
signaling. Particular strengths of the program
include an emphasis on the detailed mechanistic
analysis of signal transduction and apoptotic
Suzanne D. Conzen, MD
pathways, understanding cell cycle regulation
UCCRC SCIEN T IFI C R EPO R T 20 0 9
7
Members
8
Investigator*
Rank
Department
Kenneth Alexander MD, PhD
Eric Beyer MD, PhD
David Boone PhD
Steven Chmura MD, PhD
Suzanne Conzen MD
Wei Du PhD
Nickolai Dulin PhD
Edwin Ferguson PhD
Kathleen Goss PhD
Geoffrey Greene PhD
Rex Haydon MD, PhD
Yu Ying He PhD
Tong-Chuan He MD, PhD
Akira Imamoto PhD
Richard Jones PhD
Shohei Koide PhD
Stephen Kron MD, PhD
Bruce Lahn PhD
Deborah Lang PhD
Ernst Lengyel MD, PhD
Shutsung Liao PhD
Anning Lin PhD
Hue Luu MD
Kay Macleod PhD
Carl Maki PhD
Elizabeth McNally MD, PhD
Kathleen Millen PhD
Andy Minn MD, PhD
Ivan Moskowitz MD, PhD
Milan Mrksich PhD
Piers Nash PhD
Marcelo Nobrega MD, PhD
Marcus Peter PhD
Clifton Ragsdale PhD
Ilaria Rebay PhD
Jalees Rehman MD
Carrie Rinker-Schaeffer PhD
Bernard Roizman ScD
Marsha Rosner PhD
Benoit Roux PhD
Ravi Salgia MD, PhD
Julian Solway MD
Tobin Sosnick PhD
John Staley PhD
Wei-Jen Tang PhD
Aaron Turkewitz PhD
Jerrold Turner MD, PhD
Kevin White PhD
Chung-I Wu PhD
Yingming Zhao PhD
Associate Professor
Professor
Assistant Professor
Assistant Professor
Associate Professor
Associate Professor
Associate Professor
Professor
Assistant Professor
Professor
Assistant Professor
Instructor
Associate Professor
Associate Professor
Assistant Professor
Associate Professor
Associate Professor
Professor
Assistant Professor
Associate Professor
Professor
Professor
Assistant Professor
Associate Professor
Assistant Professor
Professor
Associate Professor
Assistant Professor
Assistant Professor
Professor
Assistant Professor
Assistant Professor
Professor
Associate Professor
Associate Professor
Assistant Professor
Associate Professor
Professor
Professor
Professor
Professor
Professor
Associate Professor
Associate Professor
Professor
Associate Professor
Professor
Professor
Professor
Associate Professor
Pediatrics
Pediatrics
Medicine
Radiation and Cellular Oncology
Medicine
Ben May
Medicine
Molecular Genetics and Cell Biology
Surgery
Ben May
Surgery
Medicine
Surgery
Ben May
Ben May
Biochemistry and Molecular Biology
Molecular Genetics and Cell Biology
Human Genetics
Medicine
OB/GYN
Ben May
Ben May
Surgery
Ben May
Radiation and Cellular Oncology
Medicine
Human Genetics
Radiation and Cellular Oncology
Pediatrics
Chemistry
Ben May
Human Genetics
Ben May
Neurology, Pharmacy and Physiology
Ben May
Medicine
Surgery
Molecular Genetics and Cell Biology
Ben May
Pediatrics
Medicine
Medicine
Biochemistry and Molecular Biology
Molecular Genetics and Cell Biology
Ben May
Molecular Genetics and Cell Biology
Pathology
Human Genetics
Ecology and Evolution
Ben May
UCCRC SCIEN T IFI C R EPO R T 20 0 9
* Reflects all Program membership during 2008-2009
Featured Faculty Research Summaries†
Cell Signaling &
Gene Regulation
Investigators in the Cell Signaling and Gene Regulation Program use a
global approach to improve the understanding of how genetic and cell
signaling alterations contribute to the pathogenesis of cancer. Research
themes reflect the scientific goals of the Program and are highlighted below.
Theme: Mechanisms of Gene Regulation
Marcus Peter, PhD
Professor of The Ben May Department for Cancer Research
For 17 years, the core interest of the Peter laboratory
has been the regulation of apoptosis signaling in
health and disease with emphasis on the function of
the death receptor Fas. The discovery of the death
inducing signaling complex (DISC) and the cloning of
a number of key signaling molecules in apoptosis, such
as caspase-8, c-FLIP, DEDD and DEDD2, was followed
by the identification of the two signaling pathways
of Fas that determine whether Fas induces apoptosis
independently of mitochondria or with the help of
mitochondrial amplification. About 6 years ago, the
emphasis shifted towards nonapoptotic activities
of Fas and its signaling components and their role
in tumor progression. Fas mediated apoptosis was
recognized to be just one of many activities of Fas.
Persistent DNA damage foci in MCF-7 breast cancer cells 24 h after treatment with
ionizing radiation and PARP inhibitor ABT-888, imaged by GFP-53BP1 chromatin
binding domain reporter. (Image by E. Efimova, R. Weichselbaum, and S. Kron)
Stimulation of Fas on apoptosis resistant cancer cells
was shown to increase motility and invasiveness of
tumor cells. These activities of Fas involve activation of the NF-kB and MAP kinase pathways. Interestingly, these
activities were also dependent on the nature of the apoptosis signaling pathway utilized by Fas. Through these
studies, the Peter lab became interested in the activity of micro(mi)RNAs, their role in tumor progression, and the
interplay between miRNAs and Fas functions.
Current specific interests of the lab include1) the role of miR-98, also known as let-7, and miR-200 in tumor
progression; 2) the function of let-7 regulated oncofetal genes (LOGs); 3) the connection between miR-200,
epithelial-mesenchymal transition (EMT) and cancer stem cells; and 4) the role of Fas and miRNAs in liver, ovarian
and colon cancer.
During the last year, the Peter lab has discovered two miRNAs as regulators of tumor progression. miRNAs are
small noncoding RNAs that negatively regulate gene expression at a posttranscriptional level. The first miRNA
family is let-7, which was found to be downregulated in tumor cells representing more advanced, less differentiated
cancers. HMGA2 was identified as a number one target for let-7. Together with Dr. Ernst Lengyel, the group went
on to demonstrate, for the first time, an inverse prognostic value of the ratio of let-7/HMGA2 expression in cancer.
Ovarian cancer patients with a high ratio of let-7 to HMGA2 were found to have a much more favorable prognosis
than patients with a low ratio.
The second miRNA family that was linked to cancer progression is miR-200. miR-200 was found to be a highly
significant marker of epithelial cancer cells and almost completely absent in advanced mesenchymal cancer cells.
Not only was miR-200 an excellent marker for epithelial cells, it turned out to be a powerful regulator of EMT.
Altering miR-200 levels in cancer cells causes a change in the epithelial nature of the cells. Both miRNA families
hold great promise as general cancer therapeutics, since they both are dysregulated in various human cancers, and
introducing them into cancer cells may reverse tumor progression.
† Note: Due to space constraints, only a small representative sample of Program members is presented here.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
9
Theme: Molecular Mechanisms of Apoptosis, Cell Growth, and Cell Survival
Kay Macleod, PhD
Associate Professor of The Ben May Department for Cancer Research
As solid tumors grow, they outstrip their ability to take up
oxygen, glucose and other nutrients from the environment by
diffusion. The deficit in oxygen (hypoxia) elicits pleiotropic
effects in mammals, including increased glycolysis, angiogenesis,
and erythropoiesis, all processes that maximize ATP generation
and nutrient delivery, while also inhibiting processes such as
cell cycle progression and protein translation that consume
large amounts of ATP. The upregulation of glycolysis in
particular results in acidification of the microenvironment,
forcing adaptation to low pH such that, even when oxygen is
restored, tumor cells continue to depend on glycolysis and, in
Students and technicians working in one of the UCCRC’s dedicated
research facilities, the Ellen and Melvin Gordon Center for Integrative
Science.
some cases, are critically dependent on metabolic enzymes for
survival. This has been referred to as the “glycolytic switch” and
may represent a novel “hallmark” of cancer that offers an opportunity to specifically target tumor cells, by blocking critical
metabolic pathways. Another feature of tumor cells that are deprived of oxygen is the induction of autophagy, a survival process
that is activated in response to starvation. Autophagy promotes turnover of cellular constituents to re-generate metabolites and
ATP. Counter-intuitively, given its role in promoting cell survival, autophagy has been proposed to act as a tumor suppressor
mechanism via its role in limiting damaging reactive oxygen species by promoting turnover of mitochondria, preventing DNA
damage by maintaining nucleotide pools, and limiting necrosis and associated pro-tumorigenic inflammatory responses.
Importantly, autophagy also induces cell cycle arrest, although the mechanism is not known.
Work in the Macleod laboratory is focused on understanding the molecular basis by which hypoxia, oxidative stress and
autophagy modulate tumor progression and metastasis. In recent years, the laboratory has focused on how cell survival is
modulated in response to hypoxia and nutrient deprivation, and showed for the first time that hypoxic cells induce autophagy
to promote survival and that this process is dependent on aspects of the function of BNIP3 and BNIP3L, both HIF-inducible
target genes. The molecular mechanism by which BNIP3 and BNIP3L promote autophagy is a key focus of on-going work in the
laboratory. Hypotheses being tested include a role in directly targeting mitochondria for degradation at the autophagosome to
an indirect role in autophagy through effects on mitochondrial fission. Translational work has identified loss of BNIP3 activity
as a potential biomarker for the progression of human breast cancer to invasiveness. Using mouse models of breast cancer to
assess this and other aspects of autophagy in tumor suppression, the laboratory discovered that some tissues express BNIP3
constitutively (such as the heart, skeletal muscle and liver). Phenotypic analysis of BNip3 null mice has highlighted a role for
BNip3 in mitochondrial integrity in normal adult hepatocytes and also a novel function for BNip3 in fatty acid metabolism
in response to starvation. Continued analysis of the phenotype in these mice is aimed at explaining these observations at the
molecular level.
The Macleod laboratory is also examining a role for autophagy in modulating outgrowth of disseminated tumor cells. The
presence of tumor cells in the blood and bone marrow of women presenting with early stage breast cancer, as well as circulating
tumor cells in a significant number of women decades after their initial diagnosis and treatment, indicates that tumor cells
can disseminate early but remain dormant for long periods of time. The mechanisms governing tumor cell dormancy in breast
cancer are not understood, but the Macleod group proposes that single cell dormancy brought about by cell cycle arrest may be
explained by the induction of autophagy as the tumor cell finds itself in an inhospitable environment to which it is not evolved
for growth. The laboratory is exploring the mechanisms by which autophagy induces cell cycle arrest and further validating this
work in mouse models. Finally, bringing together elements of tumor biology and metabolism, the laboratory is investigating
the role of autophagy, mitochondrial integrity and metabolism in genetic prediposition to specific cancer types in human
populations.
10
UCCRC SCIEN T IFI C R EPO R T 20 0 9
Marsha Rosner, PhD
The Rosner laboratory focuses on the mechanism by which signals are transmitted within the cell to specify particular
outputs leading to cell growth, differentiation or death. Dr. Rosner’s long-time focus has been on the regulation of the MAP
kinase signaling cascade, an evolutionarily conserved kinase pathway that has been implicated in tumor cell progression,
invasion and metastasis. Recent work from the laboratory has elucidated novel signaling cascades that regulate tumor
Cell Signaling &
Gene Regulation
Professor of The Ben May Department for Cancer Research
cell cycle progression and metastasis via mechanisms involving microRNAs. One aspect of Dr. Rosner’s work involves
characterizing the mechanism by which Raf Kinase Inhibitory Protein (RKIP), functions as a suppressor of breast cancer
metastasis.
Tumor metastasis suppressors are inhibitors of metastatic progression and colonization and, as such, represent important
markers for prognosis and potential effectors of therapeutic treatment. However, the mechanisms by which metastasis
suppressors function are generally not understood. RKIP has been implicated as a suppressor of lung metastasis in a murine
model using androgen-independent prostate tumor cells. A modulator of key regulatory pathways in mammalian cells, RKIP
inhibits MAP kinase (MAPK) signaling by binding to Raf-1, preventing Raf-1 phosphorylation at activating sites. RKIP also
suppresses NFkB activation, inhibits GRK2-mediated downregulation of G protein-coupled receptors, and potentiates the
efficacy of chemotherapeutic agents. The Rosner laboratory has recently shown that RKIP ensures chromosomal integrity
and genomic stability by preventing MAPK inhibition of Aurora B kinase and the spindle checkpoint. RKIP is missing or
depleted in a number of cancers including prostate, breast, melanoma, hepatocellular, and colorectal, suggesting that it may
function as a general metastasis suppressor for solid tumors. The Rosner laboratory has analyzed gene expression data from
primary human breast tumors and determined that the RKIP signaling pathway is a prognostic marker for metastasis-free
survival of breast cancer patients.
Dr. Rosner’s recent studies have shown that RKIP suppresses invasion and metastasis by inhibiting the MAP kinase (MAPK)
signaling pathway and inducing the microRNA let-7. MicroRNAs are noncoding RNAs of ~22 nucleotides that regulate key
processes in growth and development and have been implicated as tumor oncogenes or suppressors in cancer. Let-7/miR-98
is an evolutionarily conserved microRNA family that has been implicated as a tumor suppressor of colon and lung cancer, and
let-7 loss is associated with breast tumors as well as other less differentiated human cancer cells. Let-7 has also been shown
to suppress breast cancer stem cell properties (self-replication and pluripotent differentiation to multiple cell types) as well as
proliferation and breast tumor growth. Thus the microRNA let-7 is an important link between regulation of metastasis and
regulation of embryonic and cancer stem cells.
Although let-7 has been implicated as a suppressor of breast cancer metastasis, few of its downstream signaling targets are
known. To determine which potential let-7 targets regulate metastatic progression upon loss of RKIP expression, The Rosner
laboratory, in collaboration with Dr. Andy Minn, developed a new strategy based on gene set analysis of gene expression
data from >1200 human breast tumors. The goal was to negatively correlate expression of putative let-7 targets with RKIP
expression. A similar approach was used to identify bone metastasis signature (BMS) genes that might be regulated by RKIP.
The Rosner laboratory identified a novel RKIP/let-7-regulated signaling cascade, involving transcription factors that regulate
key BMS genes, and enabled the use of this cascade in predicting metastatic risk in patients. Dr. Rosner hopes to test these
predictions in the clinic to determine their prognostic and therapeutic potential for both identifying patients most likely to
suffer metastatic disease as well as to identify the most effective treatments.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
11
Theme: Cell Motility, Cell-Cell Adhesion, and Metastasis
Andy Minn, MD, PhD
Assistant Professor of Radiation and Cellular Oncology
Metastasis is responsible for the vast majority of
breast cancer-related deaths. At present, the best
way to cure breast cancer is to remove the disease
prior to metastasis. Occasionally, surgery and local
radiation are not sufficient to cure the disease because
of the microscopic spread of cancer to other organs.
In this situation, chemotherapy is administered
after surgery, but with limited success because a
significant proportion of women with such disease
manifests chemotherapy resistance and go on to
develop clinically significant metastatic disease
(stage IV) months or years later. Thus, the window of
opportunity to cure breast cancer rapidly closes once
the disease spreads. Attempts to re-open this window
have been unsuccessful, leading to the prevailing
wisdom that metastasis is incurable.
A spontaneous intestinal tumor from ApcMin/+ mice stained with anti-beta-catenin
antibody (green) and Hoechst dye (blue) to label the nuclei. In the normal intestinal
mucosa (to the right of the image), beta-catenin is localized to the basolateral
surface of the epithelial cells where it mediates cell-cell interactions via the adherens
junction. In these tumors with loss of heterozygosity of the Apc tumor suppressor,
beta-catenin accumulates in the cytoplasm and nuclei of the tumor cells (center of
image) and regulates the transcription of tumor-associated target genes. (Image by K. Goss)
For breast cancer, classical progression models
share the theme that genes controlling metastasis
and resistance are stochastically acquired through
mutation. These models dictate that metastatic potential and resistance are cell-intrinsic and passed between cells, tumors,
and disease sites, which has given rise to a common perception that cancer is uncontrollable once distant spread has occurred.
In contrast to this reasoning, Dr. Minn’s laboratory hypothesizes the existence of metastases that are biologically limited in
colonization, spread, and virulence and, therefore, represent what is called an oligometastatic state. His team envisions that
oligometastases are more likely to be sensitive to therapy due to a mechanistic coupling between genes that drive metastasis and
those that drive treatment resistance. The aims of Dr. Minn’s research are to characterize and mechanistically define genes and
pathways that both mark and mediate metastasis and its resistance to treatment.
Previous work in the laboratory identified a Lung Metastasis Gene Signature (LMS) that experimentally mediates and clinically
predicts aggressive metastasis. Although the LMS accounts for a significant percentage of metastases among breast cancer
patients that develop distant relapse, the majority of patients with LMS-expressing primary cancers do not metastasize. This
suggests an additional level of regulation and complexity that may occur subsequent to successful distant colonization.
To understand mechanisms of treatment resistance better, Dr. Minn’s laboratory is collaborating with Dr. Ralph Weichselbaum
(Clinical and Experimental Therapeutics Program) to study a gene expression signature for DNA damage resistance, denoted
the Interferon-Related DNA Damage Resistance Signature, or IRDS. Several key IRDS genes mediate experimental resistance
to chemotherapy and radiation, and their known involvement in interferon responses suggest unanticipated but interesting
biology. The team has recently shown that the IRDS is expressed in half of primary human cancers of various types and may
account for the majority of breast cancer patients with resistance to chemotherapy and radiation.
By focusing on the LMS and IRDS as two biologically and clinically relevant models for metastasis and treatment resistance, a
major research goal of Dr. Minn’s laboratory is to explore the mechanistic underpinnings of why progression toward metastasis
often goes hand-in-hand with progression toward treatment resistance. Consistent with this notion, the majority of LMSexpressing primary breast cancers also express the IRDS. Interestingly, the laboratory has discovered that tumor stroma may
be critically involved in these processes. Efforts that leverage a systems biology approach to understand important heterotypic
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interactions, paracrine factors, and intracellular signaling events that govern the biology of the each signature are currently
of primary cancer, can result in a biologically-definable period whereby immature tumor-microenvironmental interactions
limit metastatic colonization, spread, and resistance to therapy. If so, a subset of patients with metastasis may be amenable to
aggressive and perhaps curative treatment.
Carrie Rinker-Schaeffer, PhD
Cell Signaling &
Gene Regulation
underway. Ultimately, an important goal is to determine whether early detection of metastasis, similar to early detection
Associate Professor of Surgery
Cancer metastasis is a complex, dynamic process that begins with dissemination of cells from the primary tumor and
culminates in the formation of clinically detectable, overt metastases at one or more discontinuous secondary sites. The
process of invasion has been well studied, but the last steps in metastasis, metastatic colonization, remain largely unknown.
Identifying pathways that control metastatic colonization may be critical for successful clinical management of cancer
in both the metastatic and adjuvant settings. While genetic mutations or epigenetic changes may be required for cells to
separate and survive distant from the primary tumor, the environment within secondary tissues plays a substantial role in
determining whether disseminated cells survive and proliferate. Work in the Rinker-Schaeffer laboratory is focused on a
critical unanswered question: Why do the majority of disseminated cells, which should be fully malignant, fail to proliferate
immediately at secondary sites, and how do these cells initiate growth and cause lethal disease? Over the past decade, the
laboratory has created unique model systems and developed biochemical tools to address this question mechanistically.
This work is laying the foundation for the translational goal of identifying targets for inhibiting metastatic colonization and
prolonging disease-free and overall survival.
There is considerable interest in controlling the growth of cancer cells at metastatic sites. Therapeutic leads may be discerned
by determining why disseminated cancer cells, which have molecular alterations that alter their growth properties, often
lodge at target organs and persist as undetectable, or dormant disease. Many laboratories have worked on this question in
terms of angiogenesis, roles of oncogenes in conferring growth potential, or aspects of dormancy. The models used in these
studies, however, did not enable the investigators to mechanistically interrogate effects on proliferation vs. apoptosis vs.
quiescence in vivo. The Rinker-Schaeffer team chose to approach this problem from a different angle and use the unique tools
they have developed over the past decade. The laboratory discovered that the stress-signaling kinase JNKK1/MKK4 can
control an early step in metastatic colonization and extended symptom-free survival in preclinical models of prostate and
ovarian cancers. Recent studies from the group support the hypothesis that activated JNKK1/MKK4 impairs proliferation
of cells early in the course of metastatic colonization. It is remarkable that few, if any, studies have been conducted that
specifically examine growth control of cells during metastatic colonization.
The more intriguing question is how these cells ultimately bypass suppression and form overt metastases. Historically,
fundamental tenets of metastasis biology dictate that acquisition of metastatic ability is the result of the “drive” of malignant
cells towards growth. Thus it was predicted that bypass of suppression is simply the result of mutation-selection cycles
which permanently inactivate JNKK1/MKK4 or members of its signaling cascade. Published data from the Rinker-Schaeffer
laboratory challenge this paradigm and suggest that JNKK1-mediated suppression may be due to a reversible cell cycle arrest
concomitant with changes in JNKK1/MKK4 activation status. An exciting opportunity now exists to re-examine important
but scattered literature on population-dependent behaviors of metastatic cells which have heretofore been refractory to
mechanistic study. Understanding how a population of suppressed cells can adapt to its environment and initiate growth
is critical to the development of adjuvant therapies that can be used in conjunction with local therapy to delay the onset of
metastases. Ongoing studies are aimed at understanding how activated JNKK1/MKK4 regulates proliferation of disseminated
cells and the global mechanism(s) by which suppressed cells ultimately bypass suppression.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
13
Theme: Systems Biology and Genetic Evolution Relevant to Cancer
Kevin White, PhD
Professor of Human Genetics
Dr. White’s laboratory uses a combination of genomics, computational, and genetic approaches to investigate large-scale
networks of factors that control gene expression during development and disease. A major challenge in the “genomic era” of
biology is to assemble the thousands of genes and proteins encoded within each genome into comprehensive subsets that specify
particular developmental events or physiological processes. The laboratory is approaching this challenge using Drosophila
melanogaster as a model and in the human genome directly.
A recent Science publication confirms the laboratory’s successful strategy of using genomics and systems-level analysis of model
organisms to identify factors that play crucial roles in human cancer. In this study, Dr. White’s team constructed a large-scale
functional network model in D. melanogaster built around two key transcription factors involved in the process of embryonic
segmentation. Analysis of the model allowed the identification of a new role for the ubiquitin E3 ligase complex factor SPOP. In
Drosophila, the gene encoding SPOP is a target of segmentation transcription factors. Drosophila SPOP mediates degradation
of the Jun kinase phosphatase Puckered, thereby inducing tumor necrosis factor (TNF)/Eiger-dependent apoptosis. In humans,
the laboratory found that SPOP plays a conserved role in TNF-mediated JNK signaling and is highly expressed in 99% of clear
cell renal cell carcinomas (RCCs). SPOP expression distinguished histological subtypes of RCC and facilitated identification
of clear cell RCC as the primary tumor for metastatic lesions, indicating that SPOP is a highly sensitive and specific diagnostic
biomarker.
The development of personalized genomic treatments for human cancers is the long-term goal of Dr. White’s laboratory. A
program was recently launched, called “The 100 Chicago Cancer Transcriptomes (100 CCT),” with the aim of sequencing
entire expressed genome from human cancer samples. A unique aspect of the 100CCT project is that genomic researchers
work closely with physicians who routinely treat patients. The goal is to accelerate the translation of genomic discoveries into
useful diagnostic tools and therapeutic strategies. The laboratory employs the “next generation” sequencing Solexa platform to
produce “paired end” sequences in order to completely re-sequence transcript populations in a variety of human cancers, such
as t-AML, breast, prostate, ovarian, brain, head and neck, and lung carcinomas. For example, the laboratory is collaborating
with Dr. Funmi Olopade (Cancer Risk and Prevention Program) to conduct a comprehensive transcriptome profiling of breast
cancer subtypes in African-American and European American populations. The aims of this research are to 1) perform
molecular characterization of the mutational and gene expression landscape in basal-like and luminal breast carcinomas; and
2) conduct bioinformatic analysis to identify mutations and gene fusion candidates specific for these subtypes and unique
to African Americans and Europeans. Using an advanced bioinformatic approach developed in his laboratory, Dr. White’s
team recently discovered a new fusion gene in breast cancer cells that they are further screening to determine whether it is a
recurring abnormality.
Dr. White’s laboratory also studies the mechanism of Retinoic acid (RA) action in breast cancer prevention and treatment.
To define the genetic network regulated by retinoic acid receptors (RARs), Dr. White’s team recently identified RAR genomic
targets, using chromatin immunoprecipitation and expression analysis, and found that RAR binding throughout the genome
is highly co-incident with estrogen receptor α (ERα) binding, resulting in a widespread crosstalk of RA and estrogen signaling
to antagonistically regulate breast cancer-associated genes. ERα and RAR binding sites appear to be co-evolved on a large scale
throughout the human genome, often resulting in competitive binding activity at nearby or overlapping cis-regulatory elements.
The highly coordinated intersection between these critical nuclear hormone receptor signaling pathways provide a global
mechanism for balancing gene expression output via local regulatory interactions dispersed throughout the genome.
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Suzanne Conzen, MD
The overall goal of the Conzen laboratory is to identify genetic and molecular mechanisms of mammalian stress signaling
that contribute to both normal human physiology and disease. It has been long hypothesized from epidemiological and
clinical studies that a biological connection between human stress physiology and disease susceptibility exists, but the
mechanisms connecting these complex processes are poorly understood at the molecular genetics level. Glucocorticoids,
Cell Signaling &
Gene Regulation
Associate Professor of Medicine
a major hormone mediator of the stress response, provide an excellent model for studying a fundamental component of
stress circuitry. In 2000, the Conzen laboratory identified glucocorticoid receptor (GR)-initiated signaling as a novel
signaling mechanism that inhibits epithelial cell apoptosis in response to stress. Previously, glucocorticoid signaling had
been predominantly associated with inducing lymphocyte death (i.e., anti-inflammatory signaling) and with homeostatic
energy adjustment. Using systems analysis of GR-mediated gene expression and analysis of GR-regulated transcription factor
binding regions, the group’s observations have revealed novel pathways connecting the physiological stress response (GR
activation) with mechanisms of epithelial cell survival.
Currently, the Conzen laboratory is using a variety of experimental approaches, including systems and traditional molecular
biology applied to both cell culture and mouse models, to uncover fundamental pathways of glucocorticoid-mediated cell
signaling that are relevant to human epithelial cell cancers. To understand the overall gene expression network downstream
of GR signaling in both pre-malignant breast epithelial and breast cancer cells, the Conzen group has performed time-course
global gene expression analyses following GR activation and identified at least two major pathways that regulate GR-mediated
gene expression and cell survival in these cells. Interestingly, these pathways link glucocorticoid signaling to modulation of
both the PI3-K and MAPK signaling pathways.
Secondly, with Drs. Diane Yamada and Gini Fleming (Clinical and Experimental Therpauetics Program), the laboratory
has demonstrated that two key GR target genes [serum and glucocorticoid-inducible kinase1 (SGK1) and MAP kinase
phosphatase-1 (MKP1)] are indeed upregulated in human ovarian epithelium following the administration of synthetic
glucocorticoids to patients. Thirdly, the laboratory performed GR chromatin immunoprecipitation-Chip (ChIP-chip) in
breast epithelial cells exposed to physiological stress concentrations of glucocorticoid and, in collaboration with Dr. Anna
Di Rienzo (Cancer Risk and Prevention Program), identified glucocorticoid-dependent GR binding regions in the regulatory
regions of GR target genes with a strong signature of selective pressure and population-specific genetic variation. Such
variation in GR target gene regulatory regions could lead to a better understanding of differences in individual responses to
both environmental stressors and pharmacological glucocorticoid administration.
Finally, the laboratory, in collaboration with Dr. Martha McClintock (Cancer Risk and Prevention Program), is using
established mouse models of breast cancer in a transdisciplinary study to determine how chronic social stress (e.g., social
isolation) affects behavior, hormonal axes, and mammary cancer susceptibility. A component of this study is to analyze time
course gene expression in the mammary glands using pathway analysis tools. Comparison of gene networks from mammary
glands of young female mice subjected to chronic social isolation from weaning (versus group living) has revealed significant
differences in inflammatory and metabolic pathways. Unexpectedly, these mammary gland gene expression differences occur
most prominently in the mammary glands prior to the development of invasive mammary gland carcinomas. Together with
studies performed at the cellular and tissue levels, these pathways may identify novel targets for breast cancer prevention.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
15
Theme: Developmental Biology
Ilaria Rebay, PhD
Associate Professor of The Ben May Department for Cancer Research
The long-term goal of the Rebay laboratory is to
understand how cells generate, integrate, and respond
to dynamic informational cues. To address this broad
question, the laboratory uses Drosophila, and in
particular the fly eye, as a powerful model system in
which to study cross-talk between signal transduction
pathways and tissue specific transcriptional networks.
Because the signaling mechanisms studied have been
highly conserved in evolution, investigation of the
molecular circuitries used in Drosophila can advance
the understanding of how cell fates are designated and
maintained in all animals, and why misregulation results
in cancer and disease in humans. Current research
focuses on elucidating the function and regulation of
two independent but interconnected nuclear circuitries
operating downstream of the receptor tyrosine kinase
(RTK) pathway.
Protein uptake in Tetrahymena thermophilia, a ciliated protozoan, via labeling
with a GFP-tagged protein. (Image by A. Turkewitz)
First, the Rebay laboratory is studying the function and
regulation of Yan, a conserved ETS family transcriptional
repressor and RTK pathway antagonist. Reflecting critical roles in regulating cell proliferation, differentiation, and survival
during normal development, misregulated ETS protein activity contributes via a variety of mechanisms to the initiation and
progression of many human cancers. For example, translocations involving the human counterpart of Drosophila Yan, referred
to as Tel1, are among the most frequent chromosomal aberrations associated with leukemia. Both Tel1 and Yan self-associate
via an N-terminal protein-protein interaction domain called the Sterile Alpha Motif (SAM). In vitro, the isolated SAM can
form homooligomers, leading to the hypothesis that polymerization might contribute to the mechanism of Tel1/Yan-mediated
transcriptional repression. Intriguingly, in-frame fusions of the Tel1 SAM to an assortment of tyrosine kinases and transcription
factors are detected in the above mentioned leukemic translocations, suggesting that SAM-mediated self-association also
contributes to oncogenesis. Thus, the specific aim of this project is to elucidate how SAM-mediated self-association regulates
normal Tel1/Yan-mediated repression of transcriptional target genes during development. In the long-term, this knowledge may
facilitate the design of specific molecular interventions to block the oncogenic properties of Tel1-SAM leukemic fusion proteins.
The goal of the laboratory’s second project is to investigate the molecular mechanisms whereby a group of evolutionarily
conserved transcription factors, collectively termed the Retinal Determination (RD) gene network, interface with multiple
signaling pathways to direct eye specification and development. The research centers on a gene called Eyes absent (Eya),
which the laboratory identified as a node of cross-talk between the RD network and the Epidermal Growth Factor RTK
signaling pathway. The Rebay group discovered that in addition to its role as a transcription factor, Eya functions as a protein
tyrosine phosphatase. Both functions are required for Drosophila eye development, and perturbation of either activity leads to
developmental abnormalities in mammals. RD genes, either individually or as a network, also regulate proliferation and cell fate
specification in a diverse array of developmental contexts in all metazoans, and consequently both increased expression and
loss of gene function results in developmental perturbation and disease. For example, reduced Eya function results in ear, eye,
kidney, heart and cranial-facial defects, whereas upregulation of Eya proteins appears to correlate with poor clinical outcome in
patients with epithelial ovarian cancer. Thus, a primary aim of this work is to elucidate the specific developmental contexts and
signaling pathways in which Eya participates, and how its dual functions are coordinated and coregulated.
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Most recently, the laboratory discovered that subcellular partitioning of Eya protein between nucleus and cytoplasm is
interactions between Eya and the Abelson (Abl) tyrosine kinase were found to be critical for photoreceptor axon guidance in
the Drosophila visual system, and that mechanistically, Abl-mediated phosphorylation of Eya provides a critical cytoplasmic
retention signal that presumably recruits Eya phosphatase activity to relevant signaling complexes. Abl is well-known as a
potent oncogene, and its normal role in regulating actin cytoskeleton dynamics suggests that further investigation of Eya-Abl
Cell Signaling &
Gene Regulation
critical for normal eye development and that phosphatase function is predominantly required in the cytosol. Cooperative
interactions may provide new insight into the signaling networks regulating cell adhesion, motility, and invasiveness.
Geoffrey Greene, PhD
Professor of The Ben May Department for Cancer Research
The overall goal of research in Dr. Greene’s laboratory is to elucidate the molecular mechanisms by which female steroid
hormones regulate development, differentiation, cellular proliferation and survival in hormone responsive tissues and
cancers, especially breast cancer. Estrogens modulate the expression of diverse regulatory proteins and growth factors via
one or both of two estrogen receptor subtypes (ERα and ERβ). The Greene laboratory is actively studying multiple aspects of
ER action, using a combination of in vitro, cell-based, and animal models.
Current areas of focus include: 1) Defining the molecular/structural mechanisms by which selective estrogen receptor
modulators (SERMs) elicit tissue-selective agonist or antagonist responses via one or both ER subtypes; 2) identifying novel
ER subtype-selective SERMs via a combination of structure-based drug design and de novo drug discovery; 3) characterizing
a mouse knock-in model in which a mutated ERα does not recognize endogenous estrogens, but will respond to exogenous
synthetic ligands; 4) identifying the relative contributions and mechanisms of transcriptional versus rapid, nongenomic ERα
actions in estrogen target tissues; 5) developing targeted nanoparticles for imaging and therapeutic applications, especially
in breast/prostate cancers; 6) genome-wide mapping and characterization of ERα/β target genes (ER transcriptome); and 7)
identification and characterization of protein components of the ER interactome. All of these projects have direct relevance
and application to breast and uterine cancer genesis, progression, treatment and prevention, as well as to the development of
compounds that can be used for hormone replacement therapy in postmenopausal women.
The laboratory recently generated an estrogen non-responsive estrogen receptor knock-in (ENERKI) mouse model to study
the role of ERα during endocrine and neuroendocrine development and mammary tumor genesis. The mutant ERα (G525L)
that was introduced by gene replacement into these mice does not recognize endogenous estrogen but does recognize
exogenous synthetic estrogen agonists and antagonists, such as diethylstilbestrol (DES), propyl pyrazole triol (PPT) and
4-hydroxytamoxifen (OHT). Mutant ERα can be turned on or off simply by giving mice DES or PPT, both potent estrogens.
ERα signaling pathways that do not require ligand remain intact, allowing them to study these pathways as well. Female
ENERKI mice had hypoplastic uterine tissues and rudimentary mammary gland ductal trees. Females were infertile due to
anovulation, and their ovaries contained hemorrhagic cystic follicles because of chronically elevated levels of LH.
The ENERKI phenotype confirmed that ligand-induced activation of ERα is crucial in the female reproductive tract and
mammary gland development. Growth factor treatments induced uterine epithelial proliferation in ovariectomized ENERKI
females, directly demonstrating that ERα ligand-independent pathways were active. PPT treatments initiated at puberty
stimulated ENERKI uterine development, whereas neonatal treatments were needed to restore mammary gland ductal
elongation, indicating that neonatal ligand-induced ERα activation may prime mammary ducts to become more responsive to
estrogens in adult tissues. This mouse is a useful model for in vivo evaluation of ligand-induced ERα pathways and temporal
patterns of response. Interestingly, DES did not stimulate an ENERKI uterotrophic response, possibly due to the upregulation of ERβ in ENERKI mice, which is exerting an antiproliferative function in the uterus. It remains to be determined
if the mammary gland is similarly affected by DES treatment. ENERKI mice will be crossed with several mouse models
that develop spontaneous mammary tumors to better understand the role of endogenous estrogen and ERα in mammary
cancer genesis and progression. This model should also prove useful for studying the estrogen-mediated development and
homoeostasis of the reproductive tract, bone, cardiovasculature and central nervous system.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
17
Additional Program Highlights*
Research
•• The initial steps of ovarian cancer cell metastasis are mediated by
MMP-2 cleavage of vitronectin and fibronectin. Ernst Lengyel, MD,
PhD is searching for new methods to control the metastatic spread
of ovarian cancer. Since one of the first steps in the spread of this
cancer is the attachment of ovarian cancer cells to the peritoneal and
omental surfaces, identifying factors that regulate cell attachment in
the abdominal cavity is critical to the development of therapeutic agents
that prevent metastases. Dr. Lengyel and his colleagues discovered that
MMP-2 expression affects the metastatic spread of ovarian cancer cells
in a three dimensional tumor/stromal co-culture model. These findings
could help us to not only determine how to control cancer, but also how
to inhibit its ability to spread to other organs (Kenny et al. J Clin Invest
118:1367-1379, 2008).
•• The miR-200 Family Determines the Epithelial Phenotype of
Dr. Ravi Salgia
Cancer Cells by Targeting the E-Cadherin Repressors ZEB1 and ZEB2
(intraprogrammatic). In a collaborative project, Marcus Peter, PhD and Dr. Lengyel examined whether cancer progression
shares similar processes with those that occur during embryonic development. The team evaluated the expression of 207
microRNAs (miRNA) in the 60 cell lines of the drug screening panel maintained by the National Cancer Institute. They
discovered and confirmed, in primary ovarian cancer specimens, that the miR-200 miRNA family is a powerful marker
for grouping of primary cancers, consequently showing that a single key master regulating gene can control cell phenotype
(Park et al. Genes Dev 22:894-907, 2008).
•• NFkappaB Selectivity of Estrogen Receptor Ligands is Revealed by Comparative Crystallographic Analyses. Geoffrey
Greene, PhD and his colleagues showed that protein folding problems that are common to steroid hormone receptors are
circumvented by mutations that stabilize well-characterized conformations of the receptor. The approach used in this study
presents the structure of an unliganded steroid receptor, which reveals a ligand-accessible channel that allows the soaking of
pre-formed crystals. The ability to crystallize many receptor-ligand complexes with distinct pharmacophores helps to define
structural features of signaling specificity that would not be apparent in a single structure. This research exemplifies how the
work of Program 1 members continues to push the boundaries of understanding activation of transcription factors that are
highly relevant to cancer (Nettles et al. Nat Chem Biol 4:241-247, 2008).
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* Due to space constraints, only a small representative sample of Program highlights is presented here.
Selected New Funding
paxillin in non-small cell lung cancer (NSCLC), which will help uncover novel mechanisms for transformation, metastasis
and, ultimately, therapy for lung cancer.
•• Andy Minn, MD, PhD and his colleagues are the recipients of the Department of Defense Era of Hope Scholar Award to
Cell Signaling &
Gene Regulation
•• The National Cancer Institute awarded Ravi Salgia, MD, PhD and his colleagues an R01 grant to determine the role of
study how induction of the interferon-related gene signatures for DNA damage resistance by stroma increases treatment
resistance, and how the stroma regulates the lung metastasis signature genes and other metastasis genes.
•• Kevin White, PhD is the primary investigator in a program project (P50) funded by the National Institutes of Health to
create a Center for Systems Biology in an initiative to promote interdisciplinary scientific investigation and education
in Chicago. The focus of this Center’s program is on developing a robust transcriptional network in physiological,
developmental, and evolutionary time scales. The goal is being achieved through collaborations among experts in
genomics, developmental biology, evolutionary biology, stress and physiology, network modeling, high performance and
grid computing, chemistry, and physics.
•• Shohei Koide, PhD has been awarded R21 funding from the National Institutes of Health/National Institute for Drug
Abuse to develop an innovative and powerful technology platform for facile production of high-performance reagents.
This new technology will help to fill a major void in current epigenetic research, making it feasible to establish a standard
set of epigenetic capture reagents that can be widely be disseminated to the medical community.
New Faculty Recruitments and UCCRC Members
Rex Haydon, MD, PhD specializes in the surgical care of bone and soft tissue tumors and aims to understand the underlying
causes of musculoskeletal neoplasms in order to develop novel and innovative treatments. Dr. Haydon focuses his research
on signaling pathways involved in sarcoma development and on the elucidation of blocks to differentiation that occur in
osteosarcoma.
Yu-Ying He, PhD’s research interests are in the molecular mechanisms of skin carcinogenesis induced by the environment
and the development of chemopreventive and therapeutic strategies to reduce the skin cancer burden. Dr. He’s current
research projects focus on understanding the fundamental mechanisms of cell proliferation, survival, transformation, and
inflammation in the skin caused by ultraviolet radiation and other factors.
Kathleen Goss, PhD is leading a research program that is aimed at understanding the APC/beta-catenin pathway in
development and tumorigenesis in order to facilitate the design of novel therapeutic approaches to target this pathway in
cancer.
Ivan Moskowitz, MD, PhD studies the molecular basis of cardiac morphogenesis and Congenital Heart Disease. Dr.
Moskowitz aims to identify and understand the genes involved in cardiac morphogenesis using forward and reverse genetic
approaches in mouse models. Recent work has focused on early aspects of cardiac valve development.
Jalees Rehman, MD conducts cardiovascular research on the biology of regenerative stem and progenitor cells. His research
focuses on cancer stem cell differentiation and cell signaling. Dr. Rehman is also interested in determining the differences
in cell death and metabolism between mature and regenerative cells, and aims to understand how regenerative cell
transplantation can improve cardiovascular function in patients.
Yingming Zhao, PhD’s research aims to develop mass spectrometry and bioinformatic tools to understand the function of
post-translational modification (PTM) pathways which play critical roles in disease development. Dr. Zhao combines the
use of proteomic technologies with biochemical and molecular techniques to understand PTM networks further beyond that
provided by conventional techniques.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
19
Selected Publications
Luca F, Kashyap S, Southard C, Zou M, Witonsky D, Di Rienzo A, Conzen
SD. Adaptive variation regulates the expression of the human SGK1 gene in
response to stress. PLoS Genet 5(5):e1000489, 2009.
# : Interprogrammatic Collaboration
Du, Wei PhD
Alexander, Kenneth MD, PhD
Deb DK, Tanaka-Matakatsu M, Jones L, Richardson HE, Du W. Wingless
signaling directly regulates cyclin E expression in proliferating embryonic PNS
precursor cells. Mech Dev 125(9-10):857-64, 2008.
* : Intraprogrammatic Collaboration
Ishibashi KL, Koopmans J, Curlin FA, Alexander KA, Ross LF. Paediatricians’
attitudes and practices towards HPV vaccination. Acta Paediatr 97(11):1550-6,
2008.
Ishibashi KL, Koopmans J, Curlin FA, Alexander KA, Ross LF. Pediatricians are
more supportive of the human papillomavirus vaccine than the general public.
South Med J 101(12):1216-21, 2008.
Beyer, Eric MD, PhD
Kyle JW, Minogue PJ, Thomas BC, Domowicz DA, Berthoud VM, Hanck DA,
Beyer EC. An intact connexin N-terminus is required for function but not gap
junction formation. J Cell Sci 121(Pt 16):2744-50, 2008.
Lichtenstein A, Gaietta GM, Deerinck TJ, Crum J, Sosinsky GE, Beyer EC,
Berthoud VM. The cytoplasmic accumulations of the cataract-associated
mutant, Connexin50P88S, are long-lived and form in the endoplasmic
reticulum. Exp Eye Res 88(3):600-9, 2009.
Chmura, Steven MD, PhD
# Salama JK, Chmura SJ, Mehta N, Yenice KM, Stadler WM, Vokes EE, Haraf
DJ, Hellman S, Weichselbaum RR. An initial report of a radiation doseescalation trial in patients with one to five sites of metastatic disease. Clin
Cancer Res 14(16):5255-9, 2008.
# Al-Hallaq HA, Mell LK, Bradley JA, Chen LF, Ali AN, Weichselbaum RR,
Newstead GM, Chmura SJ. Magnetic resonance imaging identifies multifocal
and multicentric disease in breast cancer patients who are eligible for partial
breast irradiation. Cancer 113(9):2408-14, 2008.
# Mell LK, Schomas DA, Salama JK, Devisetty K, Aydogan B, Miller RC, Jani
AB, Kindler HL, Mundt AJ, Roeske JC, Chmura SJ. Association between bone
marrow dosimetric parameters and acute hematologic toxicity in anal cancer
patients treated with concurrent chemotherapy and intensity-modulated
radiotherapy. Int J Radiat Oncol Biol Phys 70(5):1431-7, 2008.
# Cao J, Roeske JC, Chmura SJ, Salama JK, Shoushtari AN, Boyer AL, Martel
MK. Calculation and prediction of the effect of respiratory motion on whole
breast radiation therapy dose distributions. Med Dosim 34(2):126-32, 2009.
# Altman MB, Vesper BJ, Smith BD, Stinauer MA, Pelizzari CA, Aydogan B,
Reft CS, Radosevich JA, Chmura SJ, Roeske JC. Characterization of a novel
phantom for three-dimensional in vitro cell experiments. Phys Med Biol
54(5):N75-82, 2009.
Conzen, Suzanne MD
# Jansen SA, Conzen SD, Fan X, Krausz T, Zamora M, Foxley S, River J,
Newstead GM, Karczmar GS. Detection of in situ mammary cancer in a
transgenic mouse model: in vitro and in vivo MRI studies demonstrate
histopathologic correlation. Phys Med Biol 53(19):5481-93, 2008.
Belova L, Brickley DR, Ky B, Sharma SK, Conzen SD. Hsp90 regulates the
phosphorylation and activity of serum- and glucocorticoid-regulated kinase-1. J
Biol Chem 283(27):18821-31, 2008.
# Belova L, Delgado B, Kocherginsky M, Melhem A, Olopade OI, Conzen
SD. Glucocorticoid receptor expression in breast cancer associates with older
patient age. Breast Cancer Res Treat 116(3):441-7, 2009.
Conzen SD. Minireview: nuclear receptors and breast cancer. Mol Endocrinol
22(10):2215-28, 2008.
Pew T, Zou M, Brickley DR, Conzen SD. Glucocorticoid (GC)-mediated downregulation of urokinase plasminogen activator expression via the serum and
GC regulated kinase-1/forkhead box O3a pathway. Endocrinology 149(5):263745, 2008.
# Melhem A, Yamada SD, Fleming GF, Delgado B, Brickley DR, Wu W,
Kocherginsky M, Conzen SD. Administration of Glucocorticoids to Ovarian
Cancer Patients Is Associated with Expression of the Anti-apoptotic Genes
SGK1 and MKP1/DUSP1 in Ovarian Tissues. Clin Cancer Res 15(9):3196-204,
2009.
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* # Luo X, Wang CZ, Chen J, Song WX, Luo J, Tang N, He BC, Kang Q, Wang
Y, Du W, He TC, Yuan CS. Characterization of gene expression regulated by
American ginseng and ginsenoside Rg3 in human colorectal cancer cells. Int J
Oncol 32(5):975-83, 2008.
Sukhanova MJ, Du W. Control of cell cycle entry and exiting from the second
mitotic wave in the Drosophila developing eye. BMC Dev Biol 8:7, 2008.
* # Wang CZ, Aung HH, Zhang B, Sun S, Li XL, He H, Xie JT, He TC, Du W,
Yuan CS. Chemopreventive effects of heat-processed Panax quinquefolius root
on human breast cancer cells. Anticancer Res 28(5A):2545-51, 2008.
* # Wang CZ, Xie JT, Fishbein A, Aung HH, He H, Mehendale SR, He TC,
Du W, Yuan CS. Antiproliferative effects of different plant parts of Panax
notoginseng on SW480 human colorectal cancer cells. Phytother Res 23(1):613, 2009.
Tanaka-Matakatsu M, Xu J, Cheng L, Du W. Regulation of apoptosis of rbf
mutant cells during Drosophila development. Dev Biol 326(2):347-56, 2009.
Dulin, Nickolai PhD
# Yau DM, Sethakorn N, Taurin S, Kregel S, Sandbo N, Camoretti-Mercado
B, Sperling AI, Dulin NO. Regulation of Smad-mediated gene transcription by
RGS3. Mol Pharmacol 73(5):1356-61, 2008.
Kwon IK, Schoenlein PV, Delk J, Liu K, Thangaraju M, Dulin NO, Ganapathy
V, Berger FG, Browning DD. Expression of cyclic guanosine monophosphatedependent protein kinase in metastatic colon carcinoma cells blocks tumor
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regulatory protein ICP22 with the cdc25C phosphatase is enabled in vitro
by viral protein kinases US3 and UL13. J Virol 82(9):4533-43, 2008.
Jovasevic V, Liang L, Roizman B. Proteolytic cleavage of VP1-2 is required
for release of herpes simplex virus 1 DNA into the nucleus. J Virol
82(7):3311-9, 2008.
Kalamvoki M, Qu J, Roizman B. Translocation and colocalization of ICP4
and ICP0 in cells infected with herpes simplex virus 1 mutants lacking
glycoprotein E, glycoprotein I, or the virion host shutoff product of the
UL41 gene. J Virol 82(4):1701-13, 2008.
Yang K, Poon AP, Roizman B, Baines JD. Temperature-sensitive
mutations in the putative herpes simplex virus type 1 terminase
subunits pUL15 and pUL33 preclude viral DNA cleavage/packaging
and interaction with pUL28 at the nonpermissive temperature. J Virol
82(1):487-94, 2008.
Rosner, Marsha PhD
* Zeng L, Imamoto A, Rosner MR. Raf kinase inhibitory protein (RKIP):
a physiological regulator and future therapeutic target. Expert Opin Ther
Targets 12(10):1275-87, 2008.
* Yfanti C, Mengele K, Gkazepis A, Weirich G, Giersig C, Kuo WL,
Tang WJ, Rosner M, Schmitt M. Expression of metalloprotease insulindegrading enzyme insulysin in normal and malignant human tissues. Int
J Mol Med 22(4):421-31, 2008.
* Weirich G, Mengele K, Yfanti C, Gkazepis A, Hellmann D,
Welk A, Giersig C, Kuo WL, Rosner MR, Tang WJ, Schmitt M.
Immunohistochemical evidence for ubiquitous distribution of the
metalloendoprotease insulin-degrading enzyme (IDE, insulysin)
in human non-malignant tissues and tumor cell lines. Biol Chem
389(11):1441-5, 2008.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
23
Granovsky AE, Rosner MR. Raf kinase inhibitory protein: a signal transduction
modulator and metastasis suppressor. Cell Res 18(4):452-7, 2008.
# Cohen EE, Zhu H, Lingen MW, Martin LE, Kuo WL, Choi EA, Kocherginsky
M, Parker JS, Chung CH, Rosner MR. A feed-forward loop involving protein
kinase Calpha and microRNAs regulates tumor cell cycle. Cancer Res 69(1):6574, 2009.
* Granovsky AE, Clark MC, McElheny D, Heil G, Hong J, Liu X, Kim Y,
Joachimiak G, Joachimiak A, Koide S, Rosner MR. Raf kinase inhibitory protein
function is regulated via a flexible pocket and novel phosphorylation-dependent
mechanism. Mol Cell Biol 29(5):1306-20, 2009.
* Dangi-Garimella S, Yun J, Eves EM, Newman M, Erkeland SJ, Hammond SM,
Minn AJ, Rosner MR. Raf kinase inhibitory protein suppresses a metastasis
signalling cascade involving LIN28 and let-7. EMBO J 28(4):347-58, 2009.
Solway, Julian MD
He D, Natarajan V, Stern R, Gorshkova IA, Solway J, Spannhake EW, Zhao Y.
Lysophosphatidic acid-induced transactivation of epidermal growth factor
receptor regulates cyclo-oxygenase-2 expression and prostaglandin E(2) release
via C/EBPbeta in human bronchial epithelial cells. Biochem J 412(1):153-62,
2008.
Pinto LH, Eaton E, Chen B, Fleisher J, Shuster D, McCauley J, Kedainis D,
Siepka SM, Shimomura K, Song EJ, Husain A, Lakser OJ, Mitchell RW, Dowell
ML, Brown M, Camoretti-Mercado B, Naclerio R, Sperling AI, Levin SI, Turek
FW, Solway J. Gene-environment interactions in a mutant mouse kindred with
native airway constrictor hyperresponsiveness. Mamm Genome 19(1):2-14,
2008.
Sosnick, Tobin PhD
Roux, Benoit PhD
Banavali NK, Roux B. Flexibility and charge asymmetry in the activation loop
of Src tyrosine kinases. Proteins 74(2):378-89, 2009.
Gan W, Roux B. Binding specificity of SH2 domains: Insight from free energy
simulations. Proteins 74(4):996-1007, 2009.
Pan AC, Roux B. Building Markov state models along pathways to determine
free energies and rates of transitions. J Chem Phys 129(6):064107, 2008.
Pan AC, Sezer D, Roux B. Finding transition pathways using the string method
with swarms of trajectories. J Phys Chem B 112(11):3432-40, 2008.
Yang S, Roux B. Src kinase conformational activation: thermodynamics,
pathways, and mechanisms. PLoS Comput Biol 4(3):e1000047, 2008.
Deng Y, Roux B. Computation of binding free energy with molecular dynamics
and grand canonical Monte Carlo simulations. J Chem Phys 128(11):115103,
2008.
Yang S, Banavali NK, Roux B. Mapping the conformational transition in Src
activation by cumulating the information from multiple molecular dynamics
trajectories. Proc Natl Acad Sci U S A 106(10):3776-81, 2009.
Deng Y, Roux B. Computations of standard binding free energies with
molecular dynamics simulations. J Phys Chem B 113(8):2234-46, 2009.
Park S, Bardhan JP, Roux B, Makowski L. Simulated x-ray scattering of protein
solutions using explicit-solvent models. J Chem Phys 130(13):134114, 2009.
Freddolino PL, Park S, Roux B, Schulten K. Force field bias in protein folding
simulations. Biophys J 96(9):3772-80, 2009.
Salgia, Ravi MD, PhD
# Nimeiri HS, Oza AM, Morgan RJ, Friberg G, Kasza K, Faoro L, Salgia R,
Stadler WM, Vokes EE, Fleming GF. Efficacy and safety of bevacizumab plus
erlotinib for patients with recurrent ovarian, primary peritoneal, and fallopian
tube cancer: a trial of the Chicago, PMH, and California Phase II Consortia.
Gynecol Oncol 110(1):49-55, 2008.
# Jagadeeswaran R, Surawska H, Krishnaswamy S, Janamanchi V, Mackinnon
AC, Seiwert TY, Loganathan S, Kanteti R, Reichman T, Nallasura V, Schwartz
S, Faoro L, Wang YC, Girard L, Tretiakova MS, Ahmed S, Zumba O, Soulii
L, Bindokas VP, Szeto LL, Gordon GJ, Bue. Paxillin is a target for somatic
mutations in lung cancer: implications for cell growth and invasion. Cancer Res
68(1):132-42, 2008.
Siddiqui SS, Loganathan S, Krishnaswamy S, Faoro L, Jagadeeswaran R, Salgia
R. C. elegans as a model organism for in vivo screening in cancer: effects of
human c-Met in lung cancer affect C. elegans vulva phenotypes. Cancer Biol
Ther 7(6):856-63, 2008.
Sittler T, Zhou J, Park J, Yuen NK, Sarantopoulos S, Mollick J, Salgia R, GiobbieHurder A, Dranoff G, Hodi FS. Concerted potent humoral immune responses
to autoantigens are associated with tumor destruction and favorable clinical
outcomes without autoimmunity. Clin Cancer Res 14(12):3896-905, 2008.
# Rudin CM, Salgia R, Wang X, Hodgson LD, Masters GA, Green M, Vokes EE.
Randomized phase II Study of carboplatin and etoposide with or without the
bcl-2 antisense oligonucleotide oblimersen for extensive-stage small-cell lung
cancer: CALGB 30103. J Clin Oncol 26(6):870-6, 2008.
# Seiwert TY, Jagadeeswaran R, Faoro L, Janamanchi V, Nallasura V, El Dinali
M, Yala S, Kanteti R, Cohen EE, Lingen MW, Martin L, Krishnaswamy S,
Klein-Szanto A, Christensen JG, Vokes EE, Salgia R. The MET receptor tyrosine
kinase is a potential novel therapeutic target for head and neck squamous cell
carcinoma. Cancer Res 69(7):3021-31, 2009.
24
UCCRC SCIEN T IFI C R EPO R T 20 0 9
Strickland D, Moffat K, Sosnick TR. Light-activated DNA binding in a designed
allosteric protein. Proc Natl Acad Sci U S A 105(31):10709-14, 2008.
Tang, Wei-Jen PhD
* Yfanti C, Mengele K, Gkazepis A, Weirich G, Giersig C, Kuo WL, Tang
WJ, Rosner M, Schmitt M. Expression of metalloprotease insulin-degrading
enzyme insulysin in normal and malignant human tissues. Int J Mol Med
22(4):421-31, 2008.
* Weirich G, Mengele K, Yfanti C, Gkazepis A, Hellmann D, Welk A, Giersig C,
Kuo WL, Rosner MR, Tang WJ, Schmitt M. Immunohistochemical evidence for
ubiquitous distribution of the metalloendoprotease insulin-degrading enzyme
(IDE, insulysin) in human non-malignant tissues and tumor cell lines. Biol
Chem 389(11):1441-5, 2008.
Malito E, Ralat LA, Manolopoulou M, Tsay JL, Wadlington NL, Tang WJ.
Molecular Bases for the Recognition of Short Peptide Substrates and CysteineDirected Modifications of Human Insulin-Degrading Enzyme. Biochemistry
47(48):12822-34, 2008.
Guo Q, Jureller JE, Warren JT, Solomaha E, Florian J, Tang WJ. Protein-protein
docking and analysis reveal that two homologous bacterial adenylyl cyclase
toxins interact with calmodulin differently. J Biol Chem 283(35):23836-45,
2008.
Taha HM, Schmidt J, Gottle M, Suryanarayana S, Shen Y, Tang WJ, Gille A,
Geduhn J, Konig B, Dove S, Seifert R. Molecular Analysis of the Interaction
of Anthrax Adenylyl Cyclase Toxin, Edema Factor, with 2’(3’)-O-(N-(methyl)
anthraniloyl)-Substituted Purine and Pyrimidine Nucleotides. Mol Pharmacol
75(3):693-703, 2009.
Spangler CM, Spangler C, Gottle M, Shen Y, Tang WJ, Seifert R, Schaferling M.
A fluorimetric assay for real-time monitoring of adenylyl cyclase activity based
on terbium norfloxacin. Anal Biochem. 381(1):86-93, 2008.
Kim C, Wilcox-Adelman S, Sano Y, Tang WJ, Collier RJ, Park JM.
Antiinflammatory cAMP signaling and cell migration genes co-opted by the
anthrax bacillus. Proc Natl Acad Sci U S A 105(16):6150-5, 2008.
Kuo SR, Willingham MC, Bour SH, Andreas EA, Park SK, Jackson C, Duesbery
NS, Leppla SH, Tang WJ, Frankel AE. Anthrax toxin-induced shock in rats is
associated with pulmonary edema and hemorrhage. Microb Pathog 44(6):46772, 2008.
Turner, Jerrold MD, PhD
# Weber CR, Nalle SC, Tretiakova M, Rubin DT, Turner JR. Claudin-1 and
claudin-2 expression is elevated in inflammatory bowel disease and may
contribute to early neoplastic transformation. Lab Invest 88(10):1110-20, 2008.
Shen L, Weber CR, Turner JR. The tight junction protein complex undergoes
rapid and continuous molecular remodeling at steady state. J Cell Biol
181(4):683-95, 2008.
Annaba F, Sarwar Z, Kumar P, Saksena S, Turner JR, Dudeja PK, Gill RK,
Alrefai WA. Modulation of ileal bile acid transporter (ASBT) activity by
depletion of plasma membrane cholesterol: association with lipid rafts. Am J
Physiol Gastrointest Liver Physiol 294(2):G489-97, 2008.
Gill RK, Pant N, Saksena S, Singla A, Nazir TM, Vohwinkel L, Turner JR,
Goldstein J, Alrefai WA, Dudeja PK. Function, expression, and characterization
of the serotonin transporter in the native human intestine. Am J Physiol
Gastrointest Liver Physiol 294(1):G254-62, 2008.
Yu D, Turner JR. Stimulus-induced reorganization of tight junction structure:
the role of membrane traffic. Biochim Biophys Acta 1778(3):709-16, 2008.
Cell Signaling &
Gene Regulation
Su L, Shen L, Clayburgh DR, Nalle SC, Sullivan EA, Meddings JB, Abraham
C, Turner JR. Targeted epithelial tight junction dysfunction causes
immune activation and contributes to development of experimental colitis.
Gastroenterology 136(2):551-63, 2009.
White, Kevin PhD
# Hua S, Kallen CB, Dhar R, Baquero MT, Mason CE, Russell BA, Shah PK, Liu
J, Khramtsov A, Tretiakova MS, Krausz TN, Olopade OI, Rimm DL, White KP.
Genomic analysis of estrogen cascade reveals histone variant H2A.Z associated
with breast cancer progression. Mol Syst Biol. 4:188, 2008.
Gauhar Z, Sun LV, Hua S, Mason CE, Fuchs F, Li TR, Boutros M, White KP.
Genomic mapping of binding regions for the Ecdysone receptor protein
complex. Genome Res 19(6):1006-13, 2009.
Liu J, Ghanim M, Xue L, Brown CD, Iossifov I, Angeletti C, Hua S, Negre N,
Ludwig M, Stricker T, Al-Ahmadie HA, Tretiakova M, Camp RL, PereraAlberto M, Rimm DL, Xu T, Rzhetsky A, White KP. Analysis of Drosophila
segmentation network identifies a JNK pathway factor overexpressed in kidney
cancer. Science 323(5918):1218-22, 2009.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
25
Selected Major Grants and Awards
The Cell Signaling and Gene Regulation Program has a funding base of $40,975,090 in annual total costs (current as of July 2009).
This sum includes $7,151,438 in NCI funding and $25,178,189 in other NIH funding. Due to space constraints, only new awards
presented since January 1, 2008 with funding of $100,000 or more in annual total costs are listed here.
Title
Start Date
End
Date
Annual
Total Cost
Class
Funding Agency
White, Kevin
Chicago Systems Biology Center for
the Study of Transcriptional Networks
9/1/2008
8/31/2013
$3,021,428
N/A
National Institutes of Health
Zhao, Yinming
Systematic Screening for New Histone
Marks
9/30/2008
8/3/2011
$790,454
R01
National Institutes of Health
White, Kevin
Center for Bioinformatics and
Computational Biology
7/1/2008
6/30/2011
$765,000
N/A
The Searle Funds at the
Chicago Community Trust
Rosner, Marsha
Signaling Pathways in Neuronal Cells
1/10/2009
12/31/2012
$421,202
R01
National Inst. of
Neurological Disorders and
Stroke
McNally, Elizabeth
Sarcoglycan in Myopathy and Muscle
Membrane Stability
12/1/2008
11/30/2013
$390,000
R01
National Institutes of Health
Roizman, Bernard
The Functions of the US3 Protein
Kinase of Herpes Simplex Virus
9/10/2008
8/31/2012
$385,000
R01
National Cancer Institute
Roizman, Bernard
Dissection of the Functions of Herpes
Simplex Virus ICPO
5/1/2008
4/30/2013
$382,057
R37
National Cancer Institute
McNally, Elizabeth
Nuclear Membrane Protein
Interaction in Heart and Muscle
Disease
9/1/2008
5/31/2012
$378,614
R01
National Heart, Lung, and
Blood Institute
Lin, Anning
Wiring the UV Signaling Circuitry
2/8/2008
1/31/2013
$345,375
R01
National Institute of
Environmental Health
Science
Rinker-Schaeffer,
Carrie
Prostate Cancer Metastatic
Colonization: Role of MKK4
12/1/2008
11/30/2013
$328,815
R01
National Cancer Institute
Salgia, Ravi
Role of Paxillin in Lung Cancer
6/2/2008
4/30/2013
$326,831
R01
National Cancer Institute
Millen, Kathleen
Mouse Models of Human Cerebellar
Malformations
8/15/2008
7/31/2009
$324,496
R56
National Inst. of
Neurological Disorders and
Stroke
Liao, Shutsung
Molecular Mechanisms of Growth
Control in Prostate Cancer
2/1/2009
1/31/2013
$315,168
R01
National Cancer Institute
Mrksich, Milan
Ultrahigh Performance Nanoantennas
for Surface Enhanced Raman
Spectroscopy
5/1/2008
4/30/2009
$313,001
08
Department of Defense
Lang, Deborah
Pax3, Melanocyte Stem Cells and
Melanoma
2/1/2009
12/31/2013
$312,000
R01
National Cancer Institute
Macleod, Kay
Functions of BNIP3 in Mammary
Tumorigenesis
2/1/2009
12/31/2013
$303,853
R01
National Institutes of Health
Koide, Shohei
Novel Affinity Reagents for Epigenetics
Markers
9/20/2008
7/31/2010
$301,864
N/A
National Institute on Drug
Abuse
Wu, Chung-I
MicroRNA Evolution and Species
Divergence in Drosophilia
7/1/2008
6/30/2011
$301,309
R01
National Institute of General
Medical Sciences
Chmura, Steven
A Phase 1/2, Multi-Center, Safety
and Efficacy Study Evaluating
Intravenously Administered I-TM601
in Patients with Progressive and/or
Recurrent Malignant Glioma
8/25/2008
8/24/2009
$290,258
N/A
Transmolecular, Inc.
Peter, Marcus
Novel Fas/CD95 Signaling
Mechanisms
9/17/2008
7/31/2012
$275,709
R01
National Cancer Institute
Mrksich, Milan
Peptide Arrays for Understanding
Histone Biochemistry
4/1/2008
2/29/2012
$270,736
R01
National Institute of General
Medical Sciences
Zhao, Yinming
Global Characterization of Lysine
Acetylation in Cancer by a Proteomics
Approach
6/1/2008
4/30/2013
$261,083
R01
National Cancer Institute
Investigator
26
UCCRC SCIEN T IFI C R EPO R T 20 0 9
Title
Start Date
End
Date
Annual
Total Cost
Class
Funding Agency
Salgia, Ravi
Role of c-Met in SCLC and Potential
for Novel Therapy
9/19/2008
2/28/2013
$251,380
R01
National Cancer Institute
Solway, Julian
Evaluation of Lovastatin in Severe
Persistent Asthma (ElisPA)
9/5/2008
8/31/2009
$231,000
R34
National Institute of Allergy
and Infectious Diseases
Zhao, Yinming
A Novel Proteomics Technology for
Protein Farnesylation
1/16/2009
3/31/2010
$230,949
R33
National Cancer Institute
Greene, Geoffrey
Structure-Function Analysis of ER
Alpha/Beta Bound to Bazedoxifene/CE
Mixtures
4/25/2008
4/24/2009
$230,545
N/A
Wyeth-Ayerst
Pharmaceuticals
Ferguson, Edwin
Characterization of the Interactions
between a Stem Cell and its Niche In
Drosophilla
1/1/2008
12/31/2011
$230,250
SS
Salgia, Ravi
Phase I Safety, Pharmacokinetic and
Pharmacodynamic Study of PF04217903 in Patients with Advanced
Cancer
7/9/2008
7/8/2010
$208,209
N/A
Pfizer, Inc.
Nash, Piers
Protein-protein Interactions in Signal
Transduction
9/1/2008
8/31/2009
$180,562
N/A
National Science Foundation
Kron, Stephen
MALDI Imaging of Cancer Signaling
Signatures
7/16/2008
6/30/2010
$172,687
R21
National Cancer Institute
Koide, Shohei
High-Performance Affinity Reagents
for Peptide Epitopes
4/4/2008
3/31/2010
$168,065
R21
National Cancer Institute
Salgia, Ravi
Novel Targeted Therapy in Pancreatic
Cancer
3/1/2009
2/28/2011
$156,000
R21
National Cancer Institute
Salgia, Ravi
A Phase I Followed by a Randomized,
Phase II Study of Carboplatin and
Etoposide With or Without Obatoclax
Administered Every 3 Weeks to
Patients with Extensive State Small
Cell Lung Cancer
5/28/2008
5/27/2010
$152,694
N/A
Gemin X Biotechnologies
Inc.
Lengyel, Ernst
Development of Novel Therapeutic
and Diagnostic Strategies for Ovarian
Cancer
7/1/2008
6/30/2013
$150,000
N/A
Burroughs Wellcome Fund
Rinker-Schaeffer,
Carrie
Identification of Effectors of MKK4Mediated Suppression oin Ovarian
Cancer Metastatic Colonization
6/1/2008
5/31/2009
$145,433
N/A
Pardee Foundation, Elsa U.
Boone, David
Functional Consequences of
Autophagy Mutations in Crohn’s
Disease
12/1/2008
11/30/2009
$139,274
N/A
Broad Foundation, The Eli
and Edythe L.
Solway, Julian
The Influence of Budesonide and
Formoterol on Force FluctuationInduced Relengthening of Contracted
Airway Smooth Muscle
4/28/2008
4/27/2010
$126,906
N/A
Astrazeneca
Haydon, Rex
Synergistic Use of Oteogenic BMP’s in
a New Zealand White Rabbit Model of
Spine Fusion
1/1/2009
12/31/2009
$124,496
N/A
Musculoskeletal Transplant
Foundation
Kron, Stephen
Chicago Laminome Project
11/1/2008
10/31/2010
$120,000
N/A
The Searle Funds at the
Chicago Community Trust
Mrksich, Milan
Collaborative Proposal: EMT/MISC:
Behavior Based Molecular Robotics
9/1/2008
8/31/2011
$105,000
N/A
National Science Foundation
Salgia, Ravi
Expression and Function of the RON
Receptor Tyrosine Kinase
5/22/2008
5/21/2009
$100,000
N/A
Biogen Idec Inc.
Rosner, Marsha
Regulation of Breast Cancer Stem
Cells by Raf Kinase Inhibitory Protein
1/1/2009
12/31/2009
$100,000
N/A
Geyer Foundation, Charlotte
Cell Signaling &
Gene Regulation
Investigator
The Ellison Medical
Foundation
UCCRC SCIEN T IFI C R EPO R T 20 0 9
27
P ro g r a m 2
Molecular Genetics and Hematopoiesis
RUNX1/ AML1 amplification in a pediatric pre B-ALL patient detected by fluorescence in situ
hybridization (FISH) analysis. Using a genomic probe (green) for the TEL gene at 12p13 and a
genomic probe (red) for the RUNX1/AML1 gene at 21q22, FISH analysis shows two green signals
(normal chromosomes 12), one red signal (normal chromosome 21), and multiple red signals
on a derivative chromosome 21, indicative of an amplification of the RUNX1/AML1 gene, in a
metaphase and two interphase cells. (Image by Y. Zhang)
In recent years, insights gained related to these goals have
begun to be translated into novel molecularly-targeted
Molecular Genetics
& Hematopoiesis
therapeutic approaches for hematological malignancies.
Overview & Goals
The Molecular Genetics and Hematopoiesis
management of patients with these diseases; and
Program is comprised of a tightly-integrated
(3) promote optimal use of resources within the
group of 28 members from four academic
University of Chicago Cancer Research Center
departments who are linked by common research
and collaborating departments. In recent years,
themes. Members of this program have had
insights gained related to these goals have begun
major roles in the cytogenetic and molecular
to be translated into novel molecularly-targeted
analysis of hematological malignant diseases,
therapeutic approaches for hematological
which have led to the identification of many
malignancies.
genes that are involved in normal hematopoiesis,
as well as in the pathogenesis of leukemias and
lymphomas.
The overall goals of the Molecular Genetics
and Hematopoiesis Program are to: (1) foster
scientific interactions among investigators
involved in clinical management and biological
Program Leaders:
studies of hematological malignancies; (2)
promote translational research and facilitate
the transfer of laboratory research to the
Wendy Stock, MD
Michael Thirman, MD
UCCRC SCIEN T IFI C R EPO R T 20 0 9
29
Members
30
Investigator*
Rank
Department
John Anastasi MD
Associate Professor
Pathology
Andrew Artz MD
Assistant Professor
Medicine
Beverly Baron MD
Associate Professor
Pathology
Jianjun Chen PhD
Assistant Professor
Medicine
Kenneth Cohen MD
Assistant Professor
Medicine
John Cunningham MD
Professor
Pediatrics
Lucy Godley MD, PhD
Assistant Professor
Medicine
Fotini Gounari PhD, DSc.
Assistant Professor
Medicine
Sandeep Gurbuxani MBBS, PhD
Instructor
Pathology
Barbara Kee PhD
Associate Professor
Pathology
Richard Larson MD
Professor
Medicine
Michelle Le Beau PhD
Professor
Medicine
Susana Marino MD, PhD
Associate Professor
Pathology
James Nachman MD
Professor
Pediatrics
Olatoyosi Odenike MD
Assistant Professor
Medicine
Kenan Onel MD, PhD
Assistant Professor
Pediatrics
Elizabeth Rich MD, PhD
Assistant Professor
Medicine
Janet Rowley MD, DSc
Professor
Medicine
Harinder Singh PhD
Professor
Molecular Genetics and Cell Biology
Dorothy Sipkins MD, PhD
Assistant Professor
Medicine
Sonali Smith MD
Associate Professor
Medicine
Wendy Stock MD
Professor
Medicine
Michael Thirman MD
Associate Professor
Medicine
Koen van Besien MD
Professor
Medicine
James Vardiman MD
Professor
Pathology
Amittha Wickrema PhD
Associate Professor
Medicine
Yanming Zhang MD
Assistant Professor
Medicine
Todd Zimmerman MD
Associate Professor
Medicine
UCCRC SCIEN T IFI C R EPO R T 20 0 9
* Reflects all Program membership during 2008-2009
Investigators in the Molecular Genetics and Hematopoiesis Program aim to
understand the molecular basis of normal and aberrant hematopoeisis to improve
the diagnosis and treatment of hematological diseases. Research themes include
elucidating the mechanisms of normal hematopoiesis and the pathogenesis of
leukemia, development and characterization of animal models of hematologic
malignancies, and conducting clinical trials of experimental therapeutics. Below
is a sampling of current research being conducted in the Program.
Theme: Mechanisms of Normal Hematopoiesis
Barbara Kee, PhD
Associate Professor of Pathology
Molecular Genetics
& Hematopoiesis
Featured Faculty Research Summaries†
Research in the Kee laboratory is focused on
determining the molecular mechanisms that guide cell
fate choices in the hematopoietic system. The laboratory
has been examining the role of the E2A transcription
factors and their antagonists, the Id (Inhibitor of
Differentiation) proteins, in the development of
lymphoid lineage cells. These proteins are known
to function in cell fate decisions in invertebrates. In
mammals, appropriate expression and function of these
E- and Id- proteins is required to prevent B-lymphocyte,
Dr. Koen van Besien
T-lymphocyte, and natural killer (NK) cell immune
deficiencies and T-cell malignancy.
Dr. Kee’s current specific aims are to 1) determine the role of E2A in promoting lymphoid differentiation from
hematopoietic stem cells; 2) determine the targets of E2A proteins that promote T lymphocyte lineage specification;
3) determine the mechanism underlying T cell transformation in E2A-deficient mice; and 4) determine whether Id
proteins play an essential role in NK cell lineage specification. These goals are being addressed using a combination
of in vitro and in vivo assays with cells derived from gene-targeted mice.
The laboratory has recently demonstrated that E2A proteins are required for development of lymphoid-primed
multipotent progenitors (LMPPs), which are the progeny of HSCs that have lost the capacity to differentiate into
megakaryocytes and erythrocytes but retain the ability to become lymphocytes, macrophages, and granulocytes.
This finding places the E2A proteins among the first transcription factors required for specification of the lymphoid
fate. Within LMPPs, E2A is required for proper activation of lymphoid gene expression and further differentiation
into B-lymphocytes. T lymphocyte numbers are also reduced in E2A-deficient mice and may be explained by the
failure of LMPPs to appropriately express two genes, Notch1 and Ccr9. Ccr9 encodes a chemokine receptor that
promotes migration of multipotent progenitors, such as LMPPs, into the thymus where T lymphocyte development
occurs. Notch1 encodes a transmembrane receptor that is essential for T lymphocyte lineage specification.
Importantly, a few early T-lymphocyte progenitors are present in the thymus of E2A-deficient mice, and these cells
are able to signal through Notch1, resulting in increased Notch1 expression. However, the cells still fail to undergo
proper T lymphocyte lineage specification.
Dr. Kee’s recent results indicate that this failure of T lymphocyte lineage specification is due, at least in part, to
an inability to control the expression of Gata3, a transcription factor that can block T cell development and divert
cells into non-T lymphocyte fates when expressed at high levels. How E2A prevents over-expression of Gata3
remains to be determined. Nonetheless, their results indicate that E2A promotes T lymphocyte lineage specification
through both activation and repression of multiple target genes. This work is expanding our understanding of the
mechanisms by which networks of transcription factors contribute to lymphoid specification and further reveal how
an individual transcription factor can promote specification to multiple distinct lineages.
† Note: Due to space constraints, only a small representative sample of Program members is presented here.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
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Theme: Pathogenesis of Leukemia
Dorothy Sipkins, MD, PhD
Assistant Professor of Medicine
The Sipkins laboratory focuses on defining the molecular characteristics
of tissue microenvironments, or “niches”, that foster the survival and
regeneration of both normal and cancerous hematopoietic stem cells. The
laboratory also examines the impact of malignant growth on the function
of the normal hematopoietic stem cell niche. In combination with classical
molecular and cell biology approaches, state-of-the-art in vivo multiphoton
and confocal optical imaging techniques are utilized to explore these
questions in real-time.
Applying these techniques to a mouse xenograft model of acute
Dr. Janet Rowley
lymphoblastic leukemia (ALL), the laboratory has recently shown that ALL
cell growth disrupts normal hematopoietic progenitor cell (HPC) bone marrow niches and creates abnormal microenvironments
that sequester transplanted human CD34+ (HPC enriched) cells. CD34+ cells in leukemic mice decline in number over time
and fail to mobilize into the peripheral circulation in response to cytokine stimulation. The Sipkins group demonstrated that
ALL cells secrete large quantities of a cytokine, stem cell factor (SCF), normally present at low levels in the bone marrow. By
neutralizing SCF activity, the laboratory was able to inhibit CD34+ cell migration into malignant niches, normalize CD34+
cell numbers, and restore CD34+ cell mobilization in leukemic mice. These data suggest that the tumor microenvironment
causes HPC dysfunction by usurping normal HPC niches, and that therapeutic inhibition of HPC interaction with tumor niches
may help maintain normal progenitor cell function in the setting of malignancy. This work, published recently in Science, has
exposed a novel therapeutic target that could potentially counteract the effects of cancer on normal bone marrow function.
Other projects in the laboratory include examining the interactions of breast cancer metastases with the bone marrow
microenvironment. The Sipkins group is also studying the role of microenvironmental derangements in facilitating the
progression of the Philadelphia chromosome-negative myeloproliferative disorders. The laboratory is also actively establishing
a mesenchymal stem cell transplant model to understand the regulation of the mesenchymal stem cell pool in the bone marrow
better, as well as its impact on the hematopoietic stem cell compartment.
Jianjun Chen, PhD
Assistant Professor of Medicine
The major research interest of the Chen laboratory is to conduct integrated analyses of cancer-“omics” on both protein-coding
and non-coding genes (particularly, microRNAs) regarding both genetic and epigenetic changes in the development of leukemia
and lymphoma using a variety of techniques. The laboratory aims to obtain a more complete understanding of the complex
genetic and epigenetic alterations in cancer development, and to identify novel markers and targets for the diagnosis, prognosis,
and treatment of cancers. MicroRNAs (miRNAs) are a class of small (~22 nucleotides) non-coding RNAs that regulate diverse
biological processes and, thereby, play important regulatory roles in both health and disease. In addition, Dr. Chen is also
interested in identifying leukemia-stem-cell-specific genetic and epigenetic changes on both protein-coding and non-coding
genes. These genes and the relevant pathways could serve as therapeutic targets in the future to overcome drug resistance. During the past two years, the Chen laboratory has made great progress in the study of leukemia and has reported several
important findings in the field. The Chen group, along with colleagues, performed a large-scale, genome-wide microRNA
(miRNA) expression profiling assay to understand the distinct mechanisms in leukemogenesis between acute lymphoblastic
leukemia (ALL) and acute myeloid leukemia (AML) and to identify novel markers for diagnosis and treatment. The team
identified 27 miRNAs that are differentially expressed between ALL and AML. Among them, miRNA-128a and b are
significantly overexpressed, while let-7b and miR-223 are significantly down-regulated in ALL compared to AML. They are the
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most discriminatory miRNAs between ALL and AML. Furthermore, overexpression of miR-128 in ALL was at least partly
associated with promoter hypomethylation. Using the expression signatures of a minimum of two of these miRNAs resulted
in an accuracy rate of over 95% in the diagnosis of ALL and AML.
In a second genome-wide miRNA expression analysis in 52 acute myeloid leukemia (AML) samples with common
translocations, including t(8;21)/AML1(RUNX1)-ETO(RUNX1T1), inv(16)/CBFB-MYH11, t(15;17)/PML-RARA, and MLL
factor (CBF) AMLs including both t(8;21) and inv(16) samples. Expression signatures of a minimum of two (i.e., miR-126/126),
three (i.e., miR-224, miR-368, and miR-382), and seven (miR-17-5p and miR-20a, plus the aforementioned five) miRNAs could
accurately discriminate CBF, t(15;17), and MLL-rearrangement AMLs, respectively, from each other. The Chen laboratory
and colleagues further showed that the elevated expression of miR-126/126 in CBF AMLs was associated with promoter
Molecular Genetics
& Hematopoiesis
rearrangements, distinct miRNA expression patterns were observed for t(15;17), MLL rearrangements, and core-binding
demethylation, but not with amplification or mutation of the genomic locus. Their gain- and loss-of-function experiments
showed that miR-126/126 inhibited apoptosis and increased the viability of AML cells, and enhanced the colony forming
ability of mouse normal bone marrow progenitor cells alone and particularly, in co-operation with AML1-ETO, likely through
targeting Polo-like kinase 2 (PLK2), a tumor suppressor. These results demonstrate that specific alterations in miRNA
expression distinguish AMLs with common translocations, and imply that the deregulation of specific miRNAs may play a
role in the development of leukemia with these associated genetic rearrangements.
Theme: Animal Models of Hematologic Malignancies
Beverly Baron, MD
Associate Professor of Pathology
The Baron group and others identified the BCL6 gene in
association with recurring chromosomal translocations
that accompany human lymphoid malignancies, especially
diffuse large-cell B-cell lymphomas (DLBL). The
breakpoints cluster around the first (noncoding) exon of
BCL6, and it is believed that BCL6 expression becomes
deregulated because heterologous promoters/enhancers
are substituted for the normal BCL6 regulatory sequences
as a result of these translocations. Perturbation of BCL6
biology is likely to be very important in the pathogenesis
of almost all human DLBL, since virtually all of them have
been found to contain BCL6 somatic mutations and/or
rearrangements, which are believed to result in abnormal
Intravenous injection of a novel B-lymphoma cell line into a syngeneic
C57BL6 mouse results in B220+ (green fluorescent cells) infiltrating nodular
proliferations within liver tissue. Cells expressing lower levels of B220
demonstrated plasmacytic differentiation. (Image by X. Luo and K. Cohen)
regulation of BCL6 protein expression. BCL6 is expressed
also in a number of T-cell lymphomas. The BCL6 gene encodes a nuclear zinc finger protein containing 706 amino acids,
which is similar to Kruppel-type zinc finger transcription factors, and is a transcriptional repressor. This protein is expressed
at high levels in human lymphoid germinal center B cells, is needed for germinal center formation, and interacts with other
proteins that are components of histone deacetylase complexes.
Dr. Baron’s laboratory described the first (and, to date, the only) mouse model of the human BCL6 transgene. The mice
express the human BCL6 transgene constitutively specifically in lymphocytes, both B and T, and thus mimic a common
translocation found in human lymphomas, the t(3;14)(q27;q32), in which the normal BCL6 regulatory sequences are lost, and,
instead, immunoglobulin heavy chain (IGH) sequences are juxtaposed upstream of BCL6 coding sequences. A fraction of
these mice develop spontaneous B- and T-cell lymphomas after a prolonged latency period, but the incidence is dramatically
enhanced, and the time-frame shortened, following administration of N-ethyl-N-nitrosourea (ENU), which is an alkylating
agent that induces single-base mutations. This observation suggests that cooperating mutations play a critical role in BCL6related lymphomagenesis.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
33
The ultimate goals of the laboratory are to identify new genes that interact with BCL6 and to gain a better understanding of
the role of PDCD2 in lymphoma pathogenesis. Specific research aims are to 1) identify the genes that cooperate with BCL6 in
the biological events that lead to lymphoma development; and 2) study the programmed cell death-2 (PDCD2) gene, which the
laboratory previously identified as a target of BCL6.
BCL6 may promote lymphoma development, at least in part, by interfering with normal cellular apoptosis events through
repression of PDCD2. The laboratory recently showed that the BCL6 protein binds to the PDCD2 promoter both in vitro and in
vivo, that BCL6 can repress transcription from the PDCD2 promoter, and demonstrated the anticipated inverse relationship in
the expression patterns of BCL6 and PDCD2 in mouse lymphoid tissues as well as in human B- and T-cell lymphomas. Further,
with the use of small interfering RNA duplexes, the Baron group was able to show that knockdown of the BCL6 protein in a
lymphoma cell line leads to increased PDCD2 protein expression. These studies will likely provide further insight into this
important human disease and support the development of new molecular tools for the treatment of lymphoma.
Theme: Experimental Therapeutics
Toyosi Odenike, MD
Assistant Professor of Medicine
The long term goal of Dr. Odenike’s research is to translate
our understanding of the molecular-genetic pathways involved
in malignant hematologic diseases into meaningful, more
efficacious and less toxic therapeutic interventions. An
immediate focus of this effort is the clinical and translational
development of novel agents that target epigenetic changes in
myeloid malignancies. Recruitment of histone deacetylases and
DNA hypermethylation are two pathways of epigenetic silencing
Dr. Kenan Onel with a pediatric patient
which have been linked and implicated in the transcriptional
dysregulation underlying a variety of myeloid neoplasia. Unlike gene deletions which are irreversible, epigenetic changes can
potentially be reversed by chromatin remodeling agents such as histone deacetylase and DNA methyltransferase inhibitors,
restoring tumor cells to a more transcriptionally normal state. A number of ongoing and recently-completed projects are based
on the hypothesis that chromatin remodeling agents are active in a wide spectrum of myeloid neoplasms, and that the activity of
these agents is mediated by epigenetic modulation of gene expression.
Specific aims of Dr. Odenike’s research are to 1) determine the clinical and biologic relevance of histone deacetylase (HDAC)
inhibition in AML; 2) determine the clinical and biologic relevance of DNA methyltransferase (DNMT) inhibition in chronic
myeloproliferative neoplasms; 3.) investigate the effects of these agents on modulation of gene expression; and 4) optimize the
activity of these agents in myeloid neoplasms by developing rationally-designed combinations.
The Odenike team has investigated the HDAC inhibitor, depsipeptide, in a multi-center NCI sponsored trial conducted through
the University of Chicago Phase II Consortium in relapsed and refractory AML. This trial has, for the first time, demonstrated
that depsipeptide has selective antileukemic activity in patients with Core Binding Factor (CBF) leukemias, a cytogenetic subset
of AML where recruitment of histone deacetylases is an established mechanism of leukemogenesis. In addition, specific target
genes, such as CDKN2A, CDKN2B, and MDR1, were significantly upregulated in the subset of patients with CBF leukemias as
previously hypothesized. This has served as an important “proof of principle” for the mechanism of action of HDAC inhibitors
in AML and provides a potential rationale for the clinical investigation of these compounds in combination with other agents
in AML. In addition, the Odenike team demonstrated in a multi-center NCI sponsored trial conducted through the University
of Chicago Phase II Consortium that the DNMT inhibitor, decitabine, has clinical activity in myelofibrosis, a disease for which
there is no standard therapy.
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Currently, combined DNMT and HDAC inhibition is being investigated in myeloid neoplasms in the context of an ongoing
Phase I trial, given the synergy that has been observed in vitro between these 2 pathways of epigenetic silencing. Future work
will focus on investigating combinations, involving agents that target aberrant transcription (such as chromatin remodeling
agents) with those that inhibit dysregulated signaling pathways, in an effort to optimize the clinical and biologic effects of
these agents in myeloid neoplasia.
A major challenge in developing a research agenda for Hodgkin and non-Hodgkin lymphomas is the current recognition
of nearly 60 unique clinicopathologic subtypes. Many of the subtypes are in fact rare diseases with fewer than 5000 new
cases per year throughout the country. The Lymphoma Program at The University of Chicago is a highly visible clinical and
Molecular Genetics
& Hematopoiesis
Sonali Smith, MD
Associate Professor of Medicine
translational research program that has been in a period of substantial growth since 2001 and currently consists of four
faculty members, including Drs. Koen van Besien, Sonali Smith, Kenneth Cohen, and Justin Kline. Dr. Smith, the associate
director of the program, is institutional Principal Investigator on 10 clinical trials and hosts the annual International Chicago
Lymphoma Symposium, the only lymphoma-dedicated symposium in the Midwest.
The Lymphoma Program at The University of Chicago has adopted a two-pronged approach in an effort to serve the
variety of patients seen in the clinic. The first is to provide opportunities for patients to participate in a range of clinical
trials that are either subtype specific or that target a common oncogenic pathway believed to promote lymphomagenesis.
Large scale front-line studies, intended for patients that are treatment-naïve, are primarily via collaborations forged with
CALGB. Through the CALGB, Dr. Smith has published several reports, including a relatively widely quoted negative study
of thalidomide in patients with relapsed indolent lymphomas, which contrasts with the significant activity of second
generation immunomodulatory agents derived from thalidomide. The second programmatic approach is to focus on
new drug development for relapsed lymphomas through The University of Chicago Phase II Consortium. In this venue,
investigator-initiated trials free of pharmaceutical bias are offered to patients with relapsed disease without other standard
treatment options. The University of Chicago, through this phase II mechanism, was the first to show activity of a class
of agents called mTOR inhibitors against two of the most common types of lymphomas (diffuse large B-cell lymphoma
and follicular lymphoma). mTOR, or mammalian target of rapamycin, is a ser/thr kinase that controls the start of mRNA
translation. Several known oncogenic pathways converge upon mTOR, making it an attractive target to modulate upstream
signals simultaneously. Furthermore, mTOR controls translation of several mRNA transcripts that are critical components
of lymphomagenesis, including CCND1, VEGF, and MYC. Two subsequent proposals are being explored to examine mTOR
inhibition, in combination with other biologic agents, as well as with standard cytotoxic chemotherapy. In addition, the
Program seeks to identify predictive markers for response to mTOR inhibitors.
The other major focus of the Lymphoma Program is to explore the role of both autologous and allogeneic hematopoietic stem
cell transplantation for patients with relapsed lymphomas. High dose chemotherapy followed by autologous stem cell rescue
(ASCT) can successfully salvage many patients with chemosensitive relapsed aggressive lymphomas, but relapse remains a
common and usually fatal event. The Program recently completed a trial evaluating the safety and efficacy of post-transplant
immunomodulation using GM-CSF and IL-2 to augment rituximab, with the goal of eradicating minimal/undetectable
residual disease following high dose chemotherapy to reduce relapse. Two ongoing studies are extending interest in posttransplant immunomodulation, one trial using Ontak (toxin-linked monoclonal antibody against IL-2 receptor) following
transplant for T-cell lymphomas and a second trial evaluating a novel monoclonal antibody targeting PD-1 as part of the B7family of surface receptors for patients with diffuse large B-cell lymphomas.
In summary, the Lymphoma program currently has 15 active therapeutic and database protocols addressing both common
and uncommon lymphoma patient populations. Dr. Smith’s future research objective is to expand on mTOR inhibition as a
platform for anti-lymphoma treatments.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
35
Additional Program Highlights*
Research
•• Regulation of B cell fate commitment and immunoglobulin
heavy-chain gene rearrangements by Ikaros. Harinder Singh, PhD
and colleagues have provided novel insights into B cell development
by identifying the critical role of the transcription factor Ikaros.
Drs. John Cunningham (Molecular Genetics and
Hematopoiesis Program) and Susan Cohn
(Clinical and Experimental Therapuetics Program)
These investigators demonstrated that the transcription factor EBF restored the regeneration of CD19+ pro-B cells from
Ikaros-deficient hematopoietic progenitors. These pro-B cells, despite having normal expression of key transcription factors,
EBF and Pax 5, were not committed to the B-cell fate and failed to recombine variable gene segments at the immunoblobulin
heavy-chain locus. Expression of Ikaros promoted heavy-chain gene rearrangements by inducing expression of the
recombination-activating genes as well as by controlling accessibility of the variable gene segments compaction of the
immunoglobulin heavy-chain locus. Thus, Ikaros is a key regulatory component of the network that regulates B cell fate
commitment and immunoglobulin heavy-chain gene recombination (Reynaud et al. Nat Immunol 9:927-936, 2008).
•• MDM2 SMP309 and TP53 Arg72Pro Interact to Alter Therapy-Related Acute Myeloid Leukemia Susceptibility
(Intra- and Interprogrammatic). Kenan Onel, MD and colleagues, including Program 2 members Drs. Richard Larson
and Michelle Le Beau and Dr. Nathan Ellis (Cancer Risk and Prevention Program), have determined that polymorphisms
in two DNA repair genes, MDM2 and TP53, interact to increase susceptibility to the development of therapy-related AML.
This effect was observed in patients treated with chemotherapy who had loss of chromosomes 5 and/or 7, and acquired
abnormalities associated with prior exposure to alkylator chemotherapy, but not in patients treated with radiotherapy. These
data suggest that MDM2 and TP53 variants interact to modulate responses to genotoxic therapy and are determinants of risk
for t-AML (Ellis et al. Blood 112:741-749, 2008).
•• Pretreatment C-Reactive Protein is a Predictor for Outcomes After Reduced-Intensity Allogeneic Hematopoietic
Cell Transplantation (Intraprogrammatic). Andrew Artz, MD and co-investigators, Amittha Wickrema, PhD, Lucy
Godley, MD, PhD, Toyosi Odenike, MD, Elizabeth Rich, MD, PhD, Wendy Stock, MD, Richard Larson, MD and Koen van
Besien, MD described the independent prognostic impact of two commonly used biomarkers – C-reactive protein (CRP) and
interleukin(IL)-6 – on outcome following allogeneic stem cell transplantation. Using samples from patients who underwent
a uniform reduced-intensity conditioning (RIC) regimen, they found that elevated CRP levels prior to allogeneic stem cell
transplant were highly predictive of greater non-relapse mortality. Their results are of interest since they suggest that a
simple pre-transplant blood test may be useful for predicting transplant tolerance (Artz et al, Biol Blood Marrow Transplant
14:1209-1216, 2008).
•• Genome-wide association study to identify novel loci associated with therapy-related myeloid leukemia susceptibility
(Interprogrammatic). Kenan Onel, MD and colleagues, including Program 2 members Drs. Michelle Le Beau and Richard
Larson and Dr. Nancy Cox (Cancer Risk and Prevention Program), examined whether the effect sizes of variants associated
with t-AML would be greater than in sporadic cancer and whether these variants could be detected even in a modest-sized
cohort. In an association study using Affymetrix Mapping 10K arrays, they found a significant excess of associations over
chance. The investigators genotyped the 10 most significantly associated single nucleotide polymorphisms (SNPs) in an
independent t-AML cohort and obtained evidence of association with t-AML for 3 SNPs in the subset of patients with loss of
chromosomes 5 or 7 or both, acquired abnormalities associated with prior exposure to alkylator chemotherapy. Their results
demonstrate that the effect of genetic factors contributing to cancer risk is potentiated and more readily discernable in
t-AML compared with sporadic cancer (Knight et al, Blood 113(22):5575-5582, 2009).
•• Determination of outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative
group protocols (Intraprogrammatic). James Nachman, MD and co-investigators including Drs. Wendy Stock, James
Vardiman, and Richard Larson, performed a retrospective comparison of presenting features, planned treatment, complete
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UCCRC SCIEN T IFI C R EPO R T 20 0 9
* Due to space constraints, only a small representative sample of Program highlights is presented here.
remission rate, and outcome of greater than 300 adolescents and young adults with newly diagnosed acute lymphoblastic
leukemia (ALL) who were treated on consecutive trials in either the Children’s Cancer Group (CCG) or the Cancer and
Leukemia Group B (CALGB). While complete remission rates were identical, patients in the CCG group had significantly
higher 7-year event-free and overall survival rates compared to those in the CALGB group. Comparison of the regimens
showed that CCG patients received earlier and more intensive central nervous system prophylaxis and higher cumulative
with ALL using the more successful approach of the CCG has been initiated (Stock et al, Blood 112(5):1646-54, 2008).
Selected New Funding
Molecular Genetics
& Hematopoiesis
doses of nonmyelosuppressive agents. As a result of these findings, a prospective study for adolescents and young adults
•• The National Cancer Institute awarded Lucy Godley, MD, PhD and her colleagues R01 funding to understand the
mechanisms by which epigenetic alterations originate within cancer cells. Investigators are studying how expression of
the DNMT3B gene, which encodes one of three methyltransferases, affects mouse development, methylation patterns and
phenotypes of cancer cells, and DNA methylation. Results will likely provide a basis for novel diagnostic and therapeutic
strategies applicable to virtually all forms of cancer.
•• Michelle Le Beau, PhD is the primary investigator in a program project (P01), funded by the National Cancer Institute, to
study the molecular mechanisms and genetic susceptibilities leading to therapy-related acute myeloid leukemia (t-AML)
and myelodysplastic syndrome (t-MDS) that develop after cytotoxic treatment with drugs targeting topoisomerase II.
The project aims to identify genetic variants that may be genetic risk factors or biomarkers for t-AML, somatic alterations
associated with t-AML, and myeloid leukemia tumor suppressor gene(s) (TSG). These studies may lead, ultimately, to the
development of individualized cancer prevention and early detection strategies, such as altered primary therapy. Coinvestigators include Drs. Richard Larson, Kenan Onel, and Theodore Karrison (Clinical and Experimental Therapeutics
Program).
•• Jianjun Chen, PhD has been awarded an R01 grant from the National Cancer Institute to determine the role and
functional mechanisms of an miRNA cluster in leukemogenesis. MicroRNAs (miRNAs, miRs) are an abundant class
of small non-coding RNAs that regulate diverse biological processes. Recent studies suggest that a cluster of miRNAs,
the miR-17-92 polycistron located at 13q31, functions as an oncogene in various cancers. The project aims to determine
whether the miR-17-92 cluster plays an essential role in leukemogenesis and in proliferation and differentiation of
hematopoietic progenitor cells. These studies are likely to identify the critical leukemia-related targets of the miRNAs
and their roles and relevant pathways in leukemogenesis.
New Faculty Recruitments and UCCRC Members
Jianjun Chen, PhD’s research is focused on the integrated analyses of protein-coding and non-coding genes involved in the
development of leukemia and lymphoma. Dr. Chen aims to gain an improved understanding of the genetic and epigenetic
alterations that occur during cancer development and in leukemia stem cells in order to identify new markers and targets
for cancer diagnosis and treatment. An additional goal of Dr. Chen’s research is to develop a reproducible method for the
derivation of transplantable hematopoietic stem cells from embryonic stem cells or induced pluripotent stem cells.
Kenneth Cohen, MD research aims to understand how non-malignant host cells within cancers contribute to tumor cell
growth, metastasis, and protection from anti-cancer therapies. Dr. Cohen’s current research seeks to identify molecular
mechanisms governing interactions between pro-angiogenic bone marrow-derived cells and tumor vascular development.
Sandeep Gurbuxani, MBBS, PhD is interested in the mechanisms of resistance to chemotherapy-induced cell death in
cancer. The focus of his current research is the mechanism of glucocorticoid induced cell death (and resistance to this cell
death) in acute lymphoblastic leukemia.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
37
Selected Publications
* : Intraprogrammatic Collaboration
# : Interprogrammatic Collaboration
Anastasi, John MD
* Ozer O, Zhao YD, Ostler KR, Akin C, Anastasi J, Vardiman JW, Godley LA.
The identification and characterisation of novel KIT transcripts in aggressive
mast cell malignancies and normal CD34+ cells. Leuk Lymphoma 49(8):156777, 2008.
* Baer MR, George SL, Caligiuri MA, Sanford BL, Bothun SM, Mrozek K,
Kolitz JE, Powell BL, Moore JO, Stone RM, Anastasi J, Bloomfield CD, Larson
RA. Low-dose interleukin-2 immunotherapy does not improve outcome
of patients age 60 years and older with acute myeloid leukemia in first
complete remission: Cancer and Leukemia Group B Study 9720. J Clin Oncol
26(30):4934-9, 2008.
Anastasi J. Mantle, blastic, Burkitt. Leuk Lymphoma 49(4):655-6, 2008.
Anastasi J. Identifying a new marker and potential therapeutic target in mantle
cell lymphoma: cutting to the chase. Leuk Lymphoma 49(7):1236-7, 2008.
* Qian Z, Mao L, Fernald AA, Yu H, Luo R, Jiang Y, Anastasi J, Valk PJ, Delwel
R, Le Beau MM. Enhanced expression of FHL2 leads to abnormal myelopoiesis
in vivo Leukemia, 2009.
Artz, Andrew MD
* Artz AS, Wickrema A, Dinner S, Godley LA, Kocherginsky M, Odenike O,
Rich ES, Stock W, Ulaszek J, Larson RA, van Besien K. Pretreatment C-reactive
protein is a predictor for outcomes after reduced-intensity allogeneic
hematopoietic cell transplantation. Biol Blood Marrow Transplant 14(11):120916, 2008.
* Dew A, Collins D, Artz A, Rich E, Stock W, Swanson K, van Besien K. Paucity
of HLA-identical unrelated donors for African-Americans with hematologic
malignancies: the need for new donor options. Biol Blood Marrow Transplant
14(8):938-41, 2008.
Lee SJ, Joffe S, Artz AS, Champlin RE, Davies SM, Jagasia M, Kernan NA,
Loberiza FR Jr, Soiffer RJ, Eapen M. Individual physician practice variation in
hematopoietic cell transplantation. J Clin Oncol 26(13):2162-70, 2008.
Swierczek SI, Agarwal N, Nussenzveig RH, Rothstein G, Wilson A, Artz
A, Prchal JT. Hematopoiesis is not clonal in healthy elderly women. Blood
112(8):3186-93, 2008.
Lee SJ, Astigarraga CC, Eapen M, Artz AS, Davies SM, Champlin R, Jagasia
M, Kernan NA, Loberiza FR Jr, Bevans M, Soiffer RJ, Joffe S. Variation in
supportive care practices in hematopoietic cell transplantation. Biol Blood
Marrow Transplant 14(11):1231-8, 2008.
* # Poire X, Artz A, Larson RA, Kline J, Odenike O, Rich E, Godley L, Stock W,
van Besien K. Allogeneic stem cell transplantation with alemtuzumab-based
conditioning for patients with advanced chronic myelogenous leukemia. Leuk
Lymphoma 50(1):85-91, 2009.
Besien KV, Kunavakkam R, Rondon G, De Lima M, Artz A, Oran B, Giralt S.
Fludarabine-melphalan conditioning for AML and MDS: alemtuzumab reduces
acute and chronic GVHD without affecting long-term outcomes. Biol Blood
Marrow Transplant 15(5):610-7, 2009.
Chen, Jianjun PhD
* Li Z, Luo RT, Mi S, Sun M, Chen P, Bao J, Neilly MB, Jayathilaka N, Johnson
DS, Wang L, Lavau C, Zhang Y, Tseng C, Zhang X, Wang J, Yu J, Yang H,
Wang SM, Rowley JD, Chen J, Thirman MJ. Consistent deregulation of gene
expression between human and murine MLL rearrangement leukemias. Cancer
Res 69(3):1109-16, 2009.
Wilanowski T, Caddy J, Ting SB, Hislop NR, Cerruti L, Auden A, Zhao
LL, Asquith S, Ellis S, Sinclair R, Cunningham JM, Jane SM. Perturbed
desmosomal cadherin expression in grainy head-like 1-null mice. EMBO J
27(6):886-97, 2008.
Freeman-Anderson NE, Zheng Y, McCalla-Martin AC, Treanor LM, Zhao
YD, Garfin PM, He TC, Mary MN, Thornton JD, Anderson C, Gibbons M,
Saab R, Baumer SH, Cunningham JM, Skapek SX. Expression of the Arf tumor
suppressor gene is controlled by Tgf{beta}2 during development. Development
136(12):2081-9, 2009.
Godley, Lucy MD, PhD
* # Stock W, Undevia SD, Bivins C, Ravandi F, Odenike O, Faderl S, Rich E,
Borthakur G, Godley L, Verstovsek S, Artz A, Wierda W, Larson RA, Zhang Y,
Cortes J, Ratain MJ, Giles FJ. A phase I and pharmacokinetic study of XK469R
(NSC 698215), a quinoxaline phenoxypropionic acid derivative, in patients with
refractory acute leukemia. Invest New Drugs 26(4):331-8, 2008.
* # Gordon MK, Sher D, Karrison T, Kebriaei P, Chuang K, Zhang Y,
McDonnell D, Artz A, Godley L, Odenike O, Rich E, Michaelis L, Thirman
MJ, Wickrema A, van Besien K, Larson RA, Stock W. Successful autologous
stem cell collection in patients with chronic myeloid leukemia in complete
cytogenetic response, with quantitative measurement of BCR-ABL expression
in blood, marrow, and apheresis products. Leuk Lymphoma 49(3):531-7, 2008.
* Ozer O, Zhao YD, Ostler KR, Akin C, Anastasi J, Vardiman JW, Godley LA.
The identification and characterisation of novel KIT transcripts in aggressive
mast cell malignancies and normal CD34+ cells. Leuk Lymphoma 49(8):156777, 2008.
* Klisovic RB, Stock W, Cataland S, Klisovic MI, Liu S, Blum W, Green M,
Odenike O, Godley L, Burgt JV, Van Laar E, Cullen M, Macleod AR, Besterman
JM, Reid GK, Byrd JC, Marcucci G. A phase I biological study of MG98, an
oligodeoxynucleotide antisense to DNA methyltransferase 1, in patients
with high-risk myelodysplasia and acute myeloid leukemia. Clin Cancer Res
14(8):2444-9, 2008.
Carbonaro A, Mohanty SK, Huang H, Godley LA, Sohn LL. Cell
characterization using a protein-functionalized pore. Lab Chip 8(9):1478-85,
2008.
* Artz AS, Wickrema A, Dinner S, Godley LA, Kocherginsky M, Odenike O,
Rich ES, Stock W, Ulaszek J, Larson RA, van Besien K. Pretreatment C-reactive
protein is a predictor for outcomes after reduced-intensity allogeneic
hematopoietic cell transplantation. Biol Blood Marrow Transplant 14(11):120916, 2008.
* # Poire X, Artz A, Larson RA, Kline J, Odenike O, Rich E, Godley L, Stock W,
van Besien K. Allogeneic stem cell transplantation with alemtuzumab-based
conditioning for patients with advanced chronic myelogenous leukemia. Leuk
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van Besien, Koen MD
* Artz AS, Wickrema A, Dinner S, Godley LA, Kocherginsky M, Odenike O,
Rich ES, Stock W, Ulaszek J, Larson RA, van Besien K. Pretreatment C-reactive
protein is a predictor for outcomes after reduced-intensity allogeneic
hematopoietic cell transplantation. Biol Blood Marrow Transplant 14(11):120916, 2008.
# Kline J, Subbiah S, Lazarus HM, van Besien K. Autologous graft-versus-host
disease: harnessing anti-tumor immunity through impaired self-tolerance.
Bone Marrow Transplant 41(6):505-13, 2008.
Flowers ME, Apperley JF, van Besien K, Elmaagacli A, Grigg A, Reddy V,
Bacigalupo A, Kolb HJ, Bouzas L, Michallet M, Prince HM, Knobler R, Parenti
D, Gallo J, Greinix HT. A multicenter prospective phase 2 randomized study
of extracorporeal photopheresis for treatment of chronic graft-versus-host
disease. Blood 112(7):2667-74, 2008.
van Besien KW. Superiority of reduced-intensity conditioning for Hodgkin’s
lymphoma. J Clin Oncol 26(24):4045-6, 2008.
van Besien K, Carreras J, Bierman PJ, Logan BR, Molina A, King R, Nelson
G, Fay JW, Champlin RE, Lazarus HM, Vose JM, Hari PN. Unrelated donor
hematopoietic cell transplantation for non-hodgkin lymphoma: long-term
outcomes. Biol Blood Marrow Transplant 15(5):554-63, 2009.
Martin PJ, Storer BE, Rowley SD, Flowers ME, Lee SJ, Carpenter PA, Wingard
JR, Shaughnessy PJ, DeVetten MP, Jagasia M, Fay JW, van Besien K, Gupta
V, Kitko C, Johnston LJ, Maziarz RT, Arora M, Jacobson PA, Weisdorf D.
Evaluation of mycophenolate mofetil for initial treatment of chronic graftversus-host disease. Blood 113(21):5074-82, 2009.
Molecular Genetics
& Hematopoiesis
* Klisovic RB, Stock W, Cataland S, Klisovic MI, Liu S, Blum W, Green M,
Odenike O, Godley L, Burgt JV, Van Laar E, Cullen M, Macleod AR, Besterman
JM, Reid GK, Byrd JC, Marcucci G. A phase I biological study of MG98, an
oligodeoxynucleotide antisense to DNA methyltransferase 1, in patients
with high-risk myelodysplasia and acute myeloid leukemia. Clin Cancer Res
14(8):2444-9, 2008.
Patterson ST, Li J, Kang JA, Wickrema A, Williams DB, Reithmeier
RA. Loss of specific chaperones involved in membrane glycoprotein
biosynthesis during the maturation of human erythroid progenitor cells.
J Biol Chem 284(21):14547-57, 2009.
Redig AJ, Sassano A, Majchrzak-Kita B, Katsoulidis E, Liu H, Altman JK,
Fish EN, Wickrema A, Platanias LC. Activation of Protein Kinase Cη by
Type I Interferons. J Biol Chem 284(16):10301-14, 2009.
Yamamoto ML, Clark TA, Gee SL, Kang JA, Schweitzer AC, Wickrema
A, Conboy JG. Alternative pre-mRNA splicing switches modulate gene
expression in late erythropoiesis. Blood 113(14):3363-70, 2009.
Zhang, Yanming MD
* # Stock W, Undevia SD, Bivins C, Ravandi F, Odenike O, Faderl S, Rich
E, Borthakur G, Godley L, Verstovsek S, Artz A, Wierda W, Larson RA,
Zhang Y, Cortes J, Ratain MJ, Giles FJ. A phase I and pharmacokinetic
study of XK469R (NSC 698215), a quinoxaline phenoxypropionic acid
derivative, in patients with refractory acute leukemia. Invest New Drugs
26(4):331-8, 2008.
* Li Z, Lu J, Sun M, Mi S, Zhang H, Luo RT, Chen P, Wang Y, Yan M,
Qian Z, Neilly MB, Jin J, Zhang Y, Bohlander SK, Zhang DE, Larson
RA, Le Beau MM, Thirman MJ, Golub TR, Rowley JD, Chen J. Distinct
microRNA expression profiles in acute myeloid leukemia with common
translocations. Proc Natl Acad Sci U S A 105(40):15535-40, 2008.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
41
* # Gordon MK, Sher D, Karrison T, Kebriaei P, Chuang K, Zhang Y,
McDonnell D, Artz A, Godley L, Odenike O, Rich E, Michaelis L, Thirman
MJ, Wickrema A, van Besien K, Larson RA, Stock W. Successful autologous
stem cell collection in patients with chronic myeloid leukemia in complete
cytogenetic response, with quantitative measurement of BCR-ABL expression
in blood, marrow, and apheresis products. Leuk Lymphoma 49(3):531-7, 2008.
* # Odenike OM, Alkan S, Sher D, Godwin JE, Huo D, Brandt SJ, Green M,
Xie J, Zhang Y, Vesole DH, Stiff P, Wright J, Larson RA, Stock W. Histone
deacetylase inhibitor romidepsin has differential activity in core binding
factor acute myeloid leukemia. Clin Cancer Res 14(21):7095-101, 2008.
* Li Z, Luo RT, Mi S, Sun M, Chen P, Bao J, Neilly MB, Jayathilaka N, Johnson
DS, Wang L, Lavau C, Zhang Y, Tseng C, Zhang X, Wang J, Yu J, Yang H,
Wang SM, Rowley JD, Chen J, Thirman MJ. Consistent deregulation of gene
expression between human and murine MLL rearrangement leukemias.
Cancer Res 69(3):1109-16, 2009.
Zimmerman, Todd MD
* Zhou Y, Uddin S, Zimmerman T, Kang JA, Ulaszek J, Wickrema A. Growth
control of multiple myeloma cells through inhibition of glycogen synthase
kinase-3. Leuk Lymphoma 49(10):1945-53, 2008.
Chanan-Khan AA, Niesvizky R, Hohl RJ, Zimmerman TM, Christiansen NP,
Schiller GJ, Callander N, Lister J, Oken M, Jagannath S. Phase III randomised
study of dexamethasone with or without oblimersen sodium for patients with
advanced multiple myeloma. Leuk Lymphoma 50(4):559-65,, 2009.
42
UCCRC SCIEN T IFI C R EPO R T 20 0 9
Selected Major Grants and Awards
The Molecular Genetics and Hematopoiesis Program has a funding base of $9,097,675 in annual total costs (current as of July
2009). This sum includes $3,088,137 in NCI funding and $670,795 in other NIH funding. Due to space constraints, only new
awards presented since January 1, 2008 with funding of $100,000 or more in annual total costs are listed here.
Title
Start Date
End
Date
Annual
Total Cost
Class
Le Beau, Michelle
Etiology of Alkylator-Induced Myeloid
Leukemia
9/1/2008
8/31/2013
$1,667,989
PO1
National Cancer Institute
Thirman, Michael
Peptide and Small Molecule
Therapeutics for Hematologic
Malignancies
10/1/2006
9/30/2011
$1,050,000
N/A
The Leukemia & Lymphoma
Society
Kee, Barbara
Regulation of Lymphocyte
Development by HLH Proteins
7/3/2008
5/31/2013
$292,163
R01
National Cancer Institute
Chen, Jianjun
The Role and Functional Mechanism
of a miRNA Cluster, mir-17-92 in
Leukemogenesis
6/1/2008
4/30/2013
$286,661
R01
National Cancer Institute
Chen, Jianjun
3UTR Variation of MicroRNA Targets
During Stem Cell Differentiation and
Hematopoiesis
7/1/2008
6/30/2011
$275,000
N/A
Mathers Charitable
Foundation
Smith, Sonali
A Phase 1/2a Open-Label Study
of Praletrexate and Gemcitabine
with Vitamin B12 and Folic Acid
Supplementation in Patients
with Relapsed or Refractory
Lymphoproliferative Malignancies
7/17/2008
7/16/2010
$241,344
N/A
Allos Therrapeutics, Inc.
Le Beau, Michelle
Mechanisms of Treatment
Responsiveness and Resistance in
Myeloid Malignancies
10/1/2008
9/30/2013
$229,500
SCOR
The Leukemia & Lymphoma
Society
Rowley, Janet
Comparisons of Microarray and
MicroRNA for Diagnosis and
Prognosis
10/1/2008
9/30/2011
$200,000
N/A
The Leukemia & Lymphoma
Society
Gounari, Fotini
Wnt/b-Catenin Signaling in T-Cell
Transformation
5/1/2008
4/30/2010
$191,875
R21
National Institutes of Health
Larson, Richard
A Multi-Center, Open Label, Single
Arm Study of Weekly Alvocidib in
Patients with Previously Treated
B-Cell Chronic Lymphocytic
Leukemia (CLL) or Prolymphocytic
Leukemia (PLL) Arising from CLL
4/14/2008
4/13/2010
$178,500
N/A
Sanofi-Aventis U.S. Inc.
Le Beau, Michelle
Institutional Research Grant
1/1/2009
12/31/2011
$120,000
58
Godley, Lucy
A Phase I, Multi-Dose Study of
SGN-33 (antiCD33 mAB, HuM195,
lintuzumab) in Patients with
Acute Myeloid Leukemia and
Myelodysplastic Syndrome
6/25/2008
6/24/2010
$120,000
N/A
Seattle Genetics, Inc.
Stock, Wendy
A Phase 2/3 Study to Evaluate the
Safety & Efficacy of Lumiliximab
in Combination with Fludarabine,
Cyclosphosphamide, and Rituximab
Vs. Fludarabine, Cyclophosphamide,
and Rituximab Alone in Subjects
w/Relapsed Chronic Lymphocytic
Lukemia
8/8/2008
8/7/2010
$116,000
N/A
Biogen Idec Inc.
Kee, Barbara
Transcriptional Deregulation and
Lymphocyte Transformation
7/1/2008
6/30/2013
$110,000
N/A
The Leukemia & Lymphoma
Society
Smith, Sonali
Phase I Dose-Escalation Study of
Bruton's Tyrosine Kinase (Btk)
Inhibitor PCI-32765 in Recurrent B
Cell Lymphoma
10/30/2008
12/31/2009
$104,137
N/A
Pharmacyclics, Inc.
Funding Agency
Molecular Genetics
& Hematopoiesis
Investigator
American Cancer Society
UCCRC SCIEN T IFI C R EPO R T 20 0 9
43
P ro g r a m 3
Immunology and Cancer
Scanning electron microscope image from normal circulating human blood showing red blood cells and
white blood cells, including lymphocytes, a monocyte, a neutrophil, and many small disc-shaped platelets.
(Image by B. Wetzel and H. Schaefer, National Cancer Institute)
The Program has evolved into an important example of
bi-directional translational research, with ideas moving
freely between bench and bedside.
The overall goals of the Immunology and Cancer
therefore, span the following domains: (1)
Program are to understand the interface between
fundamental investigations in immunology that
the host immune system and malignant tumors
have relevance to the cancer context; (2) mouse
and, ultimately, to manipulate the interaction to
models of anti-tumor immunity; and (3) clinical
promote immune-mediated tumor destruction in
studies of human anti-tumor immunity and novel
patients with cancer. The Program has evolved
immunotherapies. Observations made in studies
into an important example of bi-directional
of basic immunologic concepts direct the design of
translational research, with ideas moving freely
preclinical and clinical investigations, and results
between bench and bedside, and consists of 21
of clinical studies generate new hypotheses that
members (one of whom is a Howard Hughes
are being addressed back in murine systems.
Immunology
& Cancer
Overview & Goals
investigator) derived from 6 departments.
The Immunology and Cancer Program aims
to understand all definable aspects of immune
response against tumors, which will be vital
for developing and optimizing immune-based
Program Leader:
cancer therapeutics. The scientific goals,
Thomas Gajewski, MD, PhD
UCCRC SCIEN T IFI C R EPO R T 20 0 9
45
Members
46
Investigator*
Rank
Department
Erin Adams PhD
Assistant Professor
Biochemistry and Molecular Biology
Maria-Luisa Alegre MD, PhD
Associate Professor
Medicine
Albert Bendelac MD, PhD
Professor
Pathology
Anita Chong PhD
Professor
Surgery
Marcus Clark MD
Professor
Medicine
Yang-Xin Fu MD, PhD
Professor
Pathology
Thomas Gajewski MD, PhD
Associate Professor
Pathology
Tatyana Golovkina PhD
Associate Professor
Microbiology
Jose Guevara-Patino MD, PhD
Assistant Professor
Surgery
Bana Jabri MD, PhD
Associate Professor
Medicine
Justin Kline MD
Assistant Professor
Medicine
Vinay Kumar MD, PhD
Professor
Pathology
Maciej Lesniak MD
Associate Professor
Surgery
Mark McKee MD
Associate Professor
Surgery
Vu Nguyen MD
Assistant Professor
Medicine
Glenn Randall PhD
Assistant Professor
Microbiology
Raymond Roos MD
Professor
Neurology
Hans Schreiber MD, PhD
Professor
Pathology
Anne Sperling PhD
Associate Professor
Medicine
Ursula Storb MD
Professor
Molecular Genetics and Cell Biology
Ping Yu MD
Instructor
Pathology
Jian Zhang MD
Assistant Professor
Medicine
UCCRC SCIEN T IFI C R EPO R T 20 0 9
* Reflects all Program membership during 2008-2009
Featured Faculty Research Summaries†
Immunology
& Cancer
Research themes in the Immunology and Cancer Program represent a spectrum of
topics in fundamental immunology, preclinical models of tumor immunology, and
immunotherapy clinical trials. Although a major focus of the general cancer immunology
community has been on adaptive T cell responses against tumor antigens and how to
increase their frequency and efficacy, this program has expanded efforts to investigate
innate immunity as it relates to host awareness of tumor presence. The interface
between the innate and adaptive segments of the immune system likely is a major
determining factor dictating whether immune-mediated tumor control is successful. In
addition, our program has focused significantly on understanding features of the tumor
microenvironment as they relate to the success versus failure of immune-mediated tumor
destruction. Highlights for some major research themes are outlined below.
Fundamental Immunology
Albert Bendelac, MD, PhD
Professor of Pathology
Dr. Bendelac studies a subset of T cells called NKT
cells. NKT cells are viewed to be a component of the
innate immune system in that they express a memorylike surface phenotype in the periphery and can
rapidly produce effector cytokines without need of a
differentiation step following activation. Dr. Bendelac’s
laboratory has made multiple seminal observations
on the biology of NKT cells. His group has used novel
approaches to identify the ligands of the invariant NKT
cell T cell receptor. Specifically, this TCR recognizes
glycolipid antigens presented by CD1d molecules. Such
Use of the UCCRC’s Leica SP5 AOBS spectral 2-photon confocal
microscope, designed for live cell imaging.
ligands can be derived from pathogen-infected tissues,
or by upregulated expression of normal products in
self-tissues. It is thought that the latter represents the
mechanism by which NKT cells can become activated by tumor cells.
Recently, the Bendelac team has deciphered key mechanisms that govern the development of the NKT cell subset.
Using gene expression profiling and confirmatory approaches, the transcription factor PLZF has been found to
be necessary for NKT cell development. PLZF-deficient mice failed to expand and differentiate NKT cells in the
thymus. Interestingly, it also has been observed that PLZF regulates the development of a subset of γδ T cells that
have an innate-type phenotype. Together, these data have identified a specific transcriptional program that directs
the development of subsets of T cells having an innate signature. These results increase our understanding of NKT
cell biology that should guide further interrogation into their role in anti-tumor immune responses.
Erin Adams, PhD
Assistant Professor of Biochemistry and Molecular Biology
The research in Dr. Adams’ laboratory focuses on studying the molecular principles of immune recognition,
particularly in a subset of T cells called γδ T cells. Although they can express a diverse repertoire of T cell receptors
(TCRs), γδ cells are viewed as part of the innate immune system. These cells predominate in the epithelial tissues
and, in some cases, have the ability to directly recognize and lyse tumor cells. The laboratory seeks to understand
immune cell receptor-mediated signaling responsible for the discrimination of self versus non-self, and the factors
that contribute to either enhanced auto-reactivity (auto-immune diseases) or those used by pathogens or tumors to
evade immune detection. In contrast to the more abundant αβ T cells which express an αβ TCR, γδ T cells probe
their environment through a structurally similar, yet distinct, γδ TCR. Although many of the antigens for antibodies
† Note: Due to space constraints, only a small representative sample of Program members is presented here.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
47
and αβ TCRs are well known, the ligands recognized by γδ TCRs as antigenic determinants remain much of a mystery. In
addition, whether the diversity generated by the rearrangement process is even necessary for antigen recognition by these
receptors remains unclear. For known ligands, the molecular details of antigenic recognition are still unknown. The Adams
laboratory seeks to define the role(s) of these cells in the immune response, specifically against cancer, by 1) defining the ligands
they recognize in these tissues; and 2) understanding the molecular details of γδ TCR ligand recognition and how this is altered
in self/non-self discrimination.
A major set of projects pursued in the lab focuses on γδ TCR recognition of nonclassical MHC molecules. The γδ T cell
population that recognizes T22 shares a simple motif in one of the antigen recognition loops of its TCRs: Trp (W) followed by a
conserved EGYEL block of amino acids. Across the TCRs examined, there is variation in the number and nature of amino acid
residues between the W and EGYEL. Dr. Adams has previously shown how one of the T22 reactive TCRs uses this motif to bind
to T22. By solving the three dimensional structure of the G8 γδ TCR with T22, the majority of the binding interface between the
TCR and T22 was shown to involve the CDR3d loop that contains the W…EGYEL motif. Furthermore, the study demonstrated
that transferring the CDR3d loop, from these T22 reactive γδ TCRs to a naïve αβ TCR (used as a scaffold), endowed the scaffold
with T22 binding ability, with affinities greater than that of the wildtype TCRs.
The Adams laboratory is also studying three γδ TCRs that bind to the human nonclassical major histocompatibility complex
(MHC) molecule, CD1c. Unlike T22, which does not bind and present a variable ligand, CD1c binds a variety of lipid molecules.
These lipids are anchored in the CD1c molecule by their lipid tails, which are accommodated in hydrophobic “tunnels” buried
in the CD1c core. The head groups of the lipids, which come from a variety of sources, are exposed to the outer solvent and,
presumably, the TCRs that bind to this surface. The laboratory is currently pursuing the three dimensional structure of CD1c
and defining the lipid antigens that are recognized as antigenic determinants by γδ TCRs.
Together, these fundamental studies on NKT cells and γδ T cells are increasing our understanding of the development,
function, and receptor-mediated activation of these less- abundant, though critically important, lymphocyte subsets from the
innate immune system. These biologic principles will guide studies of innate recognition of tumors in other model systems, and
ultimately should point to new opportunities for therapeutic intervention.
In Vivo Tumor Immunology
Hans Schreiber, MD, PhD
Professor of Pathology
Dr. Schreiber’s laboratory focuses research efforts on
understanding the roles of tumor stromal cell elements, both
in supporting tumor growth and in mediating resistance to
immune-mediated tumor rejection. Using mouse models, Dr.
Schreiber’s group was among the first to demonstrate that a
subset of myeloid-lineage cells was important to aid in the growth
of implanted tumors, and that depletion of these Gr1+ cells could
result in tumor regression. Another critical discovery from the
Schreiber laboratory is the observation that for T cells to be
able to reject a tumor in vivo, tumor antigens need to be “crosspresented” by host antigen presenting cells. While this might
be important for the initial priming and activation of anti-tumor T cells, it also could participate at the effector phase of the
anti-tumor immune response. In fact, the Schreiber group has shown that adoptively transferred tumor antigen-specific T cells,
when they work effectively, must kill both the tumor cells and the stromal cell elements within the tumor microenvironment.
This has been a paradigm-shifting observation that is changing the way people think about T cell-mediated tumor destruction.
Using this adoptive T cell transfer system as a model, the Schreiber laboratory has more recently deciphered the mechanisms
by which effective tumor elimination occurs. Indeed, they have observed that immune-mediated elimination of tumor stromal
48
UCCRC SCIEN T IFI C R EPO R T 20 0 9
cells depends on IFN-γ and TNF, and that the stromal cells themselves must express receptors for these cytokines. Therefore,
this “bystander killing” of the tumor through destruction of stromal cells in the tumor microenvironment is cytokinemediated.
Together, these results argue for the importance of stromal cells in supporting tumor growth and indicate the utility in
targeting stromal cells as a component of immunotherapeutic interventions. They also suggest that the interaction between
T cells and stromal cells in human anti-tumor immune responses should be similarly investigated in cancer patients.
Yang-Xin Fu, MD, PhD
Professor of Pathology
Cross-talk between immune cells and stromal cells can establish a microenvironment that is necessary for lymphoid tissue
about the molecular mechanisms that underlie the interactions between lymphocytes and stromal cells. Dr. Fu proposes
that lymphotoxin (LT) from T cells and LTβR on stromal cells establishes a lymphoid microenvironment for cross-talk and
efficient and self-contained immune responses. More specifically, a set of distinct adhesion molecules and tissue chemokines
Immunology
& Cancer
development, central and peripheral tolerance, and efficient migration of immune responses. However, little is known
from stromal cells are regulated by lymphocytes for a flexible, delicate, and rapid immune response inside and outside
lymphoid tissues. Studies in the Fu laboratory have revealed that lymphotoxin, tumor necrosis factor (TNF), and LIGHT
(another ligand for LT receptor) are key cytokines for establishing organized lymphoid structures inside and outside lymphoid
organs/tissues critical for the organization of immune responses. Through gene targeting and antibody stimulation/blockade
of LT/LIGHT core family members on different lymphocytes, the Fu group has revealed the contribution of the LT/LIGHT
pathway in the formation of primary and secondary lymphoid tissues and the development of various immune responses at
the cellular and molecular level. These molecular pathways can be applied to the tumor context to generate potent antitumor immune responses that are capable of promoting complete tumor rejection in vivo.
One issue in anti-tumor immunity is that lack of effective infiltration of immune cells and proper expression of costimulatory molecules prevents effective immune response against established tumors. Understanding of the biology of
LIGHT has enabled the Fu group to study the creation of a lymphoid-like microenvironment as a new strategy to promote
tumor control. When expressed in the tumor microenvironment, LIGHT signals via the LTβR on stromal cells which attracts
T cells and other immune cells into tumor sites. In addition, LIGHT co-activates T cells via a second receptor, HVEM.
Together, these signals cause the development of lymphoid-like structures within those tumors, which allows activation
of tumor-specific T cells and promotes tumor destruction. The Fu laboratory is currently focusing on different delivery
systems to target LIGHT to tumor sites. These include adenoviral vectors for intratumoral injection, and coupling LIGHT
to monoclonal antibodies. Combination strategies integrating LIGHT expression with conventional cancer therapeutics also
are being explored. Optimal strategies that are most effective in mice will be moved forward into clinical application.
Clinical/Translational Cancer Immunology
Thomas Gajewski, MD, PhD
Associate Professor of Pathology and Medicine
Dr. Gajewski’s research team studies fundamental aspects of T cell regulation as they
are relevant for the cancer context, applies this information towards preclinical models
of anti-tumor immunity, and then uses this information to guide the development of
new immunotherapeutic approaches in cancer patients. The team has developed a
vaccine approach utilizing tumor antigen peptides combined with the cytokine IL-12.
This approach has progressed from mouse preclinical experiments through phase I and
phase II clinical trials in patients with advanced melanoma. Clinically, vaccination has
resulted in a response rate of approximately 10% and stable disease rate of 20%. Because
not all patients respond to this therapy, intensive investigations have been pursued to
identify biologic characteristics of patients and tumors that may be associated with
clinical benefit. Pre-treatment tumor biopsy gene expression profiling has identified a
Dr. Thomas Gajewski
UCCRC SCIEN T IFI C R EPO R T 20 0 9
49
transcriptional profile in the tumor site that is associated with response versus resistance to active immunization. This analysis
has revealed new key steps in the anti-tumor immune response that may dictate whether anti-tumor T cells can succeed in
causing tumor rejection. These new concepts are being studied in preclinical models, and those studied have revealed new
approaches that are being moved forward back into clinical application.
The above gene expression profiling experiments have indicated three levels of barrier that could govern efficacy of anti-tumor
immune responses. First, some tumors show evidence of innate immune activation centered on type I IFNs, which is associated
with the presence of activated T cells. Mouse experiments have confirmed that host type I IFNs are necessary for spontaneous
priming of anti-tumor T cells. Therefore, intratumoral application of type I IFNs may represent an attractive strategy to move
forward clinically. Second, only a subset of tumors express chemokines that are capable of recruiting activated T cells into
the tumor microenvironment. Tumors that lack chemokines are poor at attracting appropriately activated T cells into tumor
sites and, thus, can be resistant to immune-mediated attack. Therefore, strategies to induce chemokine production within
tumor sites also are attractive to consider for clinical translation. Third, tumors that do show evidence of inflammation and
successfully attract activated T cells paradoxically express several immune-suppressive pathways that block the activity of T
cells at the tumor site. These include the inhibitory ligand PD-L1 that engages the negative regulatory receptor PD-1 on T cells;
the tryptophan-catabolizing enzyme indoleamine-2,3-dioxygenase (IDO) that has been shown to induce peripheral tolerance;
and FoxP3+ regulatory T cells (Tregs). In addition, lack of B7 costimulatory molecules supports a state of T cell anergy.
Together, these four suppressive mechanisms create a tumor microenvironment that blocks the ability of tumor antigen-specific
T cells to induce tumor rejection. Preclinical models have indicated that interference with one or more of these mechanisms
can powerfully improve immune-mediated tumor control in vivo. Strategies to translate these approaches into the clinic are
underway.
Justin Kline, MD
Assistant Professor of Medicine
The Kline laboratory studies putative immune evasion mechanisms in pre-clinical cancer models, with the overall goal of
developing strategies aimed at their reversal in order to improve anti-tumor immune responses in ways that can be translated
into clinical application. The work has largely centered around two mechanisms, the first being suppression of conventional
T cells by regulatory T cells (Tregs), a suppressive population of CD4+ T cells. Tregs can potently inhibit anti-tumor immune
responses both in mouse models and in cancer patients. A second mechanism is T cell anergy. The Kline laboratory has
developed strategies to reverse anergy, which can have a profound impact on tumor rejection. One such approach that is
amenable to clinical translation is through homeostatic proliferation in a lymphopenic host. Pre-clinical research from the
laboratory suggests that when Tregs are depleted from a purified population of polyclonal T cells, prior to adoptive transfer
into a host rendered lymphopenic following the administration of low doses of total body irradiation, potent immunemediated tumor rejection ensues. Mechanistic studies have suggested that the combination of Treg depletion and homeostatic
proliferation leads to augmented priming and sustained effector function of tumor-antigen specific T cells. This approach
has demonstrated success in both pre-clinical solid tumor and hematological malignancy models, suggesting its potential
translation to a broad variety of cancer patients.
These data have motivated the development of clinical approaches to deplete Tregs and/or reverse T cell anergy. The Kline
team is currently developing a phase I/II study in to translate these pre-clinical findings toward cancer patients. In the phase I
portion of the study, cohorts of patients with advanced melanoma will undergo a steady-state leukapheresis, from which T cells
will be purified and Treg will be depleted. Subsequently, patients will be assigned to receive escalating fractions of low-dose
total body irradiation (50-200 cGy) to determine a non-myeloablative dose, which successfully depletes conventional T cells and
Treg and permits the homeostatic proliferation of adoptively-transferred Treg-depleted T cells. Once the optimal dose of total
body irradiation has been determined, the phase II portion of the trial will begin, in which patients will additionally receive
a cancer vaccine. Immune responses will be monitored by IFN-γ ELISpot and MHC tetramer analysis to determine whether
vaccination is capable of augmenting anti-tumor immune responses seen following adoptive T cell transfer alone. Future
studies will continue to investigate negative regulatory mechanisms in the laboratory setting, where promising findings can be
translated into early-phase clinical studies for patients with cancer.
50
UCCRC SCIEN T IFI C R EPO R T 20 0 9
Additional Program Highlights*
Research
•• Endocytic sequestration of the B cell antigen receptor and toll-like receptor
9 in anergic cells (Intraprogrammatic). Marcus Clark, MD, Marisa Alegre,
MD, PhD, and colleagues have studied the cell biology of B cell anergy. They
have found that anergic B cells, which are refractory to toll-like receptor (TLR)
activation by nucleoprotein autoantigens, show sequestration of the B cell antigen
receptor (BCR) and TLR9 just outside late endosomes. These results provide an
explanation for why anergic B cells are refractory to both BCR and TLR-mediated
activation, an observation which has relevance both for autoimmunity and for
Immunology
& Cancer
anti-tumor antibody responses against self proteins (O’Neill et al. Proc Natl Acad
Sci U S A 106:6262-7, 2009).
•• Cytosolic PLA2 is required for CTL-mediated immunopathology of celiac
disease via NKG2D and IL-15. Bana Jabri, MD, PhD and colleagues have
continued investigations into the mechanisms by which CD8+ T cells mediate
pathology in celiac disease. The have found that IL-15 and the NKG2D receptor
Drs. Maciej Lesniak (left) and Kelly Nicholas (right)
act together to promote local tissue destruction. Analysis of signal transduction
events has indicated that cytosolic phospholipase A2 (PLA2) is activated to generate arachidonic acid release, which is
necessary for the activity of these cells. This represents a distinct mechanism of activation of cytotoxic T lymphocytes
(CTLs) via a non-T cell receptor-dependent pathway. Such strategies also could be exploited to promote immunemediated tumor destruction (Tang et al. J Exp Med. 206:707-19, 2009).
•• TLR signals promote IL-6/IL-17-dependent transplant rejection (Intraprogrammatic). Marisa Alegre, MD, PhD and
Anita Chong, PhD, along with their colleagues, have continued to explore the mechanism by which TLR agonists can
break peripheral immunologic tolerance and promote rejection of transplanted allografts in vivo. They have observed
that the TLR9 agonist, CpG, can prevent transplant tolerance through a mechanism which involves induction of TH17phenotype cells. These results have implications for how to approach breaking of peripheral tolerance against growing
tumors in vivo (Chen et al. J Immunol. 182:6217-25, 2009).
•• Therapeutic effects of ablative radiation on local tumors requires CD8+ T cells: changing strategies for cancer
treatment (Interprogrammatic). The laboratories of Yang-Xin Fu, MD, PhD and Ralph Weichselbaum, MD (Clinical
and Experimental Therapeutics Program) have explored the mechanisms by which high-dose radiation can effectively
destroy tumors in mouse models in vivo. Contrary to expectations, they found that the efficacy of radiation depended
significantly upon participation by the host immune system. Thus, similar to certain chemotherapeutic drugs, CD8+
T cells are required for in vivo therapeutic efficacy. These observations have implications for how radiation should be
optimally integrated with other immunomodulatory interventions in the clinic (Lee et al. Blood 114:589-95, 2009).
•• A safety and efficacy study of local delivery of interleukin-12 transgene by PPC polymer in a model of experimental
glioma. Matt Lesniak, MD and colleagues have investigated local immunotherapeutic strategies that could support the
control of intracranial glioma tumors in mice. They found that delivery of the cytokine IL-12, as a plasmid in a novel
polymeric vehicle, could significantly improve tumor control and survival in mice, an effect which was synergistic with
biodegradable carmustine (BCNU) chemotherapy. A similar approach has potential for clinical translation in glioma
patients. (Sonabend et al. Anticancer Drugs 19:133-42, 2008).
* Due to space constraints, only a small representative sample of Program highlights is presented here.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
51
•• The impact of regulatory T cells on T cell immunity following hematopoeitic cell transplantation. Vu Nguyen, MD
has explored the impact of regulatory T cells (Tregs) in the context of graft-versus-host disease (GVHD) in allogeneic bone
marrow transplantation. Results indicate that Tregs suppress GVHD and enhance lymphoid reconstitution in a mouse
model. Along with previous results showing that a graft-versus-tumor effect was preserved, these observations form a
foundation for developing Treg-adoptive therapy protocols for patients undergoing allogeneic stem cell transplantation
(Nguyen et al. Blood 111:945-53, 2008).
•• The HLA-A2-Restricted PSMA Peptide LLHETDSAV is Poorly Immunogenic in Patients with Metastatic Prostate
Cancer (Interprogrammatic). Thomas Gajewski, MD, PhD, Walter Stadler, MD, (Clinical and Experimental Therapeutics
Program) and colleagues have pursued a clinical vaccination strategy for prostate cancer involving prostate-specific
membrane antigen (PSMA) as a potential antigen for T-cell recognition. In their study, which utilized PSMA peptide
LLHETDSAV-pulsed peripheral blood mononuclear cells (PBMC) + IL-12, they found that the vaccine was well-tolerated
but did not generate a clinical response. This was due to poor immunogenicity of this particular antigen. The results
suggest that alternative prostate cancer antigens should be pursued and establish a paradigm for carrying out additional
immunotherapy trials in patients with genitourinary malignancies (Knight et al. Prostate 69:142-148, 2008).
•• Chemokine expression in melanoma metastases associated with CD8+ T cell recruitment (Intraprogrammatic). Thomas
Gajewski, MD, PhD, Mark McKee, MD, and colleagues have studied the gene expression profile of melanoma metastases
from individual patients. They have observed that a subset of tumors expresses chemokines that can recruit activated T
cells into tumor sites. Mouse xenograft models have confirmed that high chemokine-expressing melanoma cell lines show
markedly augmented attraction of activated CD8+ T cells into the tumor microenvironment. These studies imply that
improving T cell homing may represent a novel strategy to improve immune-mediated tumor control in vivo (Harlin et al.
Cancer Res 69:3077-85, 2009).
Selected New Funding
•• Tatyana Golovkina, PhD is the recipient of a National Cancer Institute R01 award to identify mechanisms of retrovirus
resistance in I/LnJ mice. Under control of a single recessive gene, virus infectivity controller 1 (vic1), these mice confer
sustained resistance to both Mammary Tumor Virus (MMTV) and Murine Leukemia Virus (MuLV) infection. Dr.
Golovkina aims to further characterize the expression and function of vic1.
•• Lead investigator Hans Schreiber, MD, PhD, along with colleagues Thomas Gajewski, MD, PhD and Yang-Xin Fu, MD, PhD
has successfully competed for renewal of their program project, funded by the National Cancer Institute (P01), aimed to
improve the destructive power of CD8+ T cells and find strategies for enlisting additional mechanisms and treatments in a
synergistic manner. The results of these studies should highlight new strategies for therapeutic manipulation that could be
considered for clinical application in the future.
•• Justin Kline, MD was awarded a grant from the National Cancer Institute (K23) to investigate the effectiveness of total body
irradiation in inducing lymphopenia in cancer patients, and determine whether homeostatic proliferation of autologous
polyclonal T cells depleted of regulatory T cells occurs following transfer to such irradiated hosts. This research, if
successful, could serve as a platform for future clinical trials and may have a significant impact on the delivery of novel
cancer immunotherapeutic strategies to patients.
•• Anne Sperling, PhD was awarded an S10 shared instrumentation grant from the National Center for Research Resources for
a new, high sensitivity, 14-paramter BD LSRII flow cytometer in the University of Chicago Flow Cytometry Core Facility.
This instrumentation provides state-of-the-art technology for identifying and enumerating individual living cells in a precise
and rapid fashion, and serves as an indispensible tool for numerous areas of biomedical research, including host defense,
autoimmune diseases, and mechanisms of cancer and immunology.
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UCCRC SCIEN T IFI C R EPO R T 20 0 9
•• Ursula Storb, MD was the recipient of an R21 grant from the National Institute of Allergy and Infectious Diseases to
study the mechanism by which the cytidine deaminase, AID, interacts with sequences in which it deaminates cytidine
to uridine. This process initiates somatic hypermutation of immunoglobulin genes, which can result in highly specific
antibodies against pathogens or cause lymphoid malignancies and autoimmunity.
•• Vu Nguyen, MD received a Mentored Clinical Scientist Research Career Development award (K08) from the National
Institutes of Health to investigate the properties of ex vivo expanded CD4+CD25+ regulatory T cells (Treg) in animal
models of hematopoietic cell transplantation (HCT). This project will help determine whether ex vivo expanded Treg
adds benefit to HCT, which is potentially curative for a variety of hematologic cancers, but is limited in application by
graft versus host disease and the lack of donors.
glioma. Dr. Lesniak, along with co-investigators Thomas Gajewski, MD, PhD and Yang-Xin Fu, MD, PhD, aim to elucidate
the mechanisms leading to CD4+CD25+ regulatory T cell (Treg) infiltration and suppression in glioblastoma multiforme
(GBM), the most common primary malignant tumor of the adult central nervous system.
Immunology
& Cancer
•• Maciej Lesniak, MD is the recipient of a National Institutes of Health R01 award to study regulatory T cells in malignant
New Faculty Recruitments and UCCRC Members
Vu Nguyen, MD’s research examines the development and function of regulatory T cells in models of hematologic
malignancies and stem cell transplantation. The goal of his research is to develop targeted molecular and cellular treatment
strategies that separate graft-versus-host disease from the beneficial graft-versus-tumor reaction.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
53
Selected Publications
Ma L, Xiang Z, Sherrill TP, Wang L, Blackwell TS, Williams P, Chong A, Chari
R, Yin DP. Bioluminescence imaging visualizes activation of nuclear factorkappaB in mouse cardiac transplantation. Transplantation 85(6):903-10, 2008.
# : Interprogrammatic Collaboration
* Chen L, Ahmed E, Wang T, Wang Y, Ochando J, Chong AS, Alegre ML.
TLR signals promote IL-6/IL-17-dependent transplant rejection. J Immunol
182(10):6217-25, 2009.
* : Intraprogrammatic Collaboration
Adams, Erin PhD
Adams EJ, Strop P, Shin S, Chien YH, Garcia KC. An autonomous CDR3delta
is sufficient for recognition of the nonclassical MHC class I molecules T10 and
T22 by gammadelta T cells. Nat Immunol 9(7):777-84, 2008.
Alegre, Maria-Luisa MD, PhD
* Alegre ML, Leemans J, Le Moine A, Florquin S, De Wilde V, Chong A,
Goldman M. The multiple facets of toll-like receptors in transplantation
biology. Transplantation 86(1):1-9, 2008.
* Alegre ML, Goldstein DR, Chong AS. Toll-like receptor signaling in
transplantation. Curr Opin Organ Transplant 13(4):358-65, 2008.
* Chen L, Ahmed E, Wang T, Wang Y, Ochando J, Chong AS, Alegre ML.
TLR signals promote IL-6/IL-17-dependent transplant rejection. J Immunol
182(10):6217-25, 2009.
* O’Neill SK, Veselits ML, Zhang M, Labno C, Cao Y, Finnegan A, Uccellini
M, Alegre ML, Cambier JC, Clark MR. Endocytic sequestration of the B cell
antigen receptor and toll-like receptor 9 in anergic cells. Proc Natl Acad Sci U S
A 106(15):6262-7, 2009.
* Alegre ML, Chen L, Wang T, Ahmed E, Wang CR, Chong A. Antagonistic
effect of toll-like receptor signaling and bacterial infections on transplantation
tolerance. Transplantation 87(9 Suppl):S77-9, 2009.
* Molinero LL, Yang J, Gajewski T, Abraham C, Farrar MA, Alegre ML.
CARMA1 controls an early checkpoint in the thymic development of FoxP3+
regulatory T cells. J Immunol 182(11):6736-43, 2009.
Zimmer MI, Nguyen HP, Wang B, Xu H, Colmone A, Felio K, Choi HJ, Zhou P,
Alegre ML, Wang CR. Polymorphisms in CD1d affect antigen presentation and
the activation of CD1d-restricted T cells. Proc Natl Acad Sci U S A 106(6):190914, 2009.
Bendelac, Albert MD, PhD
Savage AK, Constantinides MG, Han J, Picard D, Martin E, Li B, Lantz O,
Bendelac A. The transcription factor PLZF directs the effector program of the
NKT cell lineage. Immunity 29(3):391-403, 2008.
Zajonc DM, Savage PB, Bendelac A, Wilson IA, Teyton L. Crystal structures
of mouse CD1d-iGb3 complex and its cognate Valpha14 T cell receptor
suggest a model for dual recognition of foreign and self glycolipids. J Mol Biol
377(4):1104-16, 2008.
Allende ML, Zhou D, Kalkofen DN, Benhamed S, Tuymetova G, Borowski C,
Bendelac A, Proia RL. S1P1 receptor expression regulates emergence of NKT
cells in peripheral tissues. FASEB J 22(1):307-15, 2008.
# Dose M, Sleckman BP, Han J, Bredemeyer AL, Bendelac A, Gounari F.
Intrathymic proliferation wave essential for Vα 14+ natural killer T cell
development depends on c-Myc. Proc Natl Acad Sci U S A 106(21):8641-6, 2009.
Yin N, Long X, Goff RD, Zhou D, Cantu C 3rd, Mattner J, Mezard PS, Teyton
L, Bendelac A, Savage PB. Alpha anomers of iGb3 and Gb3 stimulate cytokine
production by natural killer T cells. ACS Chem Biol 4(3):199-208, 2009.
Chong, Anita PhD
* Alegre ML, Leemans J, Le Moine A, Florquin S, De Wilde V, Chong A,
Goldman M. The multiple facets of toll-like receptors in transplantation
biology. Transplantation 86(1):1-9, 2008.
* Alegre ML, Goldstein DR, Chong AS. Toll-like receptor signaling in
transplantation. Curr Opin Organ Transplant 13(4):358-65, 2008.
Li Y, Ma L, Yin D, Shen J, Chong AS. Long-term control of alloreactive B cell
responses by the suppression of T cell help. J Immunol 180(9):6077-84, 2008.
* Wang T, Chen L, Ahmed E, Ma L, Yin D, Zhou P, Shen J, Xu H, Wang CR,
Alegre ML, Chong AS. Prevention of allograft tolerance by bacterial infection
with Listeria monocytogenes. J Immunol 180(9):5991-9, 2008.
54
UCCRC SCIEN T IFI C R EPO R T 20 0 9
Clark, Marcus MD
* O’Neill SK, Veselits ML, Zhang M, Labno C, Cao Y, Finnegan A, Uccellini
M, Alegre ML, Cambier JC, Clark MR. Endocytic sequestration of the B cell
antigen receptor and toll-like receptor 9 in anergic cells. Proc Natl Acad Sci U S
A 106(15):6262-7, 2009.
Mandal M, Crusio KM, Meng F, Liu S, Kinsella M, Clark MR, Takeuchi O,
Aifantis I. Regulation of lymphocyte progenitor survival by the proapoptotic
activities of Bim and Bid. Proc Natl Acad Sci U S A 105(52):20840-5, 2008.
Fu, Yang-Xin MD, PhD
* Yu P, Fu YX. Targeting tumors with LIGHT to generate metastasis-clearing
immunity. Cytokine Growth Factor Rev 19(3-4):285-94, 2008.
* Zhang B, Zhang Y, Bowerman NA, Schietinger A, Fu YX, Kranz DM, Rowley
DA, Schreiber H. Equilibrium between host and cancer caused by effector T
cells killing tumor stroma. Cancer Res 68(5):1563-71, 2008.
Zhu M, Fu YX. Coordinating development of medullary thymic epithelial cells.
Immunity 29(3):386-8, 2008.
Papa S, Zazzeroni F, Fu YX, Bubici C, Alvarez K, Dean K, Christiansen PA,
Anders RA, Franzoso G. Gadd45beta promotes hepatocyte survival during liver
regeneration in mice by modulating JNK signaling. J Clin Invest 118(5):1911-23,
2008.
Zhao J, Yang X, Auh SL, Kim KD, Tang H, Fu YX. Do adaptive immune cells
suppress or activate innate immunity?. Trends Immunol 30(1):8-12, 2009.
Zhao J, Kim KD, Yang X, Auh S, Fu YX, Tang H. Hyper innate responses in
neonates lead to increased morbidity and mortality after infection. Proc Natl
Acad Sci U S A 105(21):7528-33, 2008.
# Lee Y, Auh SL, Wang Y, Burnette B, Wang Y, Meng Y, Beckett M, Sharma
R, Chin R, Tu T, Weichselbaum RR, Fu YX. Therapeutic effects of ablative
radiation on local tumor require CD8+ T cells: changing strategies for cancer
treatment. Blood 114(3):589-95, 2009.
Gajewski, Thomas MD, PhD
# Knight D, Peterson AC, Rini BI, Harlin H, Gajewski TF, Stadler WM. The
HLA-A2-restricted PSMA peptide LLHETDSAV is poorly immunogenic in
patients with metastatic prostate cancer. Prostate 69(2):142-8, 2009.
* Kline J, Brown IE, Zha YY, Blank C, Strickler J, Wouters H, Zhang L, Gajewski
TF. Homeostatic proliferation plus regulatory T-cell depletion promotes potent
rejection of B16 melanoma. Clin Cancer Res 14(10):3156-67, 2008.
Zheng Y, Zha Y, Gajewski TF. Molecular regulation of T-cell anergy. EMBO Rep
9(1):50-5, 2008.
* Harlin H, Meng Y, Peterson AC, Zha Y, Tretiakova M, Slingluff C, McKee M,
Gajewski TF. Chemokine expression in melanoma metastases associated with
CD8+ T-cell recruitment. Cancer Res 69(7):3077-85, 2009.
Praveen K, Zheng Y, Rivas F, Gajewski TF. Protein kinase Ctheta focusing at the
cSMAC is a consequence rather than cause of TCR signaling and is dependent
on the MEK/ERK pathway. J Immunol 182(10):6022-30, 2009.
Camacho LH, Antonia S, Sosman J, Kirkwood JM, Gajewski TF, Redman B,
Pavlov D, Bulanhagui C, Bozon VA, Gomez-Navarro J, Ribas A. Phase I/II
trial of tremelimumab in patients with metastatic melanoma. J Clin Oncol
27(7):1075-81, 2009.
Gordon IO, Wade T, Chin K, Dickstein J, Gajewski TF. Immune-mediated
red cell aplasia after anti-CTLA-4 immunotherapy for metastatic melanoma.
Cancer Immunol Immunother 58(8):1351-3, 2009.
Golovkina, Tatyana PhD
Case LK, Petell L, Yurkovetskiy L, Purdy A, Savage KJ, Golovkina TV.
Replication of beta- and gamma retroviruses is restricted in I/LnJ mice via the
same genetic mechanism. J Virol 82(3):1438-47, 2008.
Denman CJ, McCracken J, Hariharan V, Klarquist J, Oyarbide-Valencia K,
Guevara-Patino JA, Le Poole IC. HSP70i accelerates depigmentation in a mouse
model of autoimmune vitiligo. J Invest Dermatol 128(8):2041-8, 2008.
Engelhorn ME, Guevara-Patino JA, Merghoub T, Liu C, Ferrone CR, Rizzuto
GA, Cymerman DH, Posnett DN, Houghton AN, Wolchok JD. Mechanisms of
immunization against cancer using chimeric antigens. Mol Ther 16(4):773-81,
2008.
Lundberg K, Roos AK, Pavlenko M, Leder C, Wehrum D, Guevara-Patino
J, Andersen RS, Pisa P, A modified epitope identified for generation and
monitoring of PSA-specific T cells in patients on early phases of PSA-based
immunotherapeutic protocols. Vaccine 27(10):1557-65, 2009.
Liu Y, Peng Y, Mi M, Guevara-Patino J, Munn DH, Fu N, He Y, Lentivector
immunization stimulates potent CD8 T cell responses against melanoma
self-antigen tyrosinase-related protein 1 and generates antitumor immunity in
mice. J Immunol 182(10):5960-9, 2009.
Jabri, Bana MD, PhD
# Depaolo RW, Tang F, Kim I, Han M, Levin N, Ciletti N, Lin A, Anderson D,
Schneewind O, Jabri B. Toll-like receptor 6 drives differentiation of tolerogenic
dendritic cells and contributes to LcrV-mediated plague pathogenesis. Cell
Host Microbe 4(4):350-61, 2008.
Ebert EC, Jabri B. Massive interleukin-12-induced interferon-gamma
production by interleukin-15-stimulated lamina propria lymphocytes followed
by down-regulation of the interleukin-12 receptor. Immunology 124(4):453-60,
2008.
Tang F, Chen Z, Ciszewski C, Setty M, Solus J, Tretiakova M, Ebert E, Han
J, Lin A, Guandalini S, Groh V, Spies T, Green P, Jabri B. Cytosolic PLA2 is
required for CTL-mediated immunopathology of celiac disease via NKG2D and
IL-15. J Exp Med 206(3):707-19, 2009.
Kline, Justin MD
# Kline J, Subbiah S, Lazarus HM, van Besien K. Autologous graft-versus-host
disease: harnessing anti-tumor immunity through impaired self-tolerance.
Bone Marrow Transplant 41(6):505-13, 2008.
* Kline J, Brown IE, Zha YY, Blank C, Strickler J, Wouters H, Zhang L, Gajewski
TF. Homeostatic proliferation plus regulatory T-cell depletion promotes potent
rejection of B16 melanoma. Clin Cancer Res 14(10):3156-67, 2008.
Kline J. Will changing the face of WT1 make it more attractive to T cells?. Leuk
Lymphoma 50(2):156-7, 2009.
* Zhang L, Gajewski TF, Kline J. PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model. Blood
114(8):1545-52, 2009.
# Poire X, Artz A, Larson RA, Kline J, Odenike O, Rich E, Godley L, Stock W,
van Besien K. Allogeneic stem cell transplantation with alemtuzumab-based
conditioning for patients with advanced chronic myelogenous leukemia. Leuk
Lymphoma 50(1):85-91, 2009.
* Driessens G, Kline J, Gajewski TF. Costimulatory and coinhibitory receptors
in anti-tumor immunity. Immunol Rev 229(1):126-44, 2009.
Kumar, Vinay MD, PhD
Chlewicki LK, Velikovsky CA, Balakrishnan V, Mariuzza RA, Kumar V.
Molecular basis of the dual functions of 2B4 (CD244). J Immunol 180(12):815967, 2008.
Lesniak, Maciej MD
Paul CP, Everts M, Glasgow JN, Dent P, Fisher PB, Ulasov IV, Lesniak MS, StoffKhalili MA, Roth JC, Preuss MA, Dirven CM, Lamfers ML, Siegal GP, Zhu ZB,
Curiel DT. Characterization of infectivity of knob-modified adenoviral vectors
in glioma. Cancer Biol Ther 7(5):786-93, 2008.
Ulasov IV, Tyler MA, Rivera AA, Nettlebeck DM, Douglas JT, Lesniak MS.
Evaluation of E1A double mutant oncolytic adenovectors in anti-glioma gene
therapy. J Med Virol 80(9):1595-603, 2008.
Nandi S, Ulasov IV, Tyler MA, Sugihara AQ, Molinero L, Han Y, Zhu ZB,
Lesniak MS. Low-dose radiation enhances survivin-mediated virotherapy
against malignant glioma stem cells. Cancer Res 68(14):5778-84, 2008.
Sonabend AM, Rolle CE, Lesniak MS. The role of regulatory T cells in
malignant glioma. Anticancer Res 28(2B):1143-50, 2008.
Andaloussi AE, Han Y, Lesniak MS. Progression of intracranial glioma
disrupts thymic homeostasis and induces T-cell apoptosis in vivo. Cancer
Immunol Immunother 57(12):1807-16, 2008.
Sonabend AM, Ulasov IV, Tyler MA, Rivera AA, Mathis JM, Lesniak MS.
Mesenchymal stem cells effectively deliver an oncolytic adenovirus to
intracranial glioma. Stem Cells 26(3):831-41, 2008.
Sonabend AM, Velicu S, Ulasov IV, Han Y, Tyler B, Brem H, Matar
MM, Fewell JG, Anwer K, Lesniak MS. A safety and efficacy study of
local delivery of interleukin-12 transgene by PPC polymer in a model of
experimental glioma. Anticancer Drugs 19(2):133-42, 2008.
McKee, Mark MD
* Harlin H, Meng Y, Peterson AC, Zha Y, Tretiakova M, Slingluff C,
McKee M, Gajewski TF. Chemokine expression in melanoma metastases
associated with CD8+ T-cell recruitment. Cancer Res 69(7):3077-85,
2009.
Immunology
& Cancer
Guevara-Patino, Jose MD, PhD
Nguyen, Vu MD
Nguyen VH, Shashidhar S, Chang DS, Ho L, Kambham N, Bachmann
M, Brown JM, Negrin RS. The impact of regulatory T cells on T cell
immunity following hematopoeitic cell transplantation. Blood 111(2):94553, 2008.
Randall, Glenn PhD
Berger KL, Cooper JD, Heaton NS, Yoon R, Oakland TE, Jordan TX,
Mateu G, Grakoui A, Randall G. Roles for endocytic trafficking and
phosphatidylinositol 4-kinase III alpha in hepatitis C virus replication.
Proc Natl Acad Sci U S A 106(18):7577-82, 2009.
Schreiber, Hans MD, PhD
# Zhang B, Karrison T, Rowley DA, Schreiber H. IFN-gamma- and TNFdependent bystander eradication of antigen-loss variants in established
mouse cancers. J Clin Invest 118(4):1398-404, 2008.
* Zhang B, Zhang Y, Bowerman NA, Schietinger A, Fu YX, Kranz DM,
Rowley DA, Schreiber H. Equilibrium between host and cancer caused by
effector T cells killing tumor stroma. Cancer Res 68(5):1563-71, 2008.
Schreiber H. Tumor-specific immune responses. Semin Immunol
20(5):265-6, 2008.
Schietinger A, Philip M, Schreiber H. Specificity in cancer
immunotherapy. Semin Immunol 20(5):276-85, 2008.
Chopra N, Gan W, Schreiber H, Kurutz JW, Meredith SC. Versatile cyclic
templates for assembly of axially oriented ligands. Bioconjug Chem
20(2):231-40, 2009.
Sperling, Anne PhD
# Yau DM, Sethakorn N, Taurin S, Kregel S, Sandbo N, CamorettiMercado B, Sperling AI, Dulin NO. Regulation of Smad-mediated gene
transcription by RGS3. Mol Pharmacol 73(5):1356-61, 2008.
Cannon JL, Collins A, Mody PD, Balachandran D, Henriksen KJ,
Smith CE, Tong J, Clay BS, Miller SD, Sperling AI. CD43 regulates Th2
differentiation and inflammation. J Immunol 180(11):7385-93, 2008.
Tesciuba AG, Shilling RA, Agarwal MD, Bandukwala HS, Clay BS,
Moore TV, Weinstock JV, Welcher AA, Sperling AI. ICOS costimulation
expands Th2 immunity by augmenting migration of lymphocytes to
draining lymph nodes. J Immunol 181(2):1019-24, 2008.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
55
Storb, Ursula MD
# Longerich S, Orelli BJ, Martin RW, Bishop DK, Storb U. Brca1 in
immunoglobulin gene conversion and somatic hypermutation. DNA Repair
(Amst) 7(2):253-66, 2008.
Shen HM, Bozek G, Pinkert CA, McBride K, Wang L, Kenter A, Storb U.
Expression of AID transgene is regulated in activated B cells but not in resting
B cells and kidney. Mol Immunol 45(7):1883-92, 2008.
Shen HM, Poirier MG, Allen MJ, North J, Lal R, Widom J, Storb U. The
activation-induced cytidine deaminase (AID) efficiently targets DNA in
nucleosomes but only during transcription. J Exp Med 206(5):1057-71, 2009.
Yu, Ping MD
* Yu P, Fu YX. Targeting tumors with LIGHT to generate metastasis-clearing
immunity. Cytokine Growth Factor Rev 19(3-4):285-94, 2008.
Zhang, Jian MD
* Qiao G, Li Z, Molinero L, Alegre ML, Ying H, Sun Z, Penninger JM, Zhang
J. T-cell receptor-induced NF-kappaB activation is negatively regulated by E3
ubiquitin ligase Cbl-b. Mol Cell Biol 28(7):2470-80, 2008.
Bao L, Haas M, Pippin J, Wang Y, Miwa T, Chang A, Minto AW, Petkova M,
Qiao G, Song WC, Alpers CE, Zhang J, Shankland SJ, Quigg RJ. Focal and
segmental glomerulosclerosis induced in mice lacking decay-accelerating
factor in T cells. J Clin Invest 119(5):1264-74, 2009.
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Selected Major Grants and Awards
The Immunology and Cancer Program has a funding base of $12,536,841 in annual total costs (current as of June 15, 2009).
This sum includes $3,536,249 in NCI funding and $6,551,885 in other NIH funding. Due to space constraints, only new awards
presented since January 1, 2008 with funding of $100,000 or more in annual total costs are listed here.
Title
Start Date
End
Date
Annual
Total Cost
Class
Funding Agency
Schreiber, Hans
CD8+ T Cells and Immunological
Tumor Regression
7/26/2008
5/31/2013
$1,543,335
P01
National Cancer Institute
Bendelac, Albert
Glycolipid Presentation by CD1d
4/1/2008
3/31/2013
$1,304,014
P01
National Institute of Allergy
and Infectious Diseases
Clark, Marcus
Tertiary Lymphoid Neogenesis in
Human Lupus Nephritis
8/15/2008
7/31/2013
$338,800
R01
National Institute
of Arthritis and
Musculoskeletal and Skin
Diseases
Golovkina,
Tatyana
Cloning of the Vic1 gene, a Novel
Retrovirus Restriction Factor
7/17/2008
5/31/2013
$316,675
R01
National Cancer Institute
Lesniak, Maciej
Conditionally Replicative Adenoviral
Vectors for Malignant Glioma
1/9/2008
12/31/2012
$312,556
R01
National Cancer Institute
Guevara-Patino,
Jose
Functional Profiling of Tumor-Induced
Immune Suppression
1/1/2008
12/31/2011
$240,000
08
American Cancer Society
Gajewski, Thomas
Deletion of Inhibitory Genes in PostThymic T Cells to Study Immune
Tolerance
7/1/2008
6/30/2010
$231,000
R21
National Institute of Allergy
and Infectious Diseases
Sperling, Anne
BD LSR II Flow Cytometer
1/15/2009
1/14/2010
$223,835
S10
National Center for
Research Resources
Lesniak, Maciej
Development of an Adenoviral Vector
With Chimeric Fiber for Malignant
Glioma
4/1/2008
3/31/2010
$215,325
R21
National Cancer Institute
Storb, Ursula
AID in Somatic Mutation of
Immunoglobulin Genes
2/15/2009
1/31/2011
$195,000
R21
National Institute of Allergy
and Infectious Diseases
Guevara-Patino,
Jose
Disparate Suppression of Naive
Effector and Memory T cells in
Tumor-Bearing Hosts
1/1/2008
12/31/2009
$172,688
R21
National Cancer Institute
Kline, Justin
A Study to Assess the Safety and
Biological Activity of Recombinant
Human Interleukin-18 Administered
by Intravenous Infusion in a
Combination with Rituximab in Adult
Patients with B Cell Non-Hodgkins
Lymphoma
6/5/2008
6/4/2010
$165,097
N/A
Glaxo Smith Klein
Fu, Yang-Xin
Antibody LIGHT Fusion
9/10/2008
9/10/2009
$151,872
N/A
Biogen Idec Inc.
Guevara-Patino,
Jose
DNA Vaccine for Seasonal and
Pandemic Influenza
8/1/2008
7/31/2010
$149,700
U01
National Institutes of Health
Kline, Justin
Homeostatic Proliferation and
Regulatory T Cell Depletion as Cancer
Immunotherapy
7/1/2008
6/30/2013
$129,843
K23
National Cancer Institute
Chong, Anita
The Effect of Pioglitazone on
Pancreatic Beta Cell Regeneration
3/9/2009
3/8/2011
$126,343
N/A
Takeda Chemical Industries,
LTD.
Guevara-Patino,
Jose
Targeting HSP70 in Autoimmune
Vitiligo
9/1/2008
8/31/2013
$105,217
R01
National Institutes of Health
UCCRC SCIEN T IFI C R EPO R T 20 0 9
Immunology
& Cancer
Investigator
57
P ro g r a m 4
Clinical and Experimental Therapeutics
Dr. Susan Cohn with a patient
The overall goal of the program is to foster interaction
between basic and clinical investigators that will result
in innovative and effective therapies for cancer patients.
The Clinical and Experimental Therapeutics
The scientific goals of the program are to (1)
Program is a cohesive, integrated group that
foster interaction between basic and clinical
brings together a diverse team of 53 members
investigators that will result in innovative
representing 9 different departments. The
and effective therapies; (2) to integrate new
overall goal of the program is to foster
drugs into the development of multimodality
interaction between basic and clinical
therapies for patients with advanced solid
investigators that will result in innovative and
tumors; and (3) pursue a broad program of
effective therapies for cancer patients. The
preclinical, translational, and clinical research in
translational nature of much of the research done
pharmacogenetics and pharmacology.
Clinical & Experimental
Therapeutics
Overview & Goals
in this program, along with the leadership role
assumed by many program members in studies
conducted by national clinical trials cooperative
groups, illustrates the impact of this program
in developing new therapies for oncology. The
program has a long-standing focus on drug
development at all phases of clinical testing and
a strong pharmacogenetic component. The types
Program Leaders:
of trials range from preclinical development to
investigator-initiated Phase I clinical trials, to
Phase II trials in the regional Phase II network, to
Phase III studies with CALGB.
M. Eileen Dolan, PhD
Everett Vokes, MD
UCCRC SCIEN T IFI C R EPO R T 20 0 9
59
Members
60
Investigator*
Rank
Department
Douglas Bishop PhD
Elizabeth Blair MD
Ezra Cohen MD
Susan Cohn MD
Philip Connell MD
Christopher Daugherty MD
Glyn Dawson PhD
M. Eileen Dolan PhD
Scott Eggener MD
Mark Ferguson MD
Alessandro Fichera MD
Gini Fleming MD
Harvey Golomb MD
Daniel Haraf MD
John Hart MD
Chuan He PhD
Javad Hekmatpanah MD
Philip Hoffman MD
Roger Hurst MD
Federico Innocenti MD, PhD
Edwin Kaplan MD
Theodore Karrison PhD
Hedy Kindler MD
Mark Lingen DDS, PhD
Marcy List PhD
Yves Lussier MD
Michael Maitland MD, PhD
Bruce Minsky MD
Rita Nanda MD
Terrance Peabody MD
Louis Portugal MD
Edwin Posadas MD
Mitchell Posner MD
Mark Ratain MD
Kevin Roggin MD
Charles Rubin MD
Joseph Salama MD
Richard Schilsky MD
Tanguy Seiwert MD
Arieh Shalhav MD
Mark Siegler MD
Michael Simon MD
David Song MD
Walter Stadler MD
Gary Steinberg MD
Kerstin Stenson MD
Ronald Thisted PhD
Everett Vokes MD
Ralph Weichselbaum MD
H. Rosie Xing PhD
Seiko Diane Yamada MD
Bakhtiar Yamini MD
Chun-Su Yuan MD, PhD
Professor
Associate Professor
Associate Professor
Professor
Assistant Professor
Professor
Professor
Professor
Assistant Professor
Professor
Associate Professor
Professor
Professor
Professor
Professor
Associate Professor
Professor
Professor
Associate Professor
Assistant Professor
Professor
Associate Professor
Associate Professor
Associate Professor
Associate Director Administration
Associate Professor
Assistant Professor
Professor
Assistant Professor
Professor
Associate Professor
Assistant Professor
Professor
Professor
Assistant Professor
Associate Professor
Assistant Professor
Professor
Instructor
Professor
Professor
Professor
Associate Professor
Professor
Professor
Associate Professor
Professor
Professor
Professor
Assistant Professor
Associate Professor
Assistant Professor
Associate Professor
Radiation and Cellular Oncology
Surgery
Medicine
Pediatrics
Radiation and Cellular Oncology
Medicine
Pediatrics
Medicine
Surgery
Surgery
Surgery
Medicine
Medicine
Radiation and Cellular Oncology
Pathology
Chemistry
Surgery
Medicine
Surgery
Medicine
Surgery
Health Studies
Medicine
Pathology
UCCRC
Medicine
Medicine
Radiation and Cellular Oncology
Medicine
Surgery
Surgery
Medicine
Surgery
Medicine
Surgery
Pediatrics
Radiation and Cellular Oncology
Medicine
Medicine
Surgery
Medicine
Surgery
Surgery
Medicine
Surgery
Surgery
Health Studies
Medicine
Radiation and Cellular Oncology
Pathology
OB/GYN
Surgery
Anesthesia/Critical Care
UCCRC SCIEN T IFI C R EPO R T 20 0 9
* Reflects all Program membership during 2008-2009
Featured Faculty Research Summaries†
Investigators in the Clinical and Experimental Therapeutics Program aim to
improve cancer therapies by focusing on several research themes including
the development of novel cancer therapeutics, pharmacogenomics of cancer
therapeutics, and the interaction of chemotherapy and radiation. Presented
below are highlights of current studies in the Program.
Development of Novel Cancer Therapeutic Agents and Combined Modality Therapy Concepts
Ezra Cohen, MD
Associate Professor of Medicine
Squamous Cell Carcinoma of the Head and Neck (HNSCC) is the 6th leading cause
of cancer mortality worldwide. Current therapeutic advances have clearly reached
a plateau and new avenues of research need to be explored. With few exceptions,
the benefit of available systemic therapies in recurrent or metastatic malignancies,
including SCCHN, is limited and usually of short duration. As such, Dr. Cohen’s
novel therapies to improve outcomes – the AGC kinase family and intrinsic resistance
to epidermal growth factor receptor (EGFR) inhibition.
Dr. Cohen’s studies demonstrated that protein kinase C (PKC) isoforms are critical
mediators of SCCHN growth both in vitro and in vivo. In fact, enzastaurin, an acyclic
Dr. Mitchell Posner
Clinical & Experimental
Therapeutics
previous signaling work in SCCHN cell lines focuses on two main areas in search of
bisindolylmaleimide that displays potent selective inhibition of classic and novel PKC
isoforms was active and reduced proliferation in SCCHN cell lines. To elucidate putative targets of enzastaurin in
SCCHN the Cohen laboratory performed gene expression arrays and discovered that expression of cell cycle genes,
including cyclins D and E, were significantly altered by exposure to enzastaurin. Interestingly, cyclin D1 protein levels
appeared to predict in vitro sensitivity to the agent. Moreover, inhibition of cyclin D1 expression reversed resistance in
an insensitive cell line, whereas cyclin D1 transfection in a sensitive cell line rendered the cells resistant to enzastaurin.
Initially, the underlying mechanisms for these observations were hypothesized to relate to signaling mediated by PKC
isoforms. However, dynamic modeling of putative targets of enzastaurin and cyclin D1 inhibition demonstrated that
the effect is most likely secondary to inhibition of AKT. In fact, depletion of AKT by siRNA reduces cell viability of
SCCHN cell lines, inhibits cyclin D1 expression, and reverses resistance to enzastaurin. In addition to AKT affecting
SCCHN viability and proliferation, the Cohen group implicated the pathway as a critical mediator of resistance
to EGFR inhibitors. The small molecule tyrosine kinase inhibitor (TKI), gefitinib, was tested in a panel of SCCHN
cell lines to determine the IC50 in an in vitro cell viability assay. In all cell lines, the agent inhibited phosphorylation
of EGFR, as expected. However, only in the cell lines resistant to gefitinib (defined as IC50 > 10mM) was AKT
phosphorylation preserved upon exposure to the agent. Therefore, constitutive activation of AKT independent of EGFR
contributes to resistance to an EGFR TKI. In SCCHN, dysregulation of the PI3K/AKT pathway occurs frequently
and has been linked to radiation resistance and poor outcome. Additional work supports a role of AKT in regulating
another proto-oncogene that is often amplified, CCND1, and as a major mechanism of resistance to EGFR inhibitors.
Beyond inhibiting specific targets relevant to SCCHN, the Cohen laboratory in collaboration with Argonne National
Laboratory has generated epidermal growth factor (EGF)-antibody-coated PLGA-PEG nanoparticles encapsulating
cisplatin. Since EGFR is universally expressed in SCCHN, the group hypothesized that the antibody coating
would direct the nanoparticles to SCCHN tumor cells. Furthermore, the nanoparticle shell contains iron, which
effectively allows magnetic guidance. These nanoparticles were green fluorescent protein (GFP)-tagged and injected
intraperitoneally (IP) into mice harboring SQ20B head and neck cancer hind-limb xenografts. Preliminary data
demonstrate that after 30 minutes of applied magnetic field of approximately 1 Tesla, the tracks of the fluorescent
particles can be observed and the nanoparticles concentrate in tumor cells. When mice bearing SQ20B xenografts
were treated IP with EGF-coated, cisplatin-containing nanoparticles, significant tumor regression was observed
† Note: Due to space constraints, only a small representative sample of Program members is presented here.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
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compared to mice treated with IP cisplatin alone or vehicle control. Interestingly, cisplatin-nanoparticles demonstrated greater
efficacy despite containing a 10-fold lower concentration of the drug than was administered to mice receiving cisplatin alone.
In summary, the Cohen laboratory is interested in extending findings into therapy for patients with SCCHN. Specifically,
the group is investigating the role of PI3K/AKT pathway inhibition using agents in development. Moreover, the laboratory is
continuing to study other mechanisms of resistance to therapy in SCCHN by developing second generation EGFR inhibitors and
improving agent delivery using nanoparticles.
Joseph Salama, MD
Assistant Professor of Radiation and Cellular Oncology
Dr. Salama studies the outcomes of patients with upper aeordigestive cancers (head and neck and lung) treated with combined
chemotherapy and radiotherapy, and also has an active interest in improving the outcomes of patients with limited metastatic
cancer traditionally treated only with chemotherapy or, in select cases, surgery. Patients with limited metastatic disease,
or oligometastases, represent a subset of patients who may be curable with aggressive treatment directed at known sites of
metastasis. Dr. Salama’s research focuses on improving outcomes for oligometastatic patients by clarifying characteristics
of these patients, refining novel radiation treatment techniques for oligometastatic cancers alone or in combination with
chemotherapy, as well as identification of genetic pathways unique to oligometastatic patients.
Dr. Salama has been studying the application of a novel radiotherapy technique, hypofractionated image-guided radiotherapy,
a combination of technical advances in radiotherapy planning and delivery, specifically to all known metastatic deposits
in patients with metastases that are limited in number and location. Through an ongoing dose-escalation study, safe and
effective doses of hypofractionated image-guided radiotherapy for different body sites have been identified with 70% of treated
metastases being controlled. Further analyses have identified that escalating radiation doses are associated with improved
control rates. Additionally, of the 56 patients treated to date 32% have achieved disease control (either no evidence of disease
or no disease progression). The Salama team has analyzed tumor control with various imaging modalities, and found that
reduction in positron emission tomography intensity is the most sensitive method to gauge response to this treatment. These
initial findings have been recently published in Clinical Cancer Research. Currently, Dr. Salama is collaborating with Memorial
Sloan Kettering Cancer Center to compare a single large dose of radiotherapy versus five intermediate doses.
As the majority of patients studied had control of treated metastases, but progression within new metastatic sites, combination
of hypofractionated image-guided radiotherapy with systemic therapy seems warranted. Therefore, in collaboration with Dr.
Everett E. Vokes, the Salama team has activated a randomized phase II trial in patients with limited volume metastatic nonsmall cell lung cancer in attempt to determine if the combination of docetaxel and cisplatin and hypofractionated image-guided
radiotherapy improves survival of patients compared to those treated with docetaxel and cisplatin alone.
Additionally, in collaboration with Dr. Ralph R. Weichselbaum, Dr. Salama is seeking to understand the genetic characteristics
of patients who have limited metastatic cancer. The genetic determinants of why some patients have cancer metastasizing to
limited sites, while others have a distribution of metastasis throughout their body, is not at all understood. An analysis of tumor
specimens derived from patients with limited metastatic disease from primary tumors as well as metastases will be performed
to seek out key pathways involved in the development and response to treatment of oligometastatic patients.
Douglas Bishop, PhD
Professor of Radiation and Cellular Oncology
The Bishop laboratory has worked to identify molecular targets that can be exploited in the treatment of cancers. This has
predominantly centered on DNA repair pathways that are involved in tumor cell resistance to common cancer treatments.
Specifically, the Bishop group has focused on proteins involved in the homologous recombinational (HR) DNA repair pathway,
which is involved in radiation-induced DNA damage and is critically important for repair of cross-links induced by platinumbased chemotherapies and mitomycin C. The laboratory is primarily investigating the HR protein, RAD51, which is the central
recombinase in this DNA repair pathway. Several studies have suggested that RAD51 protein is highly expressed in a variety
of human cancer cells, and that this over-expression confers resistance to radiation therapy and chemotherapy. Projects
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in the laboratory are aimed at 1) blocking the function of RAD51
with inhibitory small molecules, in an attempt to sensitize cells to
chemotherapy and radiotherapy; and 2) stimulating RAD51, with the
goal of protecting normal tissues from cytotoxic therapies.
The laboratory recently published its first study of RAD51-modifying
compounds. This work involved a compound called RS-1, which was
identified from a high-throughput chemical screen for compounds
that enhance the ability of RAD51 to bind DNA. RS-1 was shown to
enhance assembly of functional RAD51 protein filaments on DNA and
Dr. Rita Nanda
to stimulate HR activity in-vitro. When introduced into cells in culture,
a significant dose dependent protection of normal human dermal
fibroblasts was observed against the toxic effects of cisplatin. The protective effect was observed in the same concentration
range (low micromolar) as was required for stimulation in biochemical assays. Work is ongoing to improve upon RS-1 activity
Planned and ongoing work will evaluate whether RAD51-stimulatory compounds can reduce mutagenesis and protect normal
tissues from DNA-damaging therapies in animal models. The Bishop laboratory is also testing the ability of these compounds
to treat Fanconi Anemia (FA), a cancer susceptibility syndrome in which cells have impaired HR activity. Preliminary studies
suggest that some compounds can successfully rescue the HR deficiency of cells derived from FA patients. The laboratory
Clinical & Experimental
Therapeutics
via medicinal chemistry collaborations and to identify newer, more active compounds.
also plans to explore the role of RAD51 expression, a new avenue of research derived from previous studies on homologous
recombination in budding yeast. This work demonstrated that under some circumstances, RAD51 (and its relative DMC1)
forms non-recombinogenic complexes on DNA. Results from the laboratory suggest that these “dead-end” complexes can
reduce the rate of cell proliferation. Studies are currently being initiated to determine if the high level of RAD51 expression
in tumor cells results in the formation of dead-end complexes. If so, the compounds that the laboratory has identified, which
stabilize the interaction of RAD51 with DNA, may enhance the ability of dead-end complexes to block replication of tumor
cells.
In addition, the Bishop group is working on a new functional test of alleles of the breast cancer susceptibility gene, BRCA1.
This test involves the DT40 cell line, which is a chicken Β lymphocyte cell line that exhibits high rates of homologous
recombination. Slight defects in BRCA1-dependent recombination and repair are detectable in these cells. The laboratory is in
the process of carrying out proof-of-principle experiments to determine how closely human BRCA1 function mirrors that of
chicken Brca1. If the function is conserved in chicken cells, the laboratory will be able to assess whether a particular variant
of human BRCA1 is functionally defective. This work may potentially have important prognostic value as novel BRCA1
variants are discovered.
H. Rosie Xing, PhD
Assistant Professor of Pathology
The core research conducted in the Xing laboratory is a mechanistic-driven, basic science program focused on translational
cancer biology. The main goals are to define the role of deregulated signaling transduction events in human oncogenesis and
metastatic dissemination, and to translate such mechanistic understanding for the development of novel cancer therapeutic
agents and the design of multi-modality/multi-agent treatment strategies. Through intra- and inter-programmatic
collaborations, the laboratory has integrated approaches and tools of bioinformatics and systems biology (Yves Lussier,
Clinical and Experimental Therapeutics Program), in vivo molecular imaging science (Chin-Tu Chen and Patrick La
Riviere, Advanced Imaging Program), cancer therapeutics (Everett Vokes, RalphWeischelbaum, Ezra Cohen, and Tanguy
Seiwert, Clinical and Experimental Therapeutics Program), structural biology, and molecular pathology (Mark Lingen,
Clinical and Experimental Therapeutics Program ) to accelerate discovery science and facilitate clinical translation. The
combined expertise of the laboratory’s extended scientific collaborations facilitates investigations that are relevant to cancer
management and have promising potential for translation.
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Using a structure-based rationale, the Xing laboratory targeted a non-ATP binding functional domain of KSR (a validated
effector of oncogenic Ras) and conducted a virtual screening of an NCI compound library. A small molecule inhibitor of KSR,
which exhibits broad spectrum and potent anti-neoplastic activity in vitro, was identified and characterized. The laboratory is
currently working with the NCI RAND program to develop this agent for potential clinical applications.
In two recent studies conducted in squamous carcinoma of the head and neck (HNSCC), the Xing laboratory demonstrated how
integration of systems biology approaches accelerates the translation of discovery science. In the first study, the group reported
the first computationally predicted and biologically validated microRNA-regulated protein-protein interaction network, and
uncovered previously unknown connections between microRNA regulation, network topology, and expression dynamics.
Further, the laboratory showed that miR-204, a computationally predicted and prioritized microRNA, is a potent suppressor of
HNSCC metastasis. A strong clinical association was shown between overexpression of functional miR-204 gene targets and an
earlier relapse in a sub-type of HNSCC tumors expressing an EGFR-pathway signature.
In the second study, the Xing group demonstrated that utilization of the systems strategy unbiasely and effectively identifies
deregulated signaling pathways and molecular networks associated with treatment resistance. Consequently, these aberrant
signaling mechanisms could be exploited for the development of “pathway rewiring”-based combinations as an alternative to the
individual gene target-based paradigm. Using this approach, the laboratory illustrated that HNSCC cancer cells can effectively
exploit the molecular interactions between EGFR and mTOR to confer reciprocal resistance. Thus, the combination of antiEGFR and anti-mTOR agents will likely achieve optimal prevention of resistance. Furthermore, the Xing laboratory studies the
role of a permissive tumor stromal microenvironment in tumor initiation, maintenance and response to cancer. Using xenograft
models of human cancer, the group demonstrated that in vivo administration of the combination regimen, including an EGFR
and a mTOR inhibitor, through differential and effective co-targeting of cancer cells and tumor stroma, leads to HNSCC tumor
regression. A Phase II trial is being planning at the University of Chicago to test the therapeutic efficacy of this combination for
the treatment of head and neck cancer.
In a separate study, the laboratory used a molecular in vivo optical imaging approach to characterize tumor vascular response
to anti-cancer therapies. The feasibility of serial imaging of tumor vascular response was demonstrated in real-time using live
mice, providing the first in vivo experimental evidence that the effectiveness of anti-angiogenic agents can be achieved either
through vessel destruction or, alternatively, through normalization. This approach will be used in combination with clinicallyrelevant imaging modalities (PET/CT/SPECT) to derive translational imaging markers in future studies.
Pharmacogenomics of Anticancer Agents
Mike Maitland, MD, PhD
Assistant Professor of Medicine
Dr. Maitland leads the Biomarker Development Laboratory, a
research program that bridges the Core Laboratories and the
clinical elements of the Cancer Center’s Clinical and Experimental
Therapeutics Program. Biomarkers are characteristics that are
objectively measured and frequently evaluated as indicators of
disease processes or responses to drug treatment. Biomarkers
can be helpful tools for speeding the development of or better
Dr. Philip Connell
personalizing the use of new cancer therapies. Dr. Maitland’s
laboratory addresses the many obstacles between discovering biomarkers and making them useful for advancing cancer care.
Currently, his program focuses on developing biomarkers to improve the use of angiogenesis inhibitors.
In the past year, Dr. Maitland’s team has made two important discoveries on how cancer patients differ in response to
angiogenesis inhibitors. Understanding these differences will likely facilitate safer and more effective dosing of these drugs. For
example, many patients develop high blood pressure when administered FDA-approved agents in this class of drugs, including
Avastin™, Nexavar™ (generic = sorafenib), or Sutent™ (generic = sunitinib). The time required for this effect was unclear,
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and whether the effect occurred only in patients with pre-existing hypertension was unknown. Supported, in part, by a
University of Chicago Cancer Research Center protocol-specific grant, the research team measured changes in blood pressure
with state-of-the-art equipment and detected changes on the very first day of treatment, much earlier than had been thought.
After 7 days, the average blood pressure increased from 121/71 mmHg to 132/79 mmHg, and most patients experienced
approximately 10 mmHg systolic and 8 mmHg diastolic increases in blood pressure. However, 14/54 patients had no increase,
whereas 8/54 had large increases in blood pressure. One explanation for the wide variation in response is that patients with
no increase in blood pressure are under-dosed, those with the high increases in blood pressure are overdosed, and that blood
pressure can be used to guide safe dosing of these drugs. The research team is now conducting a follow-up trial to test this
concept.
The Biomarker Development Laboratory has also been studying a blood protein marker, sVEGFR2. Levels of sVEGFR2
decrease following the administration of sorafenib, sunitinib, or similar drug therapies, but also vary between individuals.
Understanding the mechanism of sVEGFR2 variation may provide clues for why these drugs are more effective in select
patients. Dr. Maitland’s group learned that levels of sVEGFR2 vary in healthy individuals, are not dependent on the presence
Maryland who have studied a community with shared, well recorded ancestry and a lifestyle similar to that of their ancestors,
the Old Order Amish of Lancaster, Pennsylvania. The team measured sVEGFR2 in over 700 Amish volunteers and performed
genetic mapping. Results indicate that one region of a single chromosome has a large effect on the variation of sVEGFR2
levels across individuals. In future studies, the team will identify specific genes in the identified region in order to develop
a test that might predict therapeutic response to sorafenib, sunitinib, and other drugs in this important new class of anti-
Clinical & Experimental
Therapeutics
of tumors, and do not change much with exercise. The research team collaborated with geneticists at the University of
cancer agents.
M. Eileen Dolan, PhD
Professor of Medicine
Pharmacogenetics aims at both maximizing efficacy and minimizing adverse effects of chemotherapy by identifying the
genetic component of variation in drug response. The overall goal of Dr. Dolan’s research program is to identify predictive
pharmacogenetic markers in individuals at greatest risk for adverse events or non-response in efforts to improve current
oncology practice. The main approaches that are employed in the laboratory include the candidate gene approach and the
whole genome approach. The candidate gene approach considers only well understood genes and/or pathways involved in
the metabolism or mechanism of action of a given drug and is most effective if the gene product has a large effect on drug
pharmacokinetics or pharmacodynamics. However, this is often not the case. Therefore, Dr. Dolan’s laboratory has taken
advantage of the whole genome approach in an attempt to disclose previously unknown relationships between genotype
or expression and a given phenotype such as drug toxicity. This approach can be used to link multiple single nucleotide
polymorphisms (SNPs) and haplotypes to drug response with no a priori assumptions. The Dolan group is developing
strategies to corroborate initial associations through replication in independent cohorts and/or through assessment of a
functional role of the associated SNPs or haplotypes.
Specific aims of the Dolan laboratory are to 1) determine the underlying genetic and molecular mechanisms responsible
for sensitivity to toxicities or non-response associated with chemotherapeutic agents; 2) build useful cellular models for
discovery and validation of chemotherapeutic-specific genetic variants for clinical evaluation; 3) evaluate pharmacogenetic
findings related to chemotherapeutic agents in clinical trials; and 4) share information related to utility of cell lines for
discovery and validation of genetic variants important in pharmacologic endpoints.
Performing genome wide association studies with cancer patients is particularly difficult because of the large number of
patients required and because most patients receive multiple drugs. Most importantly, chemotherapy cannot be given
to unaffected family members for genetic studies; therefore, the Dolan laboratory studies cell lines from unaffected
individuals that are part of the International HapMap project, which are rich in genotypic information. Cellular phenotypes,
such as chemotherapeutic-induced toxicity or apoptosis, are evaluated for association with genotypes. Current avenues
of investigation include the incorporation of knowledge about microRNAs, the integration of epigenomic data, and
UCCRC SCIEN T IFI C R EPO R T 20 0 9
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incorporation of other genetic elements such as copy number variants (CNVs). The goal of the Dolan laboratory is to integrate
all relevant data such as SNPs, CNVs, microRNAs, and DNA methylation changes, to assemble a comprehensive model for
predicting drug response and toxicity, which could serve as the basis for designing drug therapy based on a patient’s specific
genetic profile. However, interpreting this data to prospectively guide dosage and drug regimens will require large prospective
clinical trials to validate the findings.
In a recent study, the Dolan laboratory, using lymphoblastoid cell lines derived from individuals of European (CEU) or African
(YRI) ancestry, identified genetic factors important in susceptibility to toxicity associated with cytarabine arabinoside (ara-C),
an antimetabolite used to treat hematologic malignancies. The candidate gene approach identified SNP70 within deoxycytidine
kinase (DCK), an enzyme involved in formation of AraCTP, the active drug form. LCLs that are heterozygous for SNP 70
demonstrated an increased sensitivity to ara-C, higher mRNA expression of DCK, and significantly higher intracellular levels of
ara-CTP compared to homozygous LCLs, suggesting that this SNP affects DCK function. Using the genome wide approach, the
laboratory interrogated more than 2 million SNPs for association with susceptibility to ara-C and focused on SNPs that affected
gene expression. A unique pharmacogenetic signature, consisting of 4 SNPs explaining 51% of the variability in sensitivity to
ara-C among the CEU and 5 SNPs explaining 58% of the variation among the YRI populations, was identified. Gene expressioncytotoxicity relationships were validated for a subset of genes in a separate group of lymphoblastoid cell lines. These unique
genetic signatures comprise novel genes that can now be studied further in functional studies and clinical trials.
Interaction of Chemotherapy and Radiation
Ralph Weichselbaum, MD
Professor of Radiation and Cellular Oncology
The Weichselbaum laboratory is engaged in the investigation
and clinical translation of two major gene therapies. Both
strategies involve radiotherapy, combining activation of
cytotoxic/immune activating genes by radiation within a
replication-defective adenoviruses and the activation of
replication of genetically-engineered/attenuated herpes viruses.
Research in the laboratory focuses on the identification of
basic mechanisms and clinical translation of TNFerade with
radiation, herpes simplex virus-1 (HSV-1) oncolytic therapy,
Dr. Kerstin Stenson
gene signatures and radio-chemo resistance, immune response
to radiation therapy, and control of distant metastasis by radiation therapy.
The Weichselbaum laboratory has identified radiation response elements (RREs) in the EGR1 promoter that increase gene
expression in response to ionizing radiation. When cloned upstream of therapeutic genes, RREs permit spatial and temporal
control of transgene transcription. This approach was developed using tumor necrosis factor alpha (TNFα) as the therapeutic
transgene. Although known to be a potent radiation sensitizer, systemic delivery of TNFα resulted in severe toxicity in phase
I studies. An adenovector (Ad) approach was used to design a replication-deficient Ad to transduce cells with the TNFα
gene under the control of the RRE of EGR1 (Ad.EGR.TNFα). In preclinical animal models, Ad.EGR.TNFα combined with
fractionated radiation produced enhanced expression of TNFα within tumor xenografts and tumor growth regression compared
with Ad.EGR.TNFα or radiation alone. The laboratory has demonstrated that tumor-associated endothelium is the principal
target for Ad.Egr.TNFα radiosensitization. TNFerade represents a potential therapeutic strategy that exploits nonoverlapping
toxicity to enhance the radiation response in human tumors compared with conventional radiation or chemoradiotherapy. In
collaboration with Dr. Everett Vokes and others, the effects of TNFerade will be tested in recurrent head and neck cancer and
prostate cancer in phase I trials. A phase 3 trial in pancreatic cancer is currently underway.
In collaboration with Bernard Roizman (Cell Signaling and Gene Regulation Program), the laboratory has studied activation
of genetically engineered herpes viruses by ionizing radiation and reported that radiation enhances late viral gene expression
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by activating late promoters as early as two hours after radiation. The radiation activation of late viral genes is mediated by
the P38 kinase pathway, which is not required for late viral gene expression. These results suggest that ionizing radiation
upregulates late promoters active in the course of viral DNA synthesis and provide the basis for activating viral replication and
tumor oncolysis, thereby overcoming attenuation of the virus.
As a consequence of investigating the molecular basis of radioresistance, the Weichselbaum laboratory identified a genetic
signature in the interferon pathway, referred to as the interferon related gene signature for DNA damage (IRDS). The
laboratory showed that experimentally-derived interferon-related, DNA-damage resistant signatures are associated with
resistance and/or chemotherapy across different cancer cell lines. The IRDS genes, STAT-1, ISG 15, and IFIT1 all mediate
experimental resistance. In collaboration with Andy Minn (Cell Signaling and Gene Regulation Program), analysis of clinical
databases demonstrated that IRDS-positive and -negative states exist among common human cancers. In breast cancer, the
efficacy of adjuvant chemotherapy and radiotherapy is predicted by the IRDS that is associated with a poor prognosis.
In collaboration with Yang-Xin Fu (Immunology and Cancer Program), the laboratory is also studying anti-tumor immune
effects mediated by radiotherapy. The Weichselbaum group has observed that reduction of tumor burden following modified
dendritic cell maturation for T cell priming, leading to reduction/eradication of primary tumor or metastasis in a CD8+ T celldependent fashion. The laboratory further demonstrated that radiation-initiated immune responses and tumor reduction are
abrogated by conventional fractionated radiotherapy or adjuvant chemotherapy, but greatly amplified by local immunotherapy,
leading to the eradication of metastasis. These results challenge the rationale for current commonly-used intensive radio/
Clinical & Experimental
Therapeutics
hypofractionated radiotherapy depends in part on immune responses, and that hypofractionated radiotherapy increases
chemotherapy strategies and provides the basis for combination treatments with radiotherapy and immunotherapy.
Bakhtiar Yamini, MD
Assistant Professor of Surgery
Malignant gliomas are the most common form of primary brain tumor. Patients with these lesions have an overall median
survival of approximately 1 year. Although ionizing radiation (IR) is the primary post surgical treatment modality, the
addition of chemotherapy has been shown to modestly improve patient prognosis. The monofunctional methylating agent,
temozolomide (TMZ), has become the prototypical anti-glioma agent because of its relatively predictable toxicity and its
efficacy in combination with IR. Translational studies in Dr. Yamini’s laboratory focus on combining TMZ with IR and other
therapeutic modalities to improve anti-glioma treatment efficacy. In this regard, Dr. Yamini’s work is closely affiliated with
Dr. Ralph Weichselbaum. Studies in animal models of malignant glioma also involve the use of targeted nanoparticle vectors,
which the laboratory is attempting to distribute through the brain by convection enhanced delivery (CED).
Dr. Yamini’s laboratory is also examining the mechanism of action of methylating agents like TMZ. These studies have
revealed that methylators inhibit the activation of the transcription factor, nuclear factor-κB (NF-κB). Specifically, Dr.
Yamini’s team has determined that inhibition of NF-κB is a response to mismatch repair (MMR)-directed processing of O 6methylguanine (O6-MeG), the primary cytotoxic lesion induced by TMZ. This pathway is important in the apoptotic response
to O6-MeG, and loss of the ability to inhibit NF-κB attenuates TMZ-induced killing. By mediating the O 6-MeG-induced DNA
damage response, NF-κB acts in a damage-induced tumor suppressive manner, facilitating the apoptotic removal of irreparably
damaged cells. Dr. Yamini hopes that elucidating the role of NF-κB in the response to DNA methylation will not only enable
the design of new combination anti-glioma treatment strategies, but will also enable better understanding of the carcinogenic
side-effects of methylating chemotherapeutic agents.
Specific aims of the laboratory are to 1) examine the role of NF-κB in the response to DNA methylation damage; 2) investigate
and develop combination anti-glioma treatment regimens that incorporate TMZ and IR and NF-κB modulation; and 3) develop
a nanoparticle vector for direct intraparenchymal delivery of therapeutic agent to the brain.
After initially reporting that O6-MeG lesions block NF-κB DNA-binding, the laboratory has recently been investigating the
signaling for this pathway. Studies reveal that NF-κB functions as an effector mediating the MMR-directed apoptotic response.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
67
Additional Program Highlights*
Research
•• Crystal Structures of DNA/RNA Repair Enzymes AlkB and ABH2 Bound to
dsDNA. Escherichia coli AlkB and its human homologues ABH2 and ABH3 repair
DNA/RNA base lesions by using a direct oxidative dealkylation mechanism. Chuan
He, PhD, and his colleagues determined the first crystal structures of AlkB-dsDNA and
ABH2-dsDNA complexes, stabilized by a chemical cross-linking strategy. The study also
Drs. Richard Schilsky, Ezra Cohen, and Mark Ratain
reveals that AlkB uses an unprecedented base-flipping mechanism to access the damaged base: it squeezes together the two
bases flanking the flipped-out one to maintain the base stack, explaining the preference of AlkB for repairing ssDNA lesions
over dsDNA ones. In addition, the first crystal structure of ABH2 provides a structural basis for designing inhibitors of this
human DNA repair protein (Yang, et al., Nature 452:961-965, 2008).
•• Significance of MYCN amplification in international neuroblastoma staging system stage 1 and 2 neuroblastoma: a
report from the International Neuroblastoma Risk Group database. Treatment of patients with localized neuroblastoma
with unfavorable biologic features is controversial. To evaluate the outcome of children with low-stage MYCN-amplified
neuroblastoma and develop a rational treatment strategy, Susan Cohn, MD, and her colleagues analyzed data from the
International Neuroblastoma Risk Group (INRG) database containing 2,660 patients with low-stage (International
Neuroblastoma Staging System stages 1 and 2) neuroblastoma, known MYCN status, and available follow-up data. Results
indicated that patients with MYCN-amplified, low-stage tumors had less favorable event-free survival (EFS) and overall
survival (OS) than did patients with nonamplified tumors (53% +/- 8% and 72% +/- 7% v 90% +/- 1% and 98% +/- 1%,
respectively). The data also suggest that tumor cell ploidy could potentially be used to identify candidates for reductions in
therapy (Bagatell, et al., J Clin Oncol 27(3):365-70, 2008).
•• A chemical compound that stimulates the human homologous recombination protein RAD51. RAD51 and other
members of the RecA family of strand exchange proteins assemble on ssDNA to form presynaptic filaments, which
carry out the central steps of homologous recombination. A microplate-based assay was developed for high-throughput
measurement of hRAD51 filament formation on ssDNA. With this method, Philip Connell, MD, and colleagues including
Ralph Weichselbaum, MD, and Douglas Bishop, PhD, screened a 10,000 compound library, leading to the identification of a
small molecule (RS-1) that enhances hRAD51 binding in a wide range of biochemical conditions. Results indicate that RS-1
enhances the homologous recombination activity of hRAD51 by promoting the formation of active presynaptic filaments.
Cell survival assays in normal neonatal human dermal fibroblasts demonstrated that RS-1 promotes a dose-dependent
resistance to the cross-linking chemotherapeutic drug cisplatin. Given that RAD51-dependent recombination is a major
determinant of cisplatin resistance, RS-1 seems to stimulate homologous recombination repair proficiency, and has many
potential applications in both research and medical settings. (Jayathilaka, et al., Proc Natl Acad Sci USA 105(41):15848532008, 2008).
•• Comprehensive pharmacogenetic analysis of irinotecan neutropenia and pharmacokinetics. Federico Innocenti, MD,
PhD, along with collaborators including M. Eileen Dolan, PhD and Mark Ratain, MD, identified genetic variation, in addition
to the UGT1A1*28 polymorphism, that can explain the variability in irinotecan (CPT-11) pharmacokinetics and neutropenia
in cancer patients. Using clinical and genetic data from 85 advanced cancer patients treated with single-agent CPT-11 every
3 weeks at doses of 300 mg/m2 and 350 mg/m2, forty-two common variants were genotyped in 12 candidate genes of the CPT11 pathway. Based on this exploratory analysis, common polymorphisms in genes encoding for ABC and SLC transporters
may have a significant impact on the pharmacokinetics and pharmacodynamics of CPT-11 (Innocenti, et al., J Clin Oncol
27(16):2604-14, 2009).
•• The MET receptor tyrosine kinase is a potential novel therapeutic target for head and neck squamous cell carcinoma.
Recurrent/metastatic head and neck cancer remains a devastating disease with insufficient treatment options. Tanguy
Seiwert, MD, and collaborators including Everett Vokes, MD, and Ravi Salgia, MD, PhD (Cell Signaling and Gene Regulation
Program), investigated the MET receptor tyrosine kinase as a novel target for the treatment of head and neck squamous
68
UCCRC SCIEN T IFI C R EPO R T 20 0 9
* Due to space constraints, only a small representative sample of Program highlights is presented here.
cell carcinoma (HNSCC). An analysis of HNSCC tissue samples and cell lines indicated
that MET is functionally important with prominent overexpression, increased gene
copy number, and mutations. MET inhibition abrogated MET functions, including
proliferation, migration/motility, and angiogenesis, indicating that MET is a promising,
novel target for HNSCC and that combination approaches with cisplatin or EGFR
inhibitors should be explored. (Seiwert, et al., Cancer Res 69(7):3021-31, 2009).
Dr. Walter Stadler
•• Patient anxiety about prostate cancer independently predicts early initiation of androgen deprivation therapy for
biochemical cancer recurrence in older men: a prospective cohort study. Androgen deprivation therapy (ADT) is firstline therapy for patients with prostate cancer (PCA) who experience biochemical recurrence (BCR). However, the optimal
timing of ADT initiation is uncertain, and earlier ADT initiation can cause toxicities that lower quality of life (QOL).
Walter Stadler, MD, and his colleagues tested the hypothesis that elevated cancer anxiety leads to earlier ADT initiation
for BCR in older men. Results from a prospective cohort study reveal that cancer anxiety independently and robustly
predicts earlier ADT initiation in older men with BCR. For older patients with PCA, earlier ADT initiation may not
change life expectancy and can negatively impact QOL. PCA-specific anxiety is a potential target for a decision-making
Selected New Funding
•• Chun-Su Yuan, MD, PhD, is the primary investigator in a program project (P01), funded by the National Center for
Complementary and Alternative Medicine of the National Institutes of Health, to study two selected botanicals,
Clinical & Experimental
Therapeutics
intervention in this setting (Dale, et al., J Clin Oncol 27(10):1557-63, 2009).
unsteamed and steamed American ginseng and notoginseng, as agents against colorectal cancer. The overall goal of
the project is to characterize the anti-tumor activities and mechanisms of action of these two herbs and their active
constituents through collaborative efforts with Tong-Chuan He, MD, PhD and Wei Du, PhD (members of the Cell
Signaling and Gene Regulation Program).
•• Bakhtiar Yamini, MD, with funding from the National Institutes of Health, is investigating nanoparticles and and
nanocapsules for glioma targeting. In collaboration with researchers at Argonne National Lab and LNKChemsolutions,
Dr. Yamini will optimize the fabrication of PLGA/Fe3O4 nanoparticles that encapsulate therapeutic agent and can be
distributed by convection enhanced delivery (CED) through the brain. The hypothesis is that the nanoparticles can be
tracked using in vivo MR imaging during treatment.
•• M. Eileen Dolan, PhD is the recipient of an R21 grant from the National Cancer Institute to determine the underlying
cause for the inter-ethnic differences in sensitivity to chemotherapy. The overall goal is to develop an unbiased genomewide model to identify germline genetic variants, mRNA or miRNA expression including those in an underserved
population, that predict risk for adverse reactions and non-response to chemotherapy.
•• Everett Vokes, MD, received funding from the American Society of Clinical Oncology to study concomitant
chemoradiotherapy and translational gene therapy for intermediate stage malignancy of the lung, head, and neck. The
study aims to investigate the use of TNFerade as a radiation sensitizer. TNFerade consists of the TNF gene linked to a
radiation inducible promoter and an adenovirus for delivery to tumor cells. Dr. Vokes is also studying gene therapy with
an oncolytic herpes simplex virus analog and investigating the role of the cMet pathway in possible prevention strategies
and therapeutic interventions.
New Faculty Recruitments and UCCRC Members
Scott Eggener, MD specializes in the care of patients with urologic cancers, utilizing surgical, medical, and for select
patients, non-interventional approaches. His research focuses on improving surgical techniques, optimizing outcomes, and
offering clinical trials for patients with kidney, bladder, testicular, and prostate cancer.
Arieh Shalhav, MD is a pioneer in minimally-invasive laparoscopic urologic surgery. He has the most extensive experience in
the country in laparoscopic surgery of the kidney. Dr. Shalhav’s research has enhanced medical professionals’ understanding
of the effects of renal ischemia and ways to avoid its related damage during surgery.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
69
Selected Publications
* : Intraprogrammatic Collaboration
# : Interprogrammatic Collaboration
Bishop, Douglas PhD
* Jayathilaka K, Sheridan SD, Bold TD, Bochenska K, Logan HL, Weichselbaum
RR, Bishop DK, Connell PP. A chemical compound that stimulates the
human homologous recombination protein RAD51. Proc Natl Acad Sci U S A
105(41):15848-53, 2008.
Sheridan SD, Yu X, Roth R, Heuser JE, Sehorn MG, Sung P, Egelman EH, Bishop
DK. A comparative analysis of Dmc1 and Rad51 nucleoprotein filaments.
Nucleic Acids Res 36(12):4057-66, 2008.
# Longerich S, Orelli BJ, Martin RW, Bishop DK, Storb U. Brca1 in
immunoglobulin gene conversion and somatic hypermutation. DNA Repair
(Amst) 7(2):253-66, 2008.
Ferrari SR, Grubb J, Bishop DK. The Mei5-Sae3 protein complex mediates
Dmc1 activity in Saccharomyces cerevisiae. J Biol Chem 284(18):11766-70, 2009.
Blair, Elizabeth MD
* Salama JK, Stenson KM, List MA, Mell LK, Maccracken E, Cohen EE, Blair E,
Vokes EE, Haraf DJ. Characteristics associated with swallowing changes after
concurrent chemotherapy and radiotherapy in patients with head and neck
cancer. Arch Otolaryngol Head Neck Surg 134(10):1060-5, 2008.
* # Cohen EE, Baru J, Huo D, Haraf DJ, Crowley M, Witt ME, Blair EA,
Weichselbaum RR, Rosen F, Vokes EE, Stenson K. Efficacy and safety of treating
T4 oral cavity tumors with primary chemoradiotherapy. Head Neck 31(8):101321, 2009.
* Cohen EE, Davis DW, Karrison TG, Seiwert TY, Wong SJ, Nattam S, Kozloff
MF, Clark JI, Yan DH, Liu W, Pierce C, Dancey JE, Stenson K, Blair E, Dekker A,
Vokes EE. Erlotinib and bevacizumab in patients with recurrent or metastatic
squamous-cell carcinoma of the head and neck: a phase I/II study. Lancet
Oncol 10(3):247-57, 2009.
Cohen, Ezra MD
* Seiwert TY, Haraf DJ, Cohen EE, Stenson K, Witt ME, Dekker A,
Kocherginsky M, Weichselbaum RR, Chen HX, Vokes EE. Phase I study of
bevacizumab added to fluorouracil- and hydroxyurea-based concomitant
chemoradiotherapy for poor-prognosis head and neck cancer. J Clin Oncol. Apr
1, 26(10):1732-41, 2008.
* Seiwert TY, Cohen EE. Targeting angiogenesis in head and neck cancer.
Semin Oncol 35(3):274-85, 2008.
* # Cohen EE, Zhu H, Lingen MW, Martin LE, Kuo WL, Choi EA,
Kocherginsky M, Parker JS, Chung CH, Rosner MR. A feed-forward loop
involving protein kinase Calpha and microRNAs regulates tumor cell cycle.
Cancer Res 69(1):65-74, 2009.
* # Seiwert TY, Jagadeeswaran R, Faoro L, Janamanchi V, Nallasura V, El
Dinali M, Yala S, Kanteti R, Cohen EE, Lingen MW, Martin L, Krishnaswamy S,
Klein-Szanto A, Christensen JG, Vokes EE, Salgia R. The MET receptor tyrosine
kinase is a potential novel therapeutic target for head and neck squamous cell
carcinoma. Cancer Res 69(7):3021-31, 2009.
* Cohen EE, Davis DW, Karrison TG, Seiwert TY, Wong SJ, Nattam S, Kozloff
MF, Clark JI, Yan DH, Liu W, Pierce C, Dancey JE, Stenson K, Blair E, Dekker A,
Vokes EE. Erlotinib and bevacizumab in patients with recurrent or metastatic
squamous-cell carcinoma of the head and neck: a phase I/II study. Lancet
Oncol 10(3):247-57, 2009.
Cohn, Susan MD
Schneiderman J, London WB, Brodeur GM, Castleberry RP, Look AT, Cohn
SL. Clinical significance of MYCN amplification and ploidy in favorable-stage
neuroblastoma: a report from the Children’s Oncology Group. J Clin Oncol
26(6):913-8, 2008.
Fox E, Maris JM, Widemann BC, Goodspeed W, Goodwin A, Kromplewski
M, Fouts ME, Medina D, Cohn SL, Krivoshik A, Hagey AE, Adamson PC,
Balis FM. A phase I study of ABT-751, an orally bioavailable tubulin inhibitor,
administered daily for 21 days every 28 days in pediatric patients with solid
tumors. Clin Cancer Res 14(4):1111-5, 2008.
Hartford C, Volchenboum SL, Cohn SL. 3 + 3 not equal to (Rolling) 6. J Clin
Oncol 26(2):170-1, 2008.
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UCCRC SCIEN T IFI C R EPO R T 20 0 9
Cohn SL, Pearson AD, London WB, Monclair T, Ambros PF, Brodeur GM,
Faldum A, Hero B, Iehara T, Machin D, Mosseri V, Simon T, Garaventa A,
Castel V, Matthay KK. The International Neuroblastoma Risk Group (INRG)
classification system: an INRG Task Force report. J Clin Oncol 27(2):289-97,
2009.
Monclair T, Brodeur GM, Ambros PF, Brisse HJ, Cecchetto G, Holmes K,
Kaneko M, London WB, Matthay KK, Nuchtern JG, von Schweinitz D, Simon
T, Cohn SL, Pearson AD. The International Neuroblastoma Risk Group (INRG)
staging system: an INRG Task Force report. J Clin Oncol 27(2):298-303, 2009.
Bagatell R, Beck-Popovic M, London WB, Zhang Y, Pearson AD, Matthay
KK, Monclair T, Ambros PF, Cohn SL. Significance of MYCN amplification
in international neuroblastoma staging system stage 1 and 2 neuroblastoma:
a report from the International Neuroblastoma Risk Group database. J Clin
Oncol 27(3):365-70, 2009.
Connell, Philip MD
* Jayathilaka K, Sheridan SD, Bold TD, Bochenska K, Logan HL, Weichselbaum
RR, Bishop DK, Connell PP. A chemical compound that stimulates the
human homologous recombination protein RAD51. Proc Natl Acad Sci U S A
105(41):15848-53, 2008.
Connell PP, Hellman S. Advances in radiotherapy and implications for the next
century: a historical perspective. Cancer Res 69(2):383-92, 2009.
Dawson, Glyn PhD
Kilkus JP, Goswami R, Dawson SA, Testai FD, Berdyshev EV, Han X, Dawson
G. Differential regulation of sphingomyelin synthesis and catabolism in
oligodendrocytes and neurons. J Neurochem 106(4):1745-57, 2008.
Qin J, Goswami R, Dawson S, Dawson G. Expression of the receptor for
advanced glycation end products in oligodendrocytes in response to oxidative
stress. J Neurosci Res 86(11):2414-22, 2008.
Dolan, M. Eileen PhD
# Huang RS, Chen P, Wisel S, Duan S, Zhang W, Cook EH, Das S, Cox NJ,
Dolan ME. Population Specific GSTM1 Copy Number Variation. Hum Mol
Genet 18(2):366-72, 2009.
# Huang RS, Duan S, Kistner EO, Bleibel WK, Delaney SM, Fackenthal DL,
Das S, Dolan ME. Genetic variants contributing to daunorubicin-induced
cytotoxicity. Cancer Res 68(9):3161-8, 2008.
# Duan S, Huang RS, Zhang W, Bleibel WK, Roe CA, Clark TA, Chen
TX, Schweitzer AC, Blume JE, Cox NJ, Dolan ME. Genetic architecture of
transcript-level variation in humans. Am J Hum Genet 82(5):1101-13, 2008.
# Zhang W, Duan S, Kistner EO, Bleibel WK, Huang RS, Clark TA, Chen TX,
Schweitzer AC, Blume JE, Cox NJ, Dolan ME. Evaluation of genetic variation
contributing to differences in gene expression between populations. Am J Hum
Genet 82(3):631-40, 2008.
Shukla SJ, Duan S, Badner JA, Wu X, Dolan ME. Susceptibility loci involved
in cisplatin-induced cytotoxicity and apoptosis. Pharmacogenet Genomics
18(3):253-62, 2008.
Duan S, Huang RS, Zhang W, Mi S, Bleibel WK, Kistner EO, Cox NJ, Dolan
ME. Expression and alternative splicing of folate pathway genes in HapMap
lymphoblastoid cell lines. Pharmacogenomics 10(4):549-63, 2009.
Hartford CM, Duan S, Delaney SM, Mi S, Kistner EO, Lamba JK, Huang RS,
Dolan ME. Population-specific genetic variants important in susceptibility to
cytarabine arabinoside cytotoxicity. Blood 113(10):2145-53, 2009.
Eggener, Scott MD
Eggener SE, Yossepowitch O, Roehl KA, Loeb S, Yu X, Catalona WJ.
Relationship of prostate-specific antigen velocity to histologic findings in a
prostate cancer screening program. Urology 71(6):1016-9, 2008.
Eggener SE, Yossepowitch O, Kundu S, Motzer RJ, Russo P. Risk score and
metastasectomy independently impact prognosis of patients with recurrent
renal cell carcinoma. J Urol 180(3):873-8, discussion 878, 2008.
Yossepowitch O, Thompson RH, Leibovich BC, Eggener SE, Pettus JA,
Kwon ED, Herr HW, Blute ML, Russo P. Positive surgical margins at partial
nephrectomy: predictors and oncological outcomes. J Urol 179(6):2158-63,
2008.
Berglund RK, Masterson TA, Vora KC, Eggener SE, Eastham JA, Guillonneau
BD. Pathological upgrading and up staging with immediate repeat biopsy in
patients eligible for active surveillance. J Urol 180(5):1964-7, discussion 1967-8,
2008.
Eggener SE. The clinical diversity of postchemotherapy germ cell teratoma.
Cancer 115(6):1138-41, 2009.
Eggener SE, Vickers AJ, Serio AM, Donovan MJ, Khan FM, Bayer-Zubek V,
Verbel D, Cordon-Cardo C, Reuter VE, Bianco FJ Jr, Scardino PT. Comparison
of models to predict clinical failure after radical prostatectomy. Cancer
115(2):303-10, 2009.
Ferguson, Mark MD
* Choong NW, Vokes EE, Haraf DJ, Tothy PK, Ferguson MK, Kasza K, Rudin
CM, Hoffman PC, Krauss SA, Szeto L, Mauer AM. Phase I study of induction
chemotherapy and concomitant chemoradiotherapy with irinotecan,
carboplatin, and paclitaxel for stage III non-small cell lung cancer. J Thorac
Oncol 3(1):59-67, 2008.
* # Konda VJ, Ross AS, Ferguson MK, Hart JA, Lin S, Naylor K, Noffsinger A,
Posner MC, Dye C, Cislo B, Stearns L, Waxman I. Is the risk of concomitant
invasive esophageal cancer in high-grade dysplasia in Barrett’s esophagus
overestimated?. Clin Gastroenterol Hepatol 6(2):159-64, 2008.
Ferguson MK, Lehman AG, Bolliger CT, Brunelli A. The role of diffusing
capacity and exercise tests. Thorac Surg Clin 18(1):9-17, v, 2008.
Ferguson MK, Vigneswaran WT. Diffusing capacity predicts morbidity after
lung resection in patients without obstructive lung disease. Ann Thorac Surg
85(4):1158-64, discussion 1164-5, 2008.
Ferguson MK, Vigneswaran WT. Changes in patient presentation and
outcomes for major lung resection over three decades. Eur J Cardiothorac Surg
33(3):497-501, 2008.
* # Jagadeeswaran R, Surawska H, Krishnaswamy S, Janamanchi V, Mackinnon
AC, Seiwert TY, Loganathan S, Kanteti R, Reichman T, Nallasura V, Schwartz
S, Faoro L, Wang YC, Girard L, Tretiakova MS, Ahmed S, Zumba O, Soulii
L, Bindokas VP, Szeto LL, Gordon GJ, Bue. Paxillin is a target for somatic
mutations in lung cancer: implications for cell growth and invasion. Cancer Res
68(1):132-42, 2008.
Ferguson MK, Parma CM, Celauro AD, Vigneswaran WT. Quality of life and
mood in older patients after major lung resection. Ann Thorac Surg 87(4):100712, discussion 1012-3, 2009.
Fichera, Alessandro MD
* # Dougherty U, Sehdev A, Cerda S, Mustafi R, Little N, Yuan W,
Jagadeeswaran S, Chumsangsri A, Delgado J, Tretiakova M, Joseph L, Hart J,
Cohen EE, Aluri L, Fichera A, Bissonnette M. Epidermal growth factor receptor
controls flat dysplastic aberrant crypt foci development and colon cancer
progression in the rat azoxymethane model. Clin Cancer Res 14(8):2253-62,
2008.
# Delgado JS, Mustafi R, Yee J, Cerda S, Chumsangsri A, Dougherty U,
Lichtenstein L, Fichera A, Bissonnette M. Sorafenib Triggers Antiproliferative
and Pro-Apoptotic Signals in Human Esophageal Adenocarcinoma Cells. Dig
Dis Sci 53(12):3055-64, 2008.
# Khare S, Mustafi R, Cerda S, Yuan W, Jagadeeswaran S, Dougherty U,
Tretiakova M, Samarel A, Cohen G, Wang J, Moore C, Wali R, Holgren C,
Joseph L, Fichera A, Li YC, Bissonnette M. Ursodeoxycholic acid suppresses
Cox-2 expression in colon cancer: roles of Ras, p38, and CCAAT/enhancerbinding protein. Nutr Cancer 60(3):389-400, 2008.
# Park SM, Rajapaksha TW, Zhang M, Sattar HA, Fichera A, Ashton-Rickardt
PG, Peter ME. CD95 signaling deficient mice with a wild-type hematopoietic
system are prone to hepatic neoplasia. Apoptosis 13(1):41-51, 2008.
* Fichera A, Silvestri MT, Hurst RD, Rubin MA, Michelassi F. Laparoscopic
Restorative Proctocolectomy with Ileal Pouch Anal Anastomosis: A
Comparative Observational Study on Long-term Functional Results. J
Gastrointest Surg 13(3):526-32, 2009.
* Silvestri MT, Hurst RD, Rubin MA, Michelassi F, Fichera A. Chronic
inflammatory changes in the anal transition zone after stapled ileal pouch-anal
anastomosis: is mucosectomy a superior alternative?. Surgery 144(4):533-7,
discussion 537-9, 2008.
Fleming, Gini MD
* Rudin CM, Liu W, Desai A, Karrison T, Jiang X, Janisch L, Das S,
Ramirez J, Poonkuzhali B, Schuetz E, Fackenthal DL, Chen P, Armstrong
DK, Brahmer JR, Fleming GF, Vokes EE, Carducci MA, Ratain MJ.
Pharmacogenomic and pharmacokinetic determinants of erlotinib
toxicity. J Clin Oncol 26(7):1119-27, 2008.
# Polite BN, Cirrincione C, Fleming GF, Berry DA, Seidman A, Muss H,
Norton L, Shapiro C, Bakri K, Marcom K, Lake D, Schwartz JH, Hudis
C, Winer EP. Racial differences in clinical outcomes from metastatic
breast cancer: a pooled analysis of CALGB 9342 and 9840--Cancer and
Leukemia Group B. J Clin Oncol 26(16):2659-65, 2008.
* # Nimeiri HS, Oza AM, Morgan RJ, Friberg G, Kasza K, Faoro L,
Salgia R, Stadler WM, Vokes EE, Fleming GF. Efficacy and safety of
bevacizumab plus erlotinib for patients with recurrent ovarian, primary
peritoneal, and fallopian tube cancer: a trial of the Chicago, PMH, and
California Phase II Consortia. Gynecol Oncol 110(1):49-55, 2008.
Garcia AA, Hirte H, Fleming G, Yang D, Tsao-Wei DD, Roman L,
Groshen S, Swenson S, Markland F, Gandara D, Scudder S, Morgan R,
Chen H, Lenz HJ, Oza AM. Phase II clinical trial of bevacizumab and
low-dose metronomic oral cyclophosphamide in recurrent ovarian
cancer: a trial of the California, Chicago, and Princess Margaret Hospital
phase II consortia. J Clin Oncol 26(1):76-82, 2008.
# Grushko TA, Filiaci VL, Mundt AJ, Ridderstrale K, Olopade OI,
Fleming GF. An exploratory analysis of HER-2 amplification and
overexpression in advanced endometrial carcinoma: a Gynecologic
Oncology Group study. Gynecol Oncol 108(1):3-9, 2008.
* # Melhem A, Yamada SD, Fleming GF, Delgado B, Brickley DR, Wu
W, Kocherginsky M, Conzen SD. Administration of Glucocorticoids to
Ovarian Cancer Patients Is Associated with Expression of the Antiapoptotic Genes SGK1 and MKP1/DUSP1 in Ovarian Tissues. Clin
Cancer Res 15(9):3196-204, 2009.
Clinical & Experimental
Therapeutics
Eggener SE, Mueller A, Berglund RK, Ayyathurai R, Soloway C, Soloway MS,
Abouassaly R, Klein EA, Jones SJ, Zappavigna C, Goldenberg L, Scardino
PT, Eastham JA, Guillonneau B. A multi-institutional evaluation of active
surveillance for low risk prostate cancer. J Urol 181(4):1635-41, discussion 1641,
2009.
Schultheis AM, Lurje G, Rhodes KE, Zhang W, Yang D, Garcia AA,
Morgan R, Gandara D, Scudder S, Oza A, Hirte H, Fleming G, Roman
L, Lenz HJ. Polymorphisms and clinical outcome in recurrent ovarian
cancer treated with cyclophosphamide and bevacizumab. Clin Cancer
Res 14(22):7554-63, 2008.
Haraf, Daniel MD
* Cohn AB, Lang PO, Agarwal JP, Peng SL, Alizadeh K, Stenson KM,
Haraf DJ, Cohen EE, Vokes EE, Gottlieb LJ. Free-flap reconstruction in
the doubly irradiated patient population. Plast Reconstr Surg 122(1):12532, 2008.
* Knab BR, Salama JK, Solanki A, Stenson KM, Cohen EE, Witt ME,
Haraf DJ, Vokes EE. Functional organ preservation with definitive
chemoradiotherapy for T4 laryngeal squamous cell carcinoma. Ann
Oncol 19(9):1650-4, 2008.
* Seiwert TY, Haraf DJ, Cohen EE, Stenson K, Witt ME, Dekker A,
Kocherginsky M, Weichselbaum RR, Chen HX, Vokes EE. Phase I study of
bevacizumab added to fluorouracil- and hydroxyurea-based concomitant
chemoradiotherapy for poor-prognosis head and neck cancer. J Clin
Oncol 26(10):1732-41, 2008.
* # Choong NW, Mauer AM, Haraf DJ, Lester E, Hoffman PC, Kozloff
M, Lin S, Dancey JE, Szeto L, Grushko T, Olopade OI, Salgia R, Vokes
EE. Phase I trial of erlotinib-based multimodality therapy for inoperable
stage III non-small cell lung cancer. J Thorac Oncol 3(9):1003-11, 2008.
* Choong NW, Vokes EE, Haraf DJ, Tothy PK, Ferguson MK, Kasza K,
Rudin CM, Hoffman PC, Krauss SA, Szeto L, Mauer AM. Phase I study
of induction chemotherapy and concomitant chemoradiotherapy with
irinotecan, carboplatin, and paclitaxel for stage III non-small cell lung
cancer. J Thorac Oncol 3(1):59-67, 2008.
* # Salama JK, Chmura SJ, Mehta N, Yenice KM, Stadler WM, Vokes EE,
Haraf DJ, Hellman S, Weichselbaum RR. An initial report of a radiation
dose-escalation trial in patients with one to five sites of metastatic
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* Roach PB, Roggin KK, Selkov E Jr, Posner MC, Silverstein JC. Use of a novel,
web-based educational platform facilitates intraoperative training in a surgical
oncology fellowship program. Ann Surg Oncol 16(5):1100-7, 2009.
Rubin, Charles MD
# Seibel NL, Steinherz PG, Sather HN, Nachman JB, Delaat C, Ettinger LJ,
Freyer DR, Mattano LA Jr, Hastings CA, Rubin CM, Bertolone K, Franklin
JL, Heerema NA, Mitchell TL, Pyesmany AF, La MK, Edens C, Gaynon PS.
Early postinduction intensification therapy improves survival for children and
adolescents with high-risk acute lymphoblastic leukemia: a report from the
Children’s Oncology Group. Blood 111(5):2548-55, 2008.
Salama, Joseph MD
* Salama JK, Stenson KM, List MA, Mell LK, Maccracken E, Cohen EE, Blair E,
Vokes EE, Haraf DJ. Characteristics associated with swallowing changes after
concurrent chemotherapy and radiotherapy in patients with head and neck
cancer. Arch Otolaryngol Head Neck Surg 134(10):1060-5, 2008.
* Salama JK, Stenson KM, Kistner EO, Mittal BB, Argiris A, Witt ME, Rosen
F, Brockstein BE, Cohen EE, Haraf DJ, Vokes EE. Induction chemotherapy and
concurrent chemoradiotherapy for locoregionally advanced head and neck
cancer: a multi-institutional phase II trial investigating three radiotherapy dose
levels. Ann Oncol 19(10):1787-94, 2008.
* Knab BR, Salama JK, Solanki A, Stenson KM, Cohen EE, Witt ME, Haraf DJ,
Vokes EE. Functional organ preservation with definitive chemoradiotherapy for
T4 laryngeal squamous cell carcinoma. Ann Oncol 19(9):1650-4, 2008.
* # Salama JK, Chmura SJ, Mehta N, Yenice KM, Stadler WM, Vokes EE,
Haraf DJ, Hellman S, Weichselbaum RR. An initial report of a radiation doseescalation trial in patients with one to five sites of metastatic disease. Clin
Cancer Res 14(16):5255-9, 2008.
* Macdermed DM, Weichselbaum RR, Salama JK. A rationale for the targeted
treatment of oligometastases with radiotherapy. J Surg Oncol 98(3):202-6, 2008.
# Cao J, Roeske JC, Chmura SJ, Salama JK, Shoushtari AN, Boyer AL, Martel
MK. Calculation and prediction of the effect of respiratory motion on whole
breast radiation therapy dose distributions. Med Dosim 34(2):126-32, 2009.
Schilsky, Richard MD
Schilsky RL. How not to treat cancer. Lancet Oncol 9(6):504-5, 2008.
Zon R, Meropol NJ, Catalano RB, Schilsky RL. American Society of Clinical
Oncology Statement on minimum standards and exemplary attributes of
clinical trial sites. J Clin Oncol 26(15):2562-7, 2008.
* Strauss GM, Herndon JE 2nd, Maddaus MA, Johnstone DW, Johnson EA,
Harpole DH, Gillenwater HH, Watson DM, Sugarbaker DJ, Schilsky RL,
Vokes EE, Green MR. Adjuvant Paclitaxel Plus Carboplatin Compared With
Observation in Stage IB Non-Small-Cell Lung Cancer: CALGB 9633 With the
Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North
Central Cancer Treatment Group Study Groups. J Clin Oncol 26(31):5043-51,
2008.
Lamont EB, Herndon JE 2nd, Weeks JC, Henderson IC, Lilenbaum R, Schilsky
RL, Christakis NA. Measuring clinically significant chemotherapy-related
toxicities using Medicare claims from Cancer and Leukemia Group B (CALGB)
trial participants. Med Care 46(3):303-8, 2008.
* Daugherty CK, Ratain MJ, Emanuel EJ, Farrell AT, Schilsky RL. Ethical,
scientific, and regulatory perspectives regarding the use of placebos in cancer
clinical trials. J Clin Oncol 26(8):1371-8, 2008.
* Posner MC, Niedzwiecki D, Venook AP, Hollis DR, Kindler HL, Martin
EW, Schilsky RL, Goldberg RM. A phase II prospective multi-institutional
trial of adjuvant active specific immunotherapy following curative resection
of colorectal cancer hepatic metastases: cancer and leukemia group B study
89903. Ann Surg Oncol 15(1):158-64, 2008.
Schilsky RL, Gordon G, Gilmer TM, Courtneidge SA, Matrisian LM, Grad
O, Nelson WG. The Translational Research Working Group developmental
pathway for anticancer agents (drugs or biologics). Clin Cancer Res 14(18):568591, 2008.
Shalhav, Arieh MD
* Thong AE, Shikanov S, Katz MH, Gofrit ON, Eggener S, Zagaja GP,
Shalhav AL, Zorn KC. A Single Microfocus (5% or Less) of Gleason
6 Prostate Cancer at Biopsy-Can We Predict Adverse Pathological
Outcomes?. J Urol 180(6):2436-40, 2008.
* Gofrit ON, Zorn KC, Silvestre J, Shalhav AL, Zagaja GP, Msezane LP,
Steinberg GD. The predictive value of multi-targeted fluorescent in-situ
hybridization in patients with history of bladder cancer. Urol Oncol
26(3):246-9, 2008.
* Gofrit ON, Stadler WM, Zorn KC, Lin S, Silvestre J, Shalhav AL,
Zagaja GP, Steinberg GD. Adjuvant chemotherapy in lymph node positive
bladder cancer. Urol Oncol 27(2):160-4, 2009.
* Gofrit ON, Zorn KC, Steinberg GD, Zagaja GP, Shalhav AL. The Will
Rogers phenomenon in urological oncology. J Urol 179(1):28-33, 2008.
Shalhav AL, Shikanov SA. Does radiofrequency ablation preserve longterm renal function in patients with small renal masses?. Nat Clin Pract
Urol 5(8):420-1, 2008.
* Zorn KC, Bernstein AJ, Gofrit ON, Shikanov SA, Mikhail AA, Song
DH, Zagaja GP, Shalhav AL. Long-term functional and oncological
outcomes of patients undergoing sural nerve interposition grafting
during robot-assisted laparoscopic radical prostatectomy. J Endourol
22(5):1005-12, 2008.
* Wiltz AL, Shikanov S, Eggener SE, Katz MH, Thong AE, Steinberg
GD, Shalhav AL, Zagaja GP, Zorn KC. Robotic Radical Prostatectomy in
Overweight and Obese Patients: Oncological and Validated-Functional
Outcomes. Urology 73(2):316-22, 2009.
Siegler, Mark MD
Torke AM, Simmerling M, Siegler M, Kaya D, Alexander GC. Rethinking
the ethical framework for surrogate decision making: a qualitative study
of physicians. J Clin Ethics 19(2):110-9, 2008.
Clinical & Experimental
Therapeutics
* # Mell LK, Schomas DA, Salama JK, Devisetty K, Aydogan B, Miller RC, Jani
AB, Kindler HL, Mundt AJ, Roeske JC, Chmura SJ. Association between bone
marrow dosimetric parameters and acute hematologic toxicity in anal cancer
patients treated with concurrent chemotherapy and intensity-modulated
radiotherapy. Int J Radiat Oncol Biol Phys 70(5):1431-7, 2008.
Cooley DA, Fung JJ, Young JB, Starzl TE, Siegler M, Chen PW. Transplant
innovation and ethical challenges: what have we learned? A collection
of perspectives and panel discussion. Cleve Clin J Med 75 Suppl 6:S24-9,
discussion S30-2, 2008.
Dugdale LS, Siegler M, Rubin DT. Medical professionalism and the
doctor-patient relationship. Perspect Biol Med 51(4):547-53, 2008.
Song, David MD
Seiwert, Tanguy MD
* Seiwert TY, Haraf DJ, Cohen EE, Stenson K, Witt ME, Dekker A,
Kocherginsky M, Weichselbaum RR, Chen HX, Vokes EE. Phase I study of
bevacizumab added to fluorouracil- and hydroxyurea-based concomitant
chemoradiotherapy for poor-prognosis head and neck cancer. J Clin Oncol
26(10):1732-41, 2008.
* # Jagadeeswaran R, Surawska H, Krishnaswamy S, Janamanchi V, Mackinnon
AC, Seiwert TY, Loganathan S, Kanteti R, Reichman T, Nallasura V, Schwartz
S, Faoro L, Wang YC, Girard L, Tretiakova MS, Ahmed S, Zumba O, Soulii
L, Bindokas VP, Szeto LL, Gordon GJ, Bue. Paxillin is a target for somatic
mutations in lung cancer: implications for cell growth and invasion. Cancer Res
68(1):132-42, 2008.
* Seiwert TY, Cohen EE. Targeting angiogenesis in head and neck cancer.
Semin Oncol 35(3):274-85, 2008.
* # Ma PC, Tretiakova MS, MacKinnon AC, Ramnath N, Johnson C, Dietrich
S, Seiwert T, Christensen JG, Jagadeeswaran R, Krausz T, Vokes EE, Husain AN,
Salgia R. Expression and mutational analysis of MET in human solid cancers.
Genes Chromosomes Cancer 47(12):1025-37, 2008.
* # Faoro L, Loganathan S, Westerhoff M, Modi R, Husain AN, Tretiakova M,
Seiwert T, Kindler HL, Vokes EE, Salgia R. Protein kinase C beta in malignant
pleural mesothelioma. Anticancer Drugs 19(9):841-8, 2008.
* # Seiwert TY, Jagadeeswaran R, Faoro L, Janamanchi V, Nallasura V, El
Dinali M, Yala S, Kanteti R, Cohen EE, Lingen MW, Martin L, Krishnaswamy S,
Klein-Szanto A, Christensen JG, Vokes EE, Salgia R. The MET receptor tyrosine
kinase is a potential novel therapeutic target for head and neck squamous cell
carcinoma. Cancer Res 69(7):3021-31, 2009.
* Cohen EE, Davis DW, Karrison TG, Seiwert TY, Wong SJ, Nattam S, Kozloff
MF, Clark JI, Yan DH, Liu W, Pierce C, Dancey JE, Stenson K, Blair E, Dekker A,
Vokes EE. Erlotinib and bevacizumab in patients with recurrent or metastatic
squamous-cell carcinoma of the head and neck: a phase I/II study. Lancet
Oncol 10(3):247-57, 2009.
* Zorn KC, Bernstein AJ, Gofrit ON, Shikanov SA, Mikhail AA, Song
DH, Zagaja GP, Shalhav AL. Long-term functional and oncological
outcomes of patients undergoing sural nerve interposition grafting
during robot-assisted laparoscopic radical prostatectomy. J Endourol
22(5):1005-12, 2008.
Wu LC, Iteld L, Song DH. Supercharging the transverse rectus abdominis
musculocutaneous flap: breast reconstruction for the overweight and
obese population. Ann Plast Surg 60(6):609-13, 2008.
Reynolds WS, Gottlieb LJ, Lucioni A, Rapp DE, Song DH, Bales
GT. Vesicovaginal fistula repair with rectus abdominus myofascial
interposition flap. Urology 71(6):1119-23, 2008.
Stadler, Walter MD
* # Hahn OM, Yang C, Medved M, Karczmar G, Kistner E, Karrison
T, Manchen E, Mitchell M, Ratain MJ, Stadler WM. Dynamic contrastenhanced magnetic resonance imaging pharmacodynamic biomarker
study of sorafenib in metastatic renal carcinoma. J Clin Oncol
26(28):4572-8, 2008.
* # Nimeiri HS, Oza AM, Morgan RJ, Friberg G, Kasza K, Faoro L,
Salgia R, Stadler WM, Vokes EE, Fleming GF. Efficacy and safety of
bevacizumab plus erlotinib for patients with recurrent ovarian, primary
peritoneal, and fallopian tube cancer: a trial of the Chicago, PMH, and
California Phase II Consortia. Gynecol Oncol 110(1):49-55, 2008.
* # Salama JK, Chmura SJ, Mehta N, Yenice KM, Stadler WM, Vokes EE,
Haraf DJ, Hellman S, Weichselbaum RR. An initial report of a radiation
dose-escalation trial in patients with one to five sites of metastatic
disease. Clin Cancer Res 14(16):5255-9, 2008.
* # Posadas EM, Al-Ahmadie H, Robinson VL, Jagadeeswaran R, Otto
K, Kasza KE, Tretiakov M, Siddiqui J, Pienta KJ, Stadler WM, RinkerSchaeffer C, Salgia R. FYN is overexpressed in human prostate cancer.
BJU Int 103(2):171-7, 2009.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
75
# Yang C, Karczmar GS, Medved M, Oto A, Zamora M, Stadler WM.
Reproducibility assessment of a multiple reference tissue method for
quantitative dynamic contrast enhanced-MRI analysis. Magn Reson Med
61(4):851-9, 2009.
# Dale W, Hemmerich J, Bylow K, Mohile S, Mullaney M, Stadler WM. Patient
anxiety about prostate cancer independently predicts early initiation of
androgen deprivation therapy for biochemical cancer recurrence in older men:
a prospective cohort study. J Clin Oncol 27(10):1557-63, 2009.
* Bylow KA, Atkins MB, Posadas EM, Stadler WM, McDermott DF. Phase
II trial of carboplatin and paclitaxel in papillary renal cell carcinoma. Clin
Genitourin Cancer 7(1):39-42, 2009.
Steinberg, Gary MD
Msezane L, Reynolds WS, Mhapsekar R, Gerber G, Steinberg G. Open surgical
repair of ureteral strictures and fistulas following radical cystectomy and
urinary diversion. J Urol 179(4):1428-31, 2008.
* Gofrit ON, Zorn KC, Silvestre J, Shalhav AL, Zagaja GP, Msezane LP,
Steinberg GD. The predictive value of multi-targeted fluorescent in-situ
hybridization in patients with history of bladder cancer. Urol Oncol 26(3):2469, 2008.
* Gofrit ON, Stadler WM, Zorn KC, Lin S, Silvestre J, Shalhav AL, Zagaja GP,
Steinberg GD. Adjuvant chemotherapy in lymph node positive bladder cancer.
Urol Oncol 27(2):160-4, 2009.
* Gofrit ON, Zorn KC, Steinberg GD, Zagaja GP, Shalhav AL. The Will Rogers
phenomenon in urological oncology. J Urol 179(1):28-33. Epub, 2007 Nov 13,
2008.
Katz MH, Steinberg GD. Sex and race in bladder cancer: what we have learned
and future directions. Cancer 115(1):10-2, 2009.
deVere White RW, Katz MH, Steinberg GD. The case for neoadjuvant
chemotherapy and cystectomy for muscle invasive bladder cancer. J Urol
181(5):1994-7, 2009.
* Gofrit ON, Orvieto MA, Zorn KC, Steinberg GD, Zagaja GP, Shalhav AL.
Serum creatinine can be used as a surrogate for glomerular filtration rate in
single renal unit models. Can J Urol 16(1):4452-7, discussion 4457, 2009.
Stenson, Kerstin MD
* Salama JK, Stenson KM, List MA, Mell LK, Maccracken E, Cohen EE, Blair E,
Vokes EE, Haraf DJ. Characteristics associated with swallowing changes after
concurrent chemotherapy and radiotherapy in patients with head and neck
cancer. Arch Otolaryngol Head Neck Surg 134(10):1060-5, 2008.
* Cohn AB, Lang PO, Agarwal JP, Peng SL, Alizadeh K, Stenson KM, Haraf
DJ, Cohen EE, Vokes EE, Gottlieb LJ. Free-flap reconstruction in the doubly
irradiated patient population. Plast Reconstr Surg 122(1):125-32, 2008.
* Salama JK, Stenson KM, Kistner EO, Mittal BB, Argiris A, Witt ME, Rosen
F, Brockstein BE, Cohen EE, Haraf DJ, Vokes EE. Induction chemotherapy and
concurrent chemoradiotherapy for locoregionally advanced head and neck
cancer: a multi-institutional phase II trial investigating three radiotherapy dose
levels. Ann Oncol 19(10):1787-94, 2008.
76
Vokes, Everett MD
* Rudin CM, Liu W, Desai A, Karrison T, Jiang X, Janisch L, Das S, Ramirez J,
Poonkuzhali B, Schuetz E, Fackenthal DL, Chen P, Armstrong DK, Brahmer
JR, Fleming GF, Vokes EE, Carducci MA, Ratain MJ. Pharmacogenomic and
pharmacokinetic determinants of erlotinib toxicity. J Clin Oncol 26(7):1119-27,
2008.
* Seiwert TY, Haraf DJ, Cohen EE, Stenson K, Witt ME, Dekker A,
Kocherginsky M, Weichselbaum RR, Chen HX, Vokes EE. Phase I study of
bevacizumab added to fluorouracil- and hydroxyurea-based concomitant
chemoradiotherapy for poor-prognosis head and neck cancer. J Clin Oncol
26(10):1732-41, 2008.
* Choong NW, Vokes EE, Haraf DJ, Tothy PK, Ferguson MK, Kasza K, Rudin
CM, Hoffman PC, Krauss SA, Szeto L, Mauer AM. Phase I study of induction
chemotherapy and concomitant chemoradiotherapy with irinotecan,
carboplatin, and paclitaxel for stage III non-small cell lung cancer. J Thorac
Oncol 3(1):59-67, 2008.
* # Salama JK, Chmura SJ, Mehta N, Yenice KM, Stadler WM, Vokes EE,
Haraf DJ, Hellman S, Weichselbaum RR. An initial report of a radiation doseescalation trial in patients with one to five sites of metastatic disease. Clin
Cancer Res 14(16):5255-9, 2008.
* # Jagadeeswaran R, Surawska H, Krishnaswamy S, Janamanchi V, Mackinnon
AC, Seiwert TY, Loganathan S, Kanteti R, Reichman T, Nallasura V, Schwartz
S, Faoro L, Wang YC, Girard L, Tretiakova MS, Ahmed S, Zumba O, Soulii
L, Bindokas VP, Szeto LL, Gordon GJ, Bue. Paxillin is a target for somatic
mutations in lung cancer: implications for cell growth and invasion. Cancer Res
68(1):132-42, 2008.
* # Ma PC, Tretiakova MS, MacKinnon AC, Ramnath N, Johnson C, Dietrich
S, Seiwert T, Christensen JG, Jagadeeswaran R, Krausz T, Vokes EE, Husain AN,
Salgia R. Expression and mutational analysis of MET in human solid cancers.
Genes Chromosomes Cancer 47(12):1025-37, 2008.
* # Seiwert TY, Jagadeeswaran R, Faoro L, Janamanchi V, Nallasura V, El
Dinali M, Yala S, Kanteti R, Cohen EE, Lingen MW, Martin L, Krishnaswamy S,
Klein-Szanto A, Christensen JG, Vokes EE, Salgia R. The MET receptor tyrosine
kinase is a potential novel therapeutic target for head and neck squamous cell
carcinoma. Cancer Res 69(7):3021-31, 2009.
* Cohen EE, Davis DW, Karrison TG, Seiwert TY, Wong SJ, Nattam S, Kozloff
MF, Clark JI, Yan DH, Liu W, Pierce C, Dancey JE, Stenson K, Blair E, Dekker A,
Vokes EE. Erlotinib and bevacizumab in patients with recurrent or metastatic
squamous-cell carcinoma of the head and neck: a phase I/II study. Lancet
Oncol 10(3):247-57, 2009.
Weichselbaum, Ralph MD
* Jayathilaka K, Sheridan SD, Bold TD, Bochenska K, Logan HL, Weichselbaum
RR, Bishop DK, Connell PP. A chemical compound that stimulates the
human homologous recombination protein RAD51. Proc Natl Acad Sci U S A
105(41):15848-53, 2008.
* # Salama JK, Chmura SJ, Mehta N, Yenice KM, Stadler WM, Vokes EE,
Haraf DJ, Hellman S, Weichselbaum RR. An initial report of a radiation doseescalation trial in patients with one to five sites of metastatic disease. Clin
Cancer Res 14(16):5255-9, 2008.
* Knab BR, Salama JK, Solanki A, Stenson KM, Cohen EE, Witt ME, Haraf DJ,
Vokes EE. Functional organ preservation with definitive chemoradiotherapy for
T4 laryngeal squamous cell carcinoma. Ann Oncol 19(9):1650-4, 2008.
* # Bickenbach KA, Veerapong J, Shao MY, Mauceri HJ, Posner MC, Kron SJ,
Weichselbaum RR. Resveratrol is an effective inducer of CArG-driven TNFalpha gene therapy. Cancer Gene Ther 15(3):133-9, 2008.
* Seiwert TY, Haraf DJ, Cohen EE, Stenson K, Witt ME, Dekker A,
Kocherginsky M, Weichselbaum RR, Chen HX, Vokes EE. Phase I study of
bevacizumab added to fluorouracil- and hydroxyurea-based concomitant
chemoradiotherapy for poor-prognosis head and neck cancer. J Clin Oncol
26(10):1732-41, 2008.
# Weichselbaum RR, Ishwaran H, Yoon T, Nuyten DS, Baker SW, Khodarev
N, Su AW, Shaikh AY, Roach P, Kreike B, Roizman B, Bergh J, Pawitan Y, van
de Vijver MJ, Minn AJ. An interferon-related gene signature for DNA damage
resistance is a predictive marker for chemotherapy and radiation for breast
cancer. Proc Natl Acad Sci U S A 105(47):18490-5, 2008.
* # Cohen EE, Baru J, Huo D, Haraf DJ, Crowley M, Witt ME, Blair EA,
Weichselbaum RR, Rosen F, Vokes EE, Stenson K. Efficacy and safety of treating
T4 oral cavity tumors with primary chemoradiotherapy. Head Neck 31(8):101321, 2009.
* # Cohen EE, Baru J, Huo D, Haraf DJ, Crowley M, Witt ME, Blair EA,
Weichselbaum RR, Rosen F, Vokes EE, Stenson K. Efficacy and safety of treating
T4 oral cavity tumors with primary chemoradiotherapy. Head Neck 31(8):101321, 2009.
* Cohen EE, Davis DW, Karrison TG, Seiwert TY, Wong SJ, Nattam S, Kozloff
MF, Clark JI, Yan DH, Liu W, Pierce C, Dancey JE, Stenson K, Blair E, Dekker A,
Vokes EE. Erlotinib and bevacizumab in patients with recurrent or metastatic
squamous-cell carcinoma of the head and neck: a phase I/II study. Lancet
Oncol 10(3):247-57, 2009.
# Liauw SL, Fricano J, Correa D, Weichselbaum RR, Jani AB. Dose-escalated
radiation therapy for intermediate-risk prostate cancer: patient selection
for androgen deprivation therapy using percentage of positive cores. Cancer
115(8):1784-90, 2009.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
# Lee Y, Auh SL, Wang Y, Burnette B, Wang Y, Meng Y, Beckett M, Sharma
R, Chin R, Tu T, Weichselbaum RR, Fu YX. Therapeutic effects of ablative
radiation on local tumor require CD8+ T cells: changing strategies for cancer
treatment. Blood 114(3):589-95, 2009.
Yamada, Seiko Diane MD
Yuan, Chun-Su MD, PhD
# Onujiogu N, Lengyel E, Yamada SD. Reversible posterior
leukoencephalopathy syndrome following intravenous paclitaxel and
intraperitoneal cisplatin chemotherapy for fallopian tube cancer. Gynecol
Oncol 111(3):537-9, 2008.
# Luo X, Wang CZ, Chen J, Song WX, Luo J, Tang N, He BC, Kang Q,
Wang Y, Du W, He TC, Yuan CS. Characterization of gene expression
regulated by American ginseng and ginsenoside Rg3 in human colorectal
cancer cells. Int J Oncol 32(5):975-83, 2008.
# Sawada K, Mitra AK, Radjabi AR, Bhaskar V, Kistner EO, Tretiakova M,
Jagadeeswaran S, Montag A, Becker A, Kenny HA, Peter ME, Ramakrishnan V,
Yamada SD, Lengyel E. Loss of E-cadherin promotes ovarian cancer metastasis
via alpha 5-integrin, which is a therapeutic target. Cancer Res 68(7):2329-39,
2008.
# Wang CZ, Aung HH, Zhang B, Sun S, Li XL, He H, Xie JT, He TC,
Du W, Yuan CS. Chemopreventive effects of heat-processed Panax
quinquefolius root on human breast cancer cells. Anticancer Res
28(5A):2545-51, 2008.
# Taylor JL, Szmulewitz RZ, Lotan T, Hickson J, Griend DV, Yamada SD,
Macleod K, Rinker-Schaeffer CW. New paradigms for the function of JNKK1/
MKK4 in controlling growth of disseminated cancer cells. Cancer Lett
272(1):12-22, 2008.
# Taylor J, Hickson J, Lotan T, Yamada DS, Rinker-Schaeffer C. Using
metastasis suppressor proteins to dissect interactions among cancer cells and
their microenvironment. Cancer Metastasis Rev 27(1):67-73.
* # Melhem A, Yamada SD, Fleming GF, Delgado B, Brickley DR, Wu W,
Kocherginsky M, Conzen SD. Administration of Glucocorticoids to Ovarian
Cancer Patients Is Associated with Expression of the Anti-apoptotic Genes
SGK1 and MKP1/DUSP1 in Ovarian Tissues. Clin Cancer Res 15(9):3196-204,
2009.
# Wang CZ, Xie JT, Fishbein A, Aung HH, He H, Mehendale SR, He TC,
Du W, Yuan CS. Antiproliferative effects of different plant parts of Panax
notoginseng on SW480 human colorectal cancer cells. Phytother Res
23(1):6-13, 2009.
Li XL, Wang CZ, Mehendale SR, Sun S, Wang Q, Yuan CS. Panaxadiol,
a purified ginseng component, enhances the anti-cancer effects of
5-fluorouracil in human colorectal cancer cells. Cancer Chemother
Pharmacol, 2009.
Wang CZ, Ni M, Sun S, Li XL, He H, Mehendale SR, Yuan CS. Detection
of adulteration of notoginseng root extract with other panax species by
quantitative HPLC coupled with PCA. J Agric Food Chem 57(6):2363-7,
2009.
Wang CZ, Li XL, Wang QF, Mehendale SR, Fishbein AB, Han AH, Sun S,
Yuan CS. The mitochondrial pathway is involved in American ginsenginduced apoptosis of SW-480 colon cancer cells. Oncol Rep 21(3):577-84,
2009.
Yamini, Bakhtiar MD
# Rosen DS, Smith S, Gurbuxani S, Yamini B. Extranodal hairy cell leukemia
presenting in the lumbar spine. J Neurosurg Spine 9(4):374-6, 2008.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
Clinical & Experimental
Therapeutics
# Lotan T, Hickson J, Souris J, Huo D, Taylor J, Li T, Otto K, Yamada SD,
Macleod K, Rinker-Schaeffer CW. c-Jun NH2-terminal kinase activating kinase
1/mitogen-activated protein kinase kinase 4-mediated inhibition of SKOV3ip.1
ovarian cancer metastasis involves growth arrest and p21 up-regulation. Cancer
Res 68(7):2166-75, 2008.
77
Selected Major Grants and Awards
The Clinical and Experimetnal Therapeutics Program has a funding base of $22,558,038 in annual total costs (current as of July
2009). This sum includes $6,717,757 in NCI funding and $6,586,262 in other NIH funding. Due to space constraints, only new
awards presented since January 1, 2008 with funding of $100,000 or more in annual total costs are listed here.
Investigator
78
Title
Start Date
End
Date
Annual
Total Cost
Class
9/30/2008
7/31/2013
$1,200,000
P01
National Center for
Complementary and
Alternative Medicine
Funding Agency
Yuan, Chun-Su
Center for Herbal Research on
Colorectal Cancer
Weichselbaum,
Ralph
Ludwig for Cancer Research
Program
1/1/2008
12/31/2010
$533,333
N/A
Ludwig Fund for Cancer
Research, Virginia and
D.K.
Ratain, Mark
A Randomized Discontinuation
Study of Brivanib Alanate (BMS582664) vs. Placebo In Subjects
with Advanced Tumors Focusing
on Baseline Expression of FGF-2
Protein
4/8/2008
1/31/2011
$499,440
N/A
Bristol-Myers Squibb
Company
Maitland, Michael
Phase Ib Study to Evaluate the
Safety of Combining IGF-1R
Antagonist R1507 with Multiple
Standard Chemotherapy Drug
Treatments in Patients with
Advanced Malignancies
3/9/2009
11/30/2010
$309,430
N/A
Hoffmann-Laroche
Vokes, Everett
Randomized Phase II Trial
of Taxotere, Cisplatin, and
Hypofractionated Radiotherapy
vs Cisplatin and Taxotere for
Limited Volume Stage IV Nonsmall Cell Lung Cancer (Synergistic
Metastases Annihilation with
Radiotherapy and Taxotere
(SMART)
3/27/2009
3/26/2010
$289,825
N/A
Sanofi-Aventis U.S. Inc.
Dolan, Eileen
Incorporation of microRNA
expression in pharmacogenetic
prediction models
3/1/2009
2/28/2011
$205,920
R21
National Cancer Institute
Ratain, Mark
Phase I Multicenter, Open-Label,
Dose Escalating, Clinical and
Pharmacokinetic Study of PM01183
in Patients with Advanced Solid
Tumors
2/5/2009
2/4/2011
$195,000
N/A
Pharmamar, S.A.
Kindler, Hedy
20070411: "A Phase lb/2 Open Label,
Dose Escalation Study of AMG 655
in Combination with AMG 479 in
Subjects with Advanced, Refractory,
Solid Tumors
2/11/2009
2/10/2011
$154,237
N/A
Amgen
UCCRC SCIEN T IFI C R EPO R T 20 0 9
Start Date
End
Date
Annual
Total Cost
Class
Funding Agency
Seiwert, Tanguy
1200.23: Phase IIb/III Randomized,
Double Blind Trial of BIBW 2992
Plus BSC vs Placebo Plus BSC
in Non-Small Cell Lung Cancer
Patients Failing Erlotinib or
Gefitinib
7/14/2008
7/13/2010
$124,395
N/A
Boehringer Ingelheim Ltd
Yamini, Bakhtiar
Nanoparticles and Nanocapsules for
Glioma Targeting
9/12/2008
8/31/2009
$113,333
R43
National Cancer Institute
Kindler, Hedy
MORAb-009-003: An Open-Label
Clinical Trial of MORAb-009 in
Combination with Pemetrexed
and Cisplatin in Subjects with
Mesothelioma
2/10/2009
2/9/2011
$108,619
N/A
Morphotek, Inc.
Kindler, Hedy
Phase I/II Study of a Triplet
Combination of CBP501,
Pemetrexed and Cisplatin in
Patients with Advanced Solid
Tumors and in Chemotherapy-naive
Patients with Malignant Pleural
Mesothelioma
8/1/2008
12/31/2010
$105,643
N/A
Canbas Co. LTD.
Vokes, Everett
Study to Determine the Effect
of Dose Schedules of R1507 or
Placebo, Both in Combination With
Erlotinib (Tarceva), on ProgressionFree Survival in Patients with
Advanced Non-Small Cell Lung
Cancer with Disease Progression
after Chemotherapy
12/31/2008
6/30/2010
$102,270
N/A
Hoffmann-Laroche
Vokes, Everett
Concomitant Chemradiotherapy
and Translational Gene Therapy
Trials for Intermediate Stage
Malignancy of the Lung Head and
Neck
7/1/2008
6/30/2013
$100,000
N/A
American Society of
Clinical Oncology
He, Chuan
How Staphyloccus Aureus senses
Host Immune Defenses
7/1/2008
6/30/2013
$100,000
N/A
Burroughs Wellcome
Fund
UCCRC SCIEN T IFI C R EPO R T 20 0 9
Clinical & Experimental
Therapeutics
Title
Investigator
79
P ro g r a m 5
Advanced Imaging
The University of Chicago Cancer Research Center
is at the forefront of the imaging revolution.
Overview & Goals
The University of Chicago Cancer Research Center
is at the forefront of the imaging revolution.
Extraordinary advances in imaging pioneered at the
UCCRC are helping specialists diagnose cancer in
its early, less harmful stages, and attack cancerous
tumors with greater precision and with less harm to
healthy tissue. Imaging research at the University of
Chicago ranges from studies of many animal models
of cancer, to in vitro studies of tissues and cells, to
clinical research studies of patients and volunteers.
The Advanced Imaging Program is structured so
that pre-clinical studies closely parallel clinical
research to create synergies that produce new
ideas and strongly support translational research.
Consequently, the Advanced Imaging Program plays
a key role in research at the UCCRC. The Program
consists of 27 members from two departments.
The scientific goals of the Program include (1)
investigating new methods for computerized image
analysis to help in the early diagnosis of cancer
(breast, lung, colon, and prostate carcinomas); (2)
investigating new methods of image reconstruction
for use in CT (computed tomography), SPECT
(single photon emission computed tomography),
and PET (positron emission tomography)
imaging; (3) developing new methods of image
acquisition such as MRIS (magnetic resonance
imaging and spectroscopy) and EPR (electron
paramagnetic resonance imaging); (4) identifying
imaging methods for oncology practice and
for the evaluation of response to target-based
cancer drugs; (5) providing imaging support for
clinical trials; and (6) investigating methods for
the evaluation of imaging systems, especially as
they apply to computer-aided diagnosis and new
imaging instrumentation. The Program strives to
achieve these goals by integrating and focusing
the work of investigators with established research
programs and by promoting collaborations.
Advanced
Imaging
Imaging is an increasingly critical part of cancer
diagnosis and treatment. Advances in imaging
allow early detection of cancer when it is most easily
cured. In addition, imaging can be used to assess
response to therapy and serves as an integral part
of clinical trials for new drugs, as well as facilitates
the development of customized, optimal therapies
for individual patients. Image-guidance is essential
for accurate delivery of radiotherapy and other
treatments, e.g., focused ultrasound. The rapid
development of technology for imaging and imageguided therapy is transforming cancer care. As a
result, this is a time of unprecedented opportunity
and challenge for translational imaging research. The
NCI, the ACS, and other national organizations have
made support for research in imaging a priority.
Program Leaders:
Gregory Karczmar, PhD
Heber MacMahon, MD
UCCRC SCIEN T IFI C R EPO R T 20 0 9
81
Members
82
Investigator*
Rank
Department
Hiroyuki Abe MD
Assistant Professor
Radiology
Hania Al-Hallaq PhD
Assistant Professor
Radiation and Cellular Oncology
Daniel Appelbaum MD
Assistant Professor
Radiology
Stephen Archer MD
Professor
Medicine
Samuel Armato PhD
Associate Professor
Radiology
Richard Baron MD
Professor
Radiology
Chin-Tu Chen PhD
Associate Professor
Radiology
Abraham Dachman MD
Professor
Radiology
Kunio Doi PhD
Professor
Radiology
Maryellen Giger PhD
Professor
Radiology
Howard Halpern MD, PhD
Professor
Radiation and Cellular Oncology
Yulei Jiang PhD
Associate Professor
Radiology
Chien-Min Kao PhD
Assistant Professor
Radiology
Gregory Karczmar PhD
Professor
Radiology
Patrick La Riviere PhD
Assistant Professor
Radiology
Stanley Liauw MD
Assistant Professor
Radiation and Cellular Oncology
Heber MacMahon MD
Professor
Radiology
Charles Metz PhD
Professor
Radiology
Gillian Newstead MB ChB
Professor
Radiology
Robert Nishikawa PhD
Associate Professor
Radiology
Aytekin Oto MD
Associate Professor
Radiology
Xiaochun Pan PhD
Professor
Radiology
Charles Pelizzari PhD
Associate Professor
Radiation and Cellular Oncology
Brian Roman PhD
Assistant Professor
Radiology
Charlene Sennett MD
Assistant Professor
Radiology
Kenji Suzuki PhD
Assistant Professor
Radiology
Michael Vannier MD
Professor
Radiology
UCCRC SCIEN T IFI C R EPO R T 20 0 9
* Reflects all Program membership during 2008-2009
Featured Faculty Research Summaries†
The Advanced Imaging Program plays a key role in facilitating collaborations
among investigators at the University of Chicago. Investigators have made
significant advances in computer-aided diagnosis, new methods for image
reconstruction and acquisition, new imaging techniques for cancer therapy
evaluation, and image-guided therapy for in vitro cancer-related applications.
Highlights of research progress in areas including computed tomography,
x-ray, magnetic resonance are outlined below.
Theme: Computer-Aided Diagnosis
Samuel Armato III, PhD
Associate Professor of Radiology
Dr. Armato’s research focus is in the field of computeraided diagnosis (CAD), which combines the disciplines
of physics, mathematics, computer science, and statistics
to analyze medical images for the early detection,
diagnosis, and quantification of disease. Specifically, he
has been developing and investigating CAD methods
in chest radiology for the automated detection of
(CT) scans, the automated volumetric assessment of
Dr. Kenji Suzuki
pleural mesothelioma in CT scans, the assessment of
mesothelioma response to therapy, and the analysis of temporal subtraction image quality in chest radiography. He
is also interested in the issue of inter-observer variability in diagnostic image interpretation, especially in the context
Advanced
Imaging
lung nodules in thoracic computed tomography
of establishing “truth” for CAD studies.
Due in part to the strengths of its thoracic CAD research, The University of Chicago (with Dr. Armato as Principal
Investigator) was selected by the National Cancer Institute to form the Lung Image Database Consortium (LIDC)
with four other academic institutions. This consortium is creating an image database as an international research
resource for the development, training, and evaluation of CAD methods for lung nodules in CT. The LIDC has
been engaged in a process to identify and resolve an array of challenging technical and clinical issues to provide a
solid foundation for a robust database of 1000 thoracic CT scans, each annotated by a group of four expert chest
radiologists through a two-phase reading process. Dr. Armato has been the lead investigator of several LIDC
research projects. In one study involving the first 30 LIDC cases, a total of 59 lesions were assigned to the “nodule
> 3 mm” category by at least one radiologist. Of these lesions, 27 (45.8%) received such an assignment from all four
radiologists, and 17 (28.8%) were identified as such by only a single radiologist. This study demonstrated the extent of
inter-observer variability in the task of lung nodule identification, even among experienced subspecialty radiologists.
In another study, LIDC data was used to evaluate the lung nodule detection performance of experienced radiologists
in the context of other experienced radiologists. The number of “true” nodules as defined by various combinations of
radiologists ranged from 15-89. The mean nodule-detection sensitivities across radiologists and different definitions
of “truth” ranged from 51.0-83.2%, whereas mean false-positive rates ranged from 0.33-1.39 per case.
Dr. Armato has developed computerized methods for the quantification of mesothelioma tumor extent in CT scans;
such measurements, performed in a consistent manner, are essential to the conduct of clinical trials that seek to
investigate treatment regimens for malignant pleural mesothelioma. Although manual measurement of tumor
thickness on CT scans is the current standard for assessing response to therapy, this approach is tedious and often
incomplete. The variability of manual mesothelioma tumor thickness measurements was found to be near 30% when
experienced observers were asked to obtain measurements from the same series of CT scans. When presented with
the output of a semi-automated measurement system, observers accepted the computer output without modification
† Note: Due to space constraints, only a small representative sample of Program members is presented here.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
83
in as many as 86% of the measurement sites; of all measurements across all observers, 89% were changed by 2 mm or less.
Computer-assisted methods are expected to become important components of mesothelioma treatment protocols by making
the quantification of tumor response to therapy more efficient, reproducible, and consistent. Dr. Armato’s research is now
challenging the applicability of the current response criteria used clinically to evaluate a mesothelioma patient’s response to
therapy.
Kunio Doi, PhD
Professor of Radiology
Recently, computer-aided diagnosis (CAD) has become a component of the routine clinical work for the detection of breast
cancer on mammograms. More than 8,000 CAD systems have been installed around the world, and about one half of
the facilities for breast clinics in the U.S. have implemented CAD for diagnosis of breast cancer on mammograms. These
observations indicate that CAD is beginning to be applied widely in the detection and/or differential diagnosis of many different
types of abnormalities, such as breast cancer, lung cancer, colon cancer, brain tumors and cardiovascular diseases in medical
images to assist physicians’ image interpretation.
A large-scale systematic program for research and development of CAD schemes was initiated in the early 1980s at the Kurt
Rossmann Laboratories for Radiologic Image Research in the Department of Radiology at the University of Chicago. Initially,
three research projects were selected for 1) detection and/or quantitative analysis of stenoses in vascular imaging; 2) detection of
lung nodules in chest radiographs; and 3) detection of clustered microcalcifications in mammograms. Although the sensitivities
of these schemes for detection of lesions were relatively high (about 85%) even at that time, the number of false positives (four
per image) was very large. To examine the potential uses of CAD in clinical situations, an observer performance study was
carried out with and without computer output. Surprisingly, radiologists’ performance in detecting microcalcifications was
improved significantly when the computer output was available, even with a large number of false positives.
After these initial findings, many investigators around the world have followed the research and development of many different
CAD schemes for the detection and classification of various diseases. In the future, CAD schemes are likely to be assembled
as packages and implemented as a part of PACS. For example, the package for chest CAD may include computerized detection
of lung nodules, interstitial opacities, cardiomegaly, vertebral fractures, and interval changes in chest images, as well as
computerized classification of benign and malignant nodules and the differential diagnosis of interstitial lung diseases. All of
the chest images taken for any purpose will be subjected to a computerized search for many different types of abnormalities
included in the CAD package and, thus, potential sites of lesions together with the probability of a certain disease may be
displayed on the workstation.
At present, the majority of images in PACS are not being used for clinical purposes, except for images that are compared
between time points for a single patient. Therefore, the vast majority of images in PACS are currently “sleeping”. Providing a set
of benign and malignant images, or a set of images with known pathology similar to an unknown new case in question would
be useful for providing radiologists with confidence in their differential diagnosis. The development of a reliable method for
quantifying the similarity of a pair of images (or lesions) would allow radiologists to search for and retrieve similar cases from
PACS for visual comparison. Dr. Doi’s recent studies indicate that the similarity between a pair of lung nodules in CT and
between lesions in mammograms can be quantified by a new psychophysical measure using an artificial neural network that is
trained with corresponding image features and by use of subjective ratings from a group of radiologists.
Yulei Jiang, PhD
Associate Professor of Radiology
A major goal of research in the Jiang laboratory is to develop CAD methods. With CAD, a radiologist interprets clinical
images and makes clinical diagnoses and decisions in consultation with the results of computer analysis of the same images.
Computer-aided detection techniques are used clinically to identify potential lesions in an image. Dr. Jiang’s team has
developed a computer technique that can classify breast calcifications in mammograms as malignant or benign more accurately
than radiologists can. The technique has been shown in a laboratory study to help radiologists recommend more biopsies for
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UCCRC SCIEN T IFI C R EPO R T 20 0 9
patients who actually have breast cancer and recommend fewer biopsies for patients who actually have benign lesions. The
specific aims of research in the laboratory are to 1) develop CAD methods for the detection and diagnosis of breast cancer in
mammograms and prostate cancer in histology images; 2) evaluate the clinical effectiveness of CAD methods; and 3) gain a
fundamental understanding of diagnostic observer performance.
In recent work, Dr. Jiang and collaborators developed a computer technique that recognizes prostate adenocarcinoma
in digitized immunohistochemistry images of prostate tissue sections stained with a triple-antibody cocktail of alphamethylacyl-CoA racemase (AMACR), p63, and high-molecular-weight cytokeratin (HMWCK). The computer technique was
first developed on 20 training images and 15 test images, then evaluated in a blinded study on 299 images. The sensitivity and
specificity of the computer image analysis ranged from 85–88% and 89–97%, respectively, depending on whether high-grade
prostatic intraepithelial neoplasia and cases with atypical diagnosis were included in the calculation. The study shows that
their novel automated computer technique can accurately identify prostatic adenocarcinoma in the triple-antibody cocktailstained prostate sections. Further research is ongoing to improve the computer technique and make it easy to use clinically.
Development of a similar computer technique that analyzes H&E images is also ongoing.
In another recent work, Dr. Jiang collaborated with Dr. Diana L. Miglioretti of Group Health Cooperative, Seattle,
Washington, and Drs. Charles Metz and Robert Schmidt and published an article entitled, “Breast cancer detection rate:
Designing imaging trials to demonstrate improvements” in Radiology. They analyzed data of over 2 ¼ million screening
mammograms interpreted by 510 radiologists in seven US regional registries, and found large variability in the apparent
cancer detection rate calculated for each individual radiologist. The average cancer detection rate was 3.91 cancers per
examinations. One implication of such large variability is that they estimate ascertaining the cancer detection rate in a
clinical trial is difficult and requires extremely large numbers of both screening participants and interpreting radiologists.
This difficulty is exacerbated if the goal is to show that a new imaging modality is better than the standard practice. They
Advanced
Imaging
thousand screening examinations, and the standard deviation of the cancer detection rate was 1.93 cancers per thousand
calculated the effect of this large variability on the statistical powers of clinical trials and found most published clinical trials
of digital mammography and computer-aided detection, including some very large studies, seriously lacked in power. The
study shows that ascertaining the clinical effect of computer-aided detection requires extremely large clinical studies, and the
danger is great of reaching incorrect conclusions with studies of insufficient power.
Theme: New Methods of Image Reconstruction and Acquisition
Xiaochun Pan, PhD
Professor of Radiology
The research interest of Dr. Pan’s laboratory centers on the
development of tomographic imaging methodology, theory, and
biomedical and other applications. Tomographic imaging is a
non-invasive approach to acquiring morphologic, physiologic, or
functional information within the subject under study. Computed
tomography (CT) and magnetic resonance imaging (MRI) are
two examples of tomographic imaging techniques that have
impacted tremendously on health care and biomedical research.
As tomographic imaging research is multidisciplinary, the Pan
laboratory is also collaborating with investigators of different
disciplines, including clinicians and biological scientists, on
campus and from other institutions around the world. Although
the laboratory seeks to address fundamental and theoretical
In vivo MR images of mouse
colons at 9.4 Tesla: detection of
colonic polyps and colorectal
tumors in mice. The figure
illustrates serial spin echo MR
images of the same mouse
treated with a mutagen,
azoxymethane: normal colon,
colonic polyps, and colorectal
tumor, as labeled. Small
pre-cancerous polyps can be
detected and monitored for
the progression of the disease.
(Images courtesy of D. Mustafi
reflecting work in collaboration
with M. Bissonnette, E. Chang, X.
Fan, J. Hart, and G. Karczmar)
problems that arise in advanced tomographic imaging,
research efforts are application-driven, aiming at tackling
problems of practical significance. Therefore, the laboratory
has also maintained active interactions and collaborations with
UCCRC SCIEN T IFI C R EPO R T 20 0 9
85
investigators and engineers from companies that are developing advanced tomographic imaging techniques for clinical and preclinical applications, for security scan, and for industrial non-destructive inspection.
The Pan group has been conducting research in several areas of tomographic imaging sciences, including instrumentation
development for obtaining anatomic as well as functional images of small animals in molecular imaging research, and theory
and algorithm development for cone-beam CT for clinical and other applications. Research is also being conducted with
collaborators on the development of fast imaging methods in MRI and of new technologies tailored to imaging specific organs
and diseases.
A great deal of research effort has recently been devoted to the development and evaluation of new theory and algorithms for
accurate image reconstruction in advanced, helical cone-beam CT. Advanced cone-beam CT offers high volume-scanning
speed and temporal resolution, which allows for the development and improvement of important clinical imaging applications,
such as cardiac imaging, virtual colonoscopy, and CT-based lung cancer screening. Investigators in the field have been actively
developing mathematically exact theory and practically useful algorithms for derivation of high-quality volumetric images
from data acquired with cone-beam CT. Dr. Pan’s research in this area has led to the establishment of a set of new concepts,
theory, and algorithms that offer not only a fundamental understanding of the mathematical aspects of the cone-beam CT
problem, but also the basis for the development of additional innovative algorithms for obtaining accurate images. The work also
reveals a host of possibilities in designing new imaging approaches targeted only to selected region of interests, which had been
considered theoretically impossible previously. Some of these new imaging approaches can have significant implications for
reducing the motion effect and radiation dose in in vivo CT imaging.
The Pan laboratory has also been interested in limited-data scanning in CT, where X-ray dose is reduced to the bare minimum
to accomplish a given imaging task. An example of this is digital breast tomosynthesis (DBT). This semi-tomographic modality
exposes patients to an X-ray dose not much larger than standard digital mammography, approximately 100 times less than a
typical CT scan. DBT promises to improve cancer detectability by utilizing the limited tomographic information to remove
overlapping structures from normal breast tissues. The new set of algorithms being developed may lower the required X-ray
intensity even further, which is important if DBT is to be used as a mammographic screening tool. Other similar projects
involve the development of image-reconstruction algorithms for few-view data taken with onboard imagers to support
radiation-therapy accounting and to measure respiratory motion.
Brian Roman, PhD
Assistant Professor of Radiology
Dr. Roman established the Physiological and Molecular Imaging Laboratory in 2005 in the Department of Radiology in order
to combine modern physiological and molecular biological techniques with non-invasive imaging modalities. Biological
and physiological techniques are combined with magnetic resonance imaging (MRI) to acquire images in which contrast
enhancement can be mapped to function. MR images are acquired using the UCCRC Lynn S. Florsheim Magnetic Resonance
Imaging and Spectroscopy Laboratory (http://mris.bsd.uchicago.edu)9.4T scanner. A diverse group of biologists, molecular
biologists, bioengineers, veterinary technicians, and MR physicists are responsible for implementing the wide range of
techniques used in the laboratory. Research is focused on MR techniques and how they can be used towards an understanding
of pancreatic and muscle tissue. Three specific aims of the research include 1) the use of MR to detect gene expression in the
heart; 2) the development of MR techniques for imaging pancreatic beta cell and islet function; and 3) the development of MR
techniques for early detection of pancreatic cancer.
To detect gene expression in the heart, the laboratory is developing techniques to link gene expression to MR image contrast
for early detection of cardiac hypertrophy, a process that usually cannot be reversed upon clinical detection. The laboratory
is engineering a transgenic mouse that expresses a MR reporter protein driven by an inducible cardiac hypertrophic promoter
including atrial naturetic peptide (ANP) and brain naturetic peptide (BNP). This strategy benefits from using a ubiquitous
and endogenous protein as the reporter, thereby removing problems with immunoreactivity. Additionally, since the reporter
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UCCRC SCIEN T IFI C R EPO R T 20 0 9
is induced by the pathology, a maximum dynamic range can be obtained as the heart progresses from a baseline to a
pathological state. The laboratory is adapting this strategy towards the detection of cell proliferation in cancer models.
The growing incidence of diabetes was the driving force for developing techniques to monitor pancreatic beta cell function.
Beta cell production and release of insulin is preceded by membrane depolarization, which is triggered by changes in
extracellular glucose and the influx of calcium. Early stages of this project involved proof of concept studies link these
activation steps with MRI contrast. Manganese (Mn) was implemented as a calcium analog and a MRI contrast agent, as the
laboratory was successful in demonstrating that activated beta cells take up Mn in cell lines, as well as in both animal and
human isolated islets, upon glucose stimulation. The apparent change in contrast is directly related to the release of insulin
and therefore beta cell function. The laboratory is the pioneer of this technique and has successfully translated it to in vivo
models, resulting in functional MR images of the intact pancreas.
The laboratory is currently adapting the Mn-MRI technique and developing complementary methods to detect pancreatic
adenocarcinomas. An upregulation of calcium binding proteins and associated T-tubules occurs during the development of
these tumors. As Mn is often considered a calcium analog, an underlying assumption is that these cancer cells will take up
Mn to a greater extent compared to non-cancer cells. The laboratory has obtained MR images of cultured pancreatic cancer
cells following exposure and growth with Mn, which indicate that Mn is taken up during growth and can be distinguished
from non-cancer cells. These findings have been examined in situ using xenograft models and are anticipated to facilitate a
non-invasive method for monitoring tumor growth and therapeutic effectiveness.
Theme: New Imaging Techniques for Oncology Practice and Therapy Evaluation
Advanced
Imaging
Heber MacMahon, MD
Professor of Radiology
Research in the Thoracic Imaging Section of the Department
of Radiology has been focused on clinical applications of
image processing and computer-aided diagnosis for improved
accuracy in the detection and characterization of lung cancer.
Initial detection of lung cancer is still most commonly made by
chest radiography, and much of our research has been directed
towards developing methods to facilitate earlier and more
consistent diagnosis, as well as monitoring of existing disease.
The techniques have included energy subtraction, temporal
subtraction, rib suppression, and computer-aided detection. In
recent years, the Thoracic Imaging Section has started to work
Magnetic resonance imaging of mouse mammary tumors in the
UCCRC’s Lynn S. Florsheim MRIS Lab.
with commercial companies, which are developing advanced
clinical products that incorporate these technologies.
The current thrust of imaging research is the area of improving performance of radiologists in detection and characterization
of new disease in chest radiographs and CT scans. This has involved the application and evaluation of image processing
techniques to reduce rib opacity in order to improve nodule detection, evaluation of energy subtraction, and development
of temporal subtraction to improve detection of interval change. While energy subtraction is a commercially available
technique with proven efficacy, other methods such as rib suppression and temporal subtraction are software-only
approaches that have the advantage of not requiring specialized acquisition equipment nor any increase in radiation dose.
In a recent pilot study, Dr. MacMahon’s team compared the performance of radiologists viewing standard chest radiographs
in detecting small lung cancers, compared to a novel rib suppression technique and dual energy subtraction. A significant
improvement in detection accuracy was demonstrated using rib suppression alone, while a further highly significant benefit
was shown with energy subtraction. This finding is important, because even a small improvement in detection accuracy can
UCCRC SCIEN T IFI C R EPO R T 20 0 9
87
have important clinical implications in a modality as ubiquitous as chest
radiography. Temporal subtraction is a complementary approach that can
amplify interval change on sequential radiographs. After many years of
development at the University of Chicago, it has been licensed and further
refined to the point where it is ready to be tested in clinical practice. The
team is currently working to determine how best to integrate temporal
subtraction with our clinical viewing system to initiate what would be the
first such clinical trial in the United States.
Detection of thoracic lesions is not limited to the initial disease presentation;
it can play a role in monitoring and therapy evaluation as well, and tools that
improved detection and characterization of thoracic disease have potential
for more sensitive detection of disease recurrence. Although several newer
tools, such as PET and perfusion imaging are under investigation for this
purpose, the large majority of therapy monitoring is still based on simple
measurement of selected reference lesions by radiologists. This is a necessary
but tedious task, which is time-consuming for radiologists, and suffers
Illustrations of flat lesions which exhibit uncommon flat
morphology. (a) A flat lesion on a fold (10 mm; adenoma)
in the cecum was detected correctly by our computeraided detection scheme (indicated by an arrow). (b)
A small flat lesion (6 mm; adenoma) in the cecum was
detected correctly by our computer-aided detection
scheme. (Image by K. Suzuki)
from considerable variation and inaccuracy. To address this issue, the team
is working to develop a software tool that will provide semi-automated
three-dimensional volume measurements of tumor nodules, lymph nodes and liver metastases, while tracking lesions over
time on multiple sequential scans. The goal of this project is to provide a fully-integrated system that can provide oncologists
with accurate and reproducible tumor volume measurements, while facilitating the radiologists’ task. Although the system
can actually detect new lung lesions with good accuracy, such detection tasks are being pushed onto the “back-burner” as a
direct result of the difficulty of obtaining FDA clearance for clinical use. Nonetheless, accurate measurement and tracking of
radiologist-detected reference lesions has potential to have a major impact on oncologic practice, by reducing subjectivity and
human error.
Aytekin Oto, MD
Associate Professor of Radiology
Dr. Oto is working in collaboration with the Lynn S. Florsheim MRIS Lab, directed by Drs. Karczmar and Roman, and Dr.
Walter Stadler`s (Clinical and Experimental Therapeutics Program) laboratory to explore more accurate diagnosis of prostate
cancer by MR imaging. Additionally, he is developing and validating MR image analysis methods to improve the amount and
reproducibility of diagnostic information obtained from MRI through three ongoing research projects.
The goal of the first project is to determine the role of dynamic contrast enhanced MR imaging (DCE-MRI) in the non-invasive
evaluation of histologic grading (Gleason score) and angiogenesis of prostate cancer. Specific objectives in this project are to 1)
determine the relation between DCE-MRI derived kinetic parameters and the Gleason score of the prostate cancer lesions; 2)
evaluate which parameters of DCE-MRI will correlate with mean vascular density and VEGF expression in the prostate cancer;
and 3) determine whether the pharmacokinetic parameters estimated from DCE-MRI can improve detection of prostate cancer
and extracapsular extension (ECE).
The second project focuses on MR microscopy of prostatectomy specimens for automated whole organ histopathology.
Histopathologic validation of imaging findings is required to improve the quality and consistency of new technology and
to understand prostate cancer disease processes and treatment. Currently, the gold standard method for histopathological
validation is expert visual inspection of whole mount prostatectomy specimens, a process that is costly, laborious, and not
widely available. In this project, a 9.4T MR imaging system will be used for imaging of fresh prostatectomy specimens, prior to
routine histopathological evaluation. On completion, this project will demonstrate the feasibility of using high field dedicated
MR imaging to increase efficiency and accuracy of pathologists and/or as an alternative to routine fixation and histopathological
analysis.
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UCCRC SCIEN T IFI C R EPO R T 20 0 9
This research has significant potential to improve the quality and consistency of imaging and produce improvements
in technology for prostate cancer diagnosis and treatment. Specific aims are to 1) determine the feasibility of 9.4T MRI
microscopy of fresh and fixed ex vivo prostate specimens; 2) verify imaging findings of 9.4T scans with whole mount and
standard prostate histopathology; and 3) design and test a system for registration of multimodality in vivo and ex vivo
prostate image analysis that uses MRI as the basis for superimposition of datasets.
Finally, the third project focuses on optimization of an endrorectal prostate MR protocol. One specific aim is to develop
an optimal protocol for prostate scans that includes use of the Philips endorectal probe, fast spin echo imaging, diffusion
weighted imaging, dynamic contrast enhanced MRI, and metabolic spectroscopy when appropriate. Results obtained with
these methods will be compared qualitatively and quantitatively with results obtained on GE scanners. The comparison will
be based on average image metrics over the group of patients imaged on each scanner. Comparisons will be made by patients
who are matched in terms of age and Gleason score. The second aim is to incorporate new experimental imaging approaches
into the standard Philips protocol, including new approaches to the analysis of DCE-MRI and the addition of HiSS to the
prostate imaging protocol.
Michael Vannier, MD
Professor of Radiology
Imaging plays a central role in research and clinical medicine for many diseases, especially cancer. Imaging has grown in
importance because of the advances in technology that allow more precise location of lesions, the ability to guide therapy and
spare normal tissues, and, more recently, a means to measure response to therapy and predict outcome. Clinical trials are
location and extent of cancer, and, in some cases, to determine if an individual responds to the new therapy. This is a complex
task, since many trials involve a combination of conventional and new therapies, so sensitive methods are used that can
discriminate the contribution of each. Experimental imaging methods are used in the laboratory for preclinical studies, and
Advanced
Imaging
beneficial to cancer patients by providing access to new therapies. Imaging is essential for many of these trials to measure the
the most advanced of these methods have been adapted or “translated” from the laboratory to the clinic. Some of the most
demanding applications of imaging, which require the most advanced methods, are integrated into new clinical trials.
In brain tumor therapy, for example, imaging is essential to detect lesions, locate them precisely, and to measure their extent.
In addition, imaging can measure the microvasculature, metabolism, and status of the blood-brain barrier, as well as their
changes over time due to the effects of tumors or therapies. The amount of information provided by advanced imaging has
eclipsed all other methods for certain lesions, so many clinical trials are built around the available imaging methods and
technology. During the past 2 years, the University of Chicago has joined many highly innovative and important vanguard
trials of drug-radiotherapy-surgery combination trials underway at the nation’s leading centers. To qualify as a site, enroll
volunteer subjects, complete the complex protocols, and evaluate each new therapy, advanced technology was installed
and tested for image acquisition, intravenous contrast administration, data archiving, post-processing analysis, and quality
control. The benefits of the new therapies are difficult to evaluate while these trials are underway, but it appears likely that
some of them will soon replace conventional therapies since the outcomes are superior, and toxicity is less.
Nowadays, it is not unusual for a clinical trial to use dynamic contrast enhancement (where a multitude of images are
acquired over time after IV contrast injection), proton spectroscopy, diffusion weighted imaging (that is sensitive to
apoptosis, for example), perfusion measurement, and 3D morphometrics to evaluate tumors before and after therapy. In some
instances, several of these techniques are combined to evaluate multimodal therapy, such as chemoradiotherapy.
Through the Advanced Imaging Program, the University of Chicago has been among the nation’s most productive centers
based on the number of subjects enrolled who have completed these trials. The efforts of many clinical disciplines are
involved, for example, in brain tumor therapy. Drs. M. Kelly Nicholas, Director of the Neuro-Oncology Program, Steven
Chmura in radiotherapy, and Michael Vannier in radiology have worked together closely with Dr. Maryann Schroeder, in
radiation oncology who oversees the protocol and procedures, and Paul Worthington, technical supervisor in MRI. Sponsors
of this research include the National Cancer Institute, oncology cooperative groups (ACRIN and RTOG), and industry.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
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Theme: Image-Guided Therapy
Charles Pelizzari, PhD
Associate Professor of Radiation and Cellular Oncology
Radiation therapy has relied on image guidance in the form of CT and
MRI based planning for patient irradiations, and planar radiography for
verification of correct patient position since the early 1980’s. Today and
into the future, image guidance takes many forms, including the use of
3D imaging modalities such as ultrasound and cone-beam CT for patient
setup, real-time monitoring of patient motion during treatment, and
the use of functional and molecular imaging in planning and also in the
assessment of therapy response. The aim of image-guided therapy research
is to develop innovative applications of multiple imaging modalities, with
the goal of optimizing the treatment of each individual patient with the
Dr. Charlene Sennett
highest geometric accuracy, taking full account of the relevant aspects of
the patient’s tumor biology revealed by imaging, as they may affect the
course of treatment.
For pretreatment patient localization, Drs. Pelizzari and Xiaochaun Pan are developing new approaches to cone-beam CT, such
as targeted imaging where only the immediate surroundings of the treatment region are illuminated by the imaging X-ray beam.
This both reduces unnecessary dose to non-tumor tissues and improves image quality by reducing the contribution of scattered
radiation. They are also working in collaboration with Dr. Gregory Karczmar to investigate the potential for creating small
lesions with high-intensity focused ultrasound that can serve as fiducial marks to guide various forms of therapy.
Research into the use of functional imaging for planning and assessment of therapy is exemplified by the collaborations among
Drs. Charles Pelizzari, Howard Halpern, Gregory Karczmar, and Ralph Weichselbaum (Clinical and Experimental Therpauetics),
concerning multimodality imaging to characterize functional changes in response to a combined radiation and antiangiogenic
gene therapy. The ultimate goal of the project is to develop an image-guided adaptive therapeutic approach, where a local
imaging “signature” of tumor response can be used to identify regions which are and are not responding well, and to use this
information to adapt the spatial distribution of gene vector injection and/or intensity-modulated radiation dose distribution to
boost the less well responding regions. Preclinical studies have utilized a combination of perfusion sensitive dynamic contrast
enhanced (DCE) MRI with the 4.7T and 9.4T magnets in the MRIS facility, and electron paramagnetic resonance (EPR) oxygen
mapping using the spectroscopic imaging techniques pioneered in Dr. Halpern’s EPR research resource. EPR imaging is capable
of mapping oxygenation in vivo with resolution of 1mm in space, and 3 mm Hg in oxygen tension. A significant and reproducible effect has been revealed through registration of spin echo MRI, DCE MRI contrast uptake,
and EPR oxygen tension images of the same tumor, before and 3 days after radiation-inducible antiangiogenic gene therapy.
Following treatment, the tumor appears better perfused (increased MRI contrast uptake) and better oxygenated (higher values
in EPR pO2 map). This is consistent with the concept of vascular normalization by antiangiogenic agents leading to reperfusion
and reoxygenation.Additional Program Highlights*
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UCCRC SCIEN T IFI C R EPO R T 20 0 9
Additional Program Highlights*
Research
•• Power spectral analysis of mammographic parenchymal patterns for breast cancer risk assessment. Maryellen
Giger, PhD and colleagues (Olopade, Cancer Risk and Prevention Program) performed a study evaluating the usefulness of
power law spectral analysis on mammographic mutant cell patterns in breast cancer risk assessment. The study collected
and digitized the mammograms from 172 subjects (women with BRCA1/BRCA2 gene mutation and low-risk women).
Understanding these different patterns could help to explain which women may need to be more aggressively screened for
breast cancer to prevent the growth and development of mutant cells. The results of this study suggested that there was
a significant difference between the 30 BRCA1/BRCA2 gene mutation carriers and the 142 low-risk women. This study
is an example of how the successful development of innovative and personalized treatments can benefit from the close
integration of clinical and technical skills (Li et al. J Digit Imaging 21:145-152, 2008).
•• Magnetic resonance imaging identifies multifocal and multicentric disease in breast cancer patients who are
eligible for partial breast irradiation. In a retrospective study led by Hania Al-Hallaq, PhD, Gillian Newstead, MB
ChB, and Ralph Weichselbaum, MD, (Clinical and Experimental Therapeutics Program), the authors hypothesized that
magnetic resonance imaging (MRI) would alter partial breast irradiation (PBI) eligibility by identifying cancers outside
the PBI volume - as compared with mammography alone. Since 2002, 450 patients with invasive breast cancer were
considered for this study, 110 of which were identified as eligible for PBI. Patients were randomized to receive either
whole-breast radiotherapy or PBI, and MRI reports were reviewed to determine whether the MRI was effective in helping
multifocal disease in 3.6 percent, multicentric disease in 4.5 percent, and contralateral disease in 1.8 percent of patients.
These results suggest that MRI usage should be considered to assess PBI eligibility to minimize potential failures and
Advanced
Imaging
to identify secondary lesions. The results suggest that the MRI was able to identify secondary lesions in 10-percent,
identify secondary cancers with more accuracy (Al-Hallaq et al. Cancer 113:2408-2414, 2008).
•• Detection of in situ mammary cancer in a transgenic mouse model: in vitro and in vito MRI studies demonstrate
histopathologic correlation. Sunnaz Jansen, PhD, Greg Karczmar, PhD, Gillian Newstead, MB ChB, and their colleagues
(Suzanne Conzen, Cell Signaling and Gene Regulation Program) studied a transgenic
mouse model that develops mammary cancer very similar to that of human breast cancer.
Eleven mice were subjected to in vivo and in vitro imaging using the 9.4 Tesla magnet, and
the ratio of image-detected versus histologically-detected cancers was examined. The
results showed that 12/12 intramammary lymph nodes, 1/1 relatively large (approximately
5mm) tumor, 17/18 small (approximately 1mm) tumors, and 13/16 ducts distended with
DCIS greater than 300 microns, were detected by MR images with no false-positives. The
results indicate that the new magnetic imaging procedure can detect very early breast
cancer in mice, a precursor to invasive cancer. These studies of model systems are leading
to more effective MRI methods that can be used clinically to effectively diagnose and treat
cancer patients (Jansen et al. Phys Med Biol 53:5481-5493, 2008).
•• Electron paramagnetic resonance oxygen image hypoxic fraction plus radiation dose
strongly correlates with tumor cure in FSa fibrosarcomas. Howard Halpern, MD,
PhD, and his colleagues have pioneered the use of electron paramagnetic imaging to map
hypoxia in tumors based on the linewidth of the EPR (electron paramagnetic resonance
imaging) signal from specially-designed probes. Experiments were performed on 34 FSa
fibrosarcomas implanted in the legs of mice. EPR images were acquired from the tumors
while mice were breathing air and under conditions where blood flow to the tumor was
interrupted so that the tumors were hypoxic. Under the same conditions, the tumors were
* Due to space constraints, only a small representative sample of Program highlights is presented here.
In vivo magnetic resonance (MR) image
and corresponding H&E stained section
demonstrating a murine invasive tumor.
(Image by S. Jansen, S. Conzen, X. Fan, T.
Krausz, M. Zamora, S. Foxley, J. River, G.
Newstead, and G. Karczmar)
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irradiated to a variety of doses near the dose at which fifty-percent of FSa tumors are cured. Tumor tissue was distinguished
from normal tissue using co-registration of the EPR oxygen images with spin-echo magnetic resonance images, and oxygen
levels in tumor and surrounding tissue were calculated from EPR data. Bivariate analysis of the tumors demonstrated that
cure rate correlated with radiation dose (p = 0.004) and with EPR measurements of oxygen tension lower than 10 mm of
mercury (p = 0.023). These results demonstrate that the degree of hypoxia measured by MRI, combined with the radiation
dose, accurately predicts the response of tumors and suggest the potential of non-invasive electron paramagnetic resonance
to guide clinical treatment planning and improve outcomes for patients (Elas et al. Int J Radiat Oncol Biol Phys 71:542-549,
2008).
•• Sensitivity to tumor microvasculature without contrast agents in high spectral and spatial resolution MR images.
Greg Karczmar, PhD, and his colleagues investigated whether high spectral and spatial resolution (HiSS) MRI detects tumor
vasculature without contrast agents, based on the sensitivity of the water resonance line shape to tumor blood vessels.
HiSS data from AT6.1 tumors inoculated in the hind legs of rats (N = 8) were collected pre- and post-blood pool contrast
agent (iron-oxide particles) injection. The waterline in small voxels was significantly more asymmetric at the tumor rim
compared to the tumor center and normal muscle (P < 0.003). Composite images were synthesized, with the intensity in
each voxel determined by the Fourier component (FC) of the water resonance having the greatest relative image contrast at
that position. Regions with high contrast in FC images (FCIs) were compared to FCIs with CE-MRI as the “gold standard” of
vascular density. The FCIs had 75% +/- 13% sensitivity, 74% +/- 10% specificity, and 91% +/- 4% positive predictive value (PPV)
for vasculature detection at the tumor rim. These results suggest that tumor microvasculature can be detected using HiSS
imaging without the use of contrast agents (Foxley et al., Magn Reson Med 61(2):291-298, 2009).
Selected New Funding
•• Xiaochuan Pan, PhD, and his colleagues are the recipients of an Illinois Department of Public Health grant to examine an
enhanced form of magnetic resonance imaging (MRI). Dynamic contrast enhanced MRI (DCEMRI) is a powerful MRI
method, but its sensitivity and specificity are limited. Dr. Pan and his team are, therefore, pursuing another innovative
approach to obtaining accurate breast images from a variety of k-space samples. The data would be used to increase
the sensitivity and specificity of DCEMRI, which would ultimately lead to enhanced early detection of cancer when it is
relatively easy to cure.
•• Patrick La Riviere, PhD, and his colleagues are developing a new method to overcome the limitations of non-contrast
computed tomography (NC-CT) scans. Funded by an R01 grant from the National Cancer Institute, Dr. La Riviere plans
to accomplish this by increasing the intrinsic contrast-to-noise ratio by reducing noise while preserving resolution using
projection-domain smoothing and restoration with explicit models of measurement statistics. Successful completion
of this work may help to provide superior CT imaging performance for patients with chronic kidney disease, contrast
allergy, obesity, and for screening applications where radiation dose is limited. It would also lead to improved diagnostic
performance in emergency examinations.
•• The National Center for Research Resources has supported the acquisition of a high-performance hybrid microCT/
microSPECT imaging system and the setup of an animal imaging facility for both structural and functional imaging. With
this instrument, Chin-Tu Chen, PhD and colleagues have established routine SPECT and CT imaging capabilities at the
University of Chicago for quantitative measurements of important anatomic and physiological parameters in animal studies,
thus greatly enhancing the research of a number of NIH funded investigators, and offering pilot study opportunities to many
others. Employing SPECT/CT imaging is anticipated to improve the diagnosis of diseases, effectively monitor treatment,
and enhance the development of new drugs and therapies.
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•• Maryellen Giger, PhD, received funding from the Department of Energy to develop multi-modality, image-based markers
for assessing breast density and parenchymal structure that may be used alone or together with clinical measures, as well
as biomarkers, for use in determining the risk of breast cancer. Such image-based markers are expected to be useful for
improved assessment of patients at high risk for breast cancer and for monitoring the response of preventive treatments.
The research involves the multimodality optimization of methods for breast image acquisition, analysis, and display.
Image analysis is being optimized for full-field digital mammography, breast ultrasound, and breast MRI.
•• Howard Halpern, MD, PhD, and colleagues were awarded a grant from the National Institute of Biological Imaging and
Bioengineering to develop very low frequency electron paramagnetic resonance imaging (EPRI) for in vivo physiology.
High resolution images of molecular oxygenation can provide crucial guides to the delivery and monitoring of cancer
therapy. EPR imaging of oxygen provides a unique combination of spatial and oxygen resolution and uniform sensitivity
with depth in tissue. The project reflects a multidisciplinary effort to improve the resolution of EPRI oxygen images for
small animals with the long term goal of human image acquisition.
•• Chien-Min Kao, PhD, was the recipient of an R21 grant from the National Cancer Institute to investigate and develop
novel TOF PET reconstruction methods and imaging strategies. These new methods and strategies will more fully realize
the potentials of TOF PET imaging and hence enhance the already important role of PET imaging in cancer research and
in the clinic. Results from this study are anticipated to advance TOF-PET imaging by creating new choices and flexibilities
New Faculty Recruitments and UCCRC Members
Stanley Liauw, MD specializes in the treatment of genitourinary and gastrointestinal cancers. Dr. Liauw’s research interests
Advanced
Imaging
in data utilization, imaging strategies and system design.
include prostate cancer outcomes after dose-escalated external beam radiation therapy or brachytherapy, toxicity modeling
following radiation therapy, adjuvant radiation therapy after prostatectomy, quality of life issues, and mechanisms of
radiation resistance.
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Selected Publications
* : Intraprogrammatic Collaboration
Lee, C.-H., Cheng, S.-H., Wang, Y.-J., Chen, Y.-C., Chen, N.-T., Souris, J.,
Chen, C.-T., Mou, C.-Y., Yang, C.-S., and Lo, L.-W. Near-Infrared Mesoporous
Silica Nanoparticles for Optical Imaging: Characterization and In Vivo
Biodistribution. Advanced Functional Materials 19:215-222, 2009.
# : Interprogrammatic Collaboration
Dachman, Abraham MD
Abe, Hiroyuki MD
* Jansen SA, Fan X, Karczmar GS, Abe H, Schmidt RA, Newstead GM.
Differentiation between benign and malignant breast lesions detected by. Magn
Reson Med 59(4):747-54, 2008.
* Jansen SA, Fan X, Karczmar GS, Abe H, Schmidt RA, Giger M, Newstead
GM. DCEMRI of breast lesions: is kinetic analysis equally effective for both
mass and nonmass-like enhancement?. Med Phys 35(7):3102-9, 2008.
* Abe H, Schmidt RA, Kulkarni K, Sennett CA, Mueller JS, Newstead GM.
Axillary Lymph Nodes Suspicious for Breast Cancer Metastasis: Sampling with
US-guided 14-Gauge Core-Needle Biopsy--Clinical Experience in 100 Patients.
Radiology 250(1):41-9, 2009.
* Shiraishi J, Abe H, Ichikawa K, Schmidt RA, Doi K. Observer Study for
Evaluating Potential Utility of a Super-High-Resolution LCD in the Detection
of Clustered Microcalcifications on Digital Mammograms. J Digit Imaging,
2009.
Sheran J, Dachman AH. Quality of CT colonography-related web sites for
consumers. J Am Coll Radiol 5(4):593-7, 2008.
Flicker MS, Tsoukas AT, Hazra A, Dachman AH. Economic impact of
extracolonic findings at computed tomographic colonography. J Comput Assist
Tomogr 32(4):497-503, 2008.
Johnson CD, Chen MH, Toledano AY, Heiken JP, Dachman A, Kuo MD, Menias
CO, Siewert B, Cheema JI, Obregon RG, Fidler JL, Zimmerman P, Horton KM,
Coakley K, Iyer RB, Hara AK, Halvorsen RA Jr, Casola G, Yee J, Herman BA,
Burgart LJ, Limburg PJ. Accuracy of CT colonography for detection of large
adenomas and cancers. N Engl J Med 359(12):1207-17, 2008.
Al-Hallaq, Hania PhD
Dachman AH, Kelly KB, Zintsmaster MP, Rana R, Khankari S, Novak JD, Ali
AN, Qalbani A, Fletcher JG. Formative evaluation of standardized training for
CT colonographic image interpretation by novice readers. Radiology 249(1):16777, 2008.
* # Al-Hallaq HA, Mell LK, Bradley JA, Chen LF, Ali AN, Weichselbaum RR,
Newstead GM, Chmura SJ. Magnetic resonance imaging identifies multifocal
and multicentric disease in breast cancer patients who are eligible for partial
breast irradiation. Cancer 113(9):2408-14, 2008.
Liedenbaum MH, de Vries AH, Halligan S, Bossuyt PM, Dachman AH, Dekker
E, Florie J, Gryspeerdt SS, Jensch S, Johnson CD, Laghi A, Taylor SA, Stoker J.
CT colonography polyp matching: differences between experienced readers.
Eur Radiol 19(7):1723-30, 2009.
Appelbaum, Daniel MD
Doi, Kunio PhD
Rubin DT, Surma BL, Gavzy SJ, Schnell KM, Bunnag AP, Huo D, Appelbaum
DE. Positron emission tomography (PET) used to image subclinical
inflammation associated with ulcerative colitis (UC) in remission. Inflamm
Bowel Dis 15(5):750-5, 2009.
* Li F, Engelmann R, Metz CE, Doi K, MacMahon H. Lung cancers missed
on chest radiographs: results obtained with a commercial computer-aided
detection program. Radiology 246(1):273-80, 2008.
Archer, Stephen MD
* Li F, Engelmann R, Doi K, MacMahon H. Improved detection of small lung
cancers with dual-energy subtraction chest radiography. AJR Am J Roentgenol
190(4):886-91, 2008.
Marsboom G, Archer SL. Pathways of proliferation: new targets to inhibit the
growth of vascular smooth muscle cells. Circ Res 103(10):1047-9, 2008.
Kasai S, Li F, Shiraishi J, Doi K. Usefulness of computer-aided diagnosis
schemes for vertebral fractures and lung nodules on chest radiographs. AJR Am
J Roentgenol 191(1):260-5, 2008.
Armato, Samuel PhD
Shiraishi J, Sugimoto K, Moriyasu F, Kamiyama N, Doi K. Computer-aided
diagnosis for the classification of focal liver lesions by use of contrast-enhanced
ultrasonography. Med Phys 35(5):1734-46, 2008.
# Armato SG 3rd, Entwisle J, Truong MT, Nowak AK, Ceresoli GL, Zhao
B, Misri R, Kindler HL. Current state and future directions of pleural
mesothelioma imaging. Lung Cancer 59(3):411-20, 2008.
Armato S 3rd, Meyer C, McNitt-Gray M, McLennan G, Reeves A, Croft B,
Clarke L. The Reference Image Database to Evaluate Response to Therapy in
Lung Cancer (RIDER) Project: A Resource for the Development of ChangeAnalysis Software. Clin Pharmacol Ther 84(4):448-56, 2008.
* Suzuki K, Yoshida H, Nappi J, Armato SG 3rd, Dachman AH. Mixture of
expert 3D massive-training ANNs for reduction of multiple types of false
positives in CAD for detection of polyps in CT colonography. Med Phys
35(2):694-703, 2008.
Sensakovic WF, Starkey A, Roberts RY, Armato SG 3rd. Discrete-space versus
continuous-space lesion boundary and area definitions. Med Phys 35(9):4070-8,
2008.
# Faoro L, Hutto JY, Salgia R, El-Zayaty SA, Ferguson MK, Cheney RT, Reid
ME, Armato SG 3rd, Krausz T, Husain AN. Lymphatic vessel density is not
associated with lymph node metastasis in non-small cell lung carcinoma. Arch
Pathol Lab Med 132(12):1882-8, 2008.
* Armato SG 3rd, Roberts RY, Kocherginsky M, Aberle DR, Kazerooni EA,
Macmahon H, van Beek EJ, Yankelevitz D, McLennan G, McNitt-Gray MF,
Meyer CR, Reeves AP, Caligiuri P, Quint LE, Sundaram B, Croft BY, Clarke
LP. Assessment of radiologist performance in the detection of lung nodules:
dependence on the definition of “truth”. Acad Radiol 16(1):28-38, 2009.
Chen, Chin-Tu PhD
Lin KM, Hsu CH, Chang WS, Chen CT, Lee TW, Chen CT. Human breast
tumor cells express multimodal imaging reporter genes. Mol Imaging Biol
10(5):253-63, 2008.
94
* Suzuki K, Yoshida H, Nappi J, Armato SG 3rd, Dachman AH. Mixture of
expert 3D massive-training ANNs for reduction of multiple types of false
positives in CAD for detection of polyps in CT colonography. Med Phys
35(2):694-703, 2008.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
* Shiraishi J, Abe H, Ichikawa K, Schmidt RA, Doi K. Observer Study for
Evaluating Potential Utility of a Super-High-Resolution LCD in the Detection
of Clustered Microcalcifications on Digital Mammograms. J Digit Imaging,
2009.
* Li F, Engelmann R, Doi K, Macmahon H. True Detection Versus “Accidental”
Detection of Small Lung Cancer by a Computer-Aided Detection (CAD)
Program on Chest Radiographs. J Digit Imaging, 2009.
Muramatsu C, Li Q, Schmidt R, Shiraishi J, Doi K. Investigation of
psychophysical similarity measures for selection of similar images in the
diagnosis of clustered microcalcifications on mammograms. Med Phys
35(12):5695-702, 2008.
Giger, Maryellen PhD
# Li H, Giger ML, Olopade OI, Chinander MR. Power spectral analysis of
mammographic parenchymal patterns for breast cancer risk assessment. J Digit
Imaging 21(2):145-52, 2008.
Wilkie JR, Giger ML, Chinander MR, Engh CA, Hopper RH Jr, Martell JM.
Temporal radiographic texture analysis in the detection of periprosthetic
osteolysis. Med Phys 35(1):377-87, 2008.
* Drukker K, Gruszauskas NP, Sennett CA, Giger ML. Breast US computeraided diagnosis workstation: performance with a large clinical diagnostic
population. Radiology 248(2):392-7, 2008.
* Gruszauskas NP, Drukker K, Giger ML, Sennett CA, Pesce LL. Performance
of breast ultrasound computer-aided diagnosis: dependence on image selection.
Acad Radiol 15(10):1234-45, 2008.
* Li H, Giger ML, Yuan Y, Chen W, Horsch K, Lan L, Jamieson AR, Sennett CA,
Jansen SA. Evaluation of computer-aided diagnosis on a large clinical full-field
digital mammographic dataset. Acad Radiol 15(11):1437-45, 2008.
* Yuan Y, Giger ML, Li H, Sennett C. Correlative feature analysis on FFDM.
Med Phys 35(12):5490-500, 2008.
Giger ML, Chan HP, Boone J. Anniversary paper: History and status of CAD
and quantitative image analysis: the role of Medical Physics and AAPM. Med
Phys 35(12):5799-820, 2008.
Drukker K, Sennett CA, Giger ML. Automated method for improving system
performance of computer-aided diagnosis in breast ultrasound. IEEE Trans
Med Imaging 28(1):122-8, 2009.
Halpern, Howard MD, PhD
* Elas M, Bell R, Hleihel D, Barth ED, McFaul C, Haney CR, Bielanska J,
Pustelny K, Ahn KH, Pelizzari CA, Kocherginsky M, Halpern HJ. Electron
paramagnetic resonance oxygen image hypoxic fraction plus radiation dose
strongly correlates with tumor cure in FSa fibrosarcomas. Int J Radiat Oncol
Biol Phys 71(2):542-9, 2008.
* # Haney CR, Parasca AD, Fan X, Bell RM, Zamora MA, Karczmar GS,
Mauceri HJ, Halpern HJ, Weichselbaum RR, Pelizzari CA. Characterization
of response to radiation mediated gene therapy by means of multimodality
imaging. Magn Reson Med 62(2):348-56, 2009.
Jiang, Yulei PhD
Krupinski EA, Jiang Y. Anniversary paper: evaluation of medical imaging
systems. Med Phys 35(2):645-59, 2008.
Peng Y, Jiang Y, Chuang ST, Yang XJ. Computer-aided Detection of Prostate
Cancer on Tissue Sections. Appl Immunohistochem Mol Morphol, 2009.
Kao, Chien-Min PhD
Kao CM. Windowed image reconstruction for time-of-flight positron emission
tomography. Phys Med Biol 53(13):3431-45, 2008.
Karczmar, Gregory PhD
* Jansen SA, Fan X, Karczmar GS, Abe H, Schmidt RA, Newstead GM.
Differentiation between benign and malignant breast lesions detected by. Magn
Reson Med 59(4):747-54, 2008.
# Hahn OM, Yang C, Medved M, Karczmar G, Kistner E, Karrison T, Manchen
E, Mitchell M, Ratain MJ, Stadler WM. Dynamic contrast-enhanced magnetic
resonance imaging pharmacodynamic biomarker study of sorafenib in
metastatic renal carcinoma. J Clin Oncol 26(28):4572-8, 2008.
* # Jansen SA, Conzen SD, Fan X, Krausz T, Zamora M, Foxley S, River
J, Newstead GM, Karczmar GS. Detection of in situ mammary cancer in
a transgenic mouse model: in vitro and in vivo MRI studies demonstrate
histopathologic correlation. Phys Med Biol 53(19):5481-93, 2008.
* # Yang C, Karczmar GS, Medved M, Oto A, Zamora M, Stadler WM.
Reproducibility assessment of a multiple reference tissue method for
quantitative dynamic contrast enhanced-MRI analysis. Magn Reson Med
61(4):851-9, 2009.
* # Haney CR, Parasca AD, Fan X, Bell RM, Zamora MA, Karczmar GS,
Mauceri HJ, Halpern HJ, Weichselbaum RR, Pelizzari CA. Characterization
of response to radiation mediated gene therapy by means of multimodality
imaging. Magn Reson Med 62(2):348-56, 2009.
Foxley S, Fan X, Mustafi D, Haney C, Zamora M, Markiewicz E, Medved M,
Wood AM, Karczmar GS. Sensitivity to tumor microvasculature without
contrast agents in high spectral and spatial resolution MR images. Magn Reson
Med 61(2):291-8, 2009.
# Liauw SL, Weichselbaum RR, Zagaja GP, Jani AB. Salvage radiotherapy
after postprostatectomy biochemical failure: does pretreatment
radioimmunoscintigraphy help select patients with locally confined
disease?. Int J Radiat Oncol Biol Phys 71(5):1316-21, 2008.
# Liauw SL, Fricano J, Correa D, Weichselbaum RR, Jani AB. Doseescalated radiation therapy for intermediate-risk prostate cancer: patient
selection for androgen deprivation therapy using percentage of positive
cores. Cancer 115(8):1784-90, 2009.
# Gutt R, Liauw SL, Weichselbaum RR. Adjuvant radiotherapy for
resected pancreatic cancer: a lack of benefit or a lack of adequate trials?.
Nat Clin Pract Gastroenterol Hepatol 6(1):38-46, 2009.
Jani AB, Johnstone PA, Liauw SL, Master VA, Brawley OW. Age and grade
trends in prostate cancer (1974-2003): a Surveillance, Epidemiology, and
End Results Registry analysis. Am J Clin Oncol 31(4):375-8, 2008.
Trabulsi EJ, Valicenti RK, Hanlon AL, Pisansky TM, Sandler HM,
Kuban DA, Catton CN, Michalski JM, Zelefsky MJ, Kupelian PA, Lin
DW, Anscher MS, Slawin KM, Roehrborn CG, Forman JD, Liauw SL,
Kestin LL, DeWeese TL, Scardino PT, Stephenson AJ, Pollack A. A
multi-institutional matched-control analysis of adjuvant and salvage
postoperative radiation therapy for pT3-4N0 prostate cancer. Urology
72(6):1298-302, discussion 1302-4, 2008.
Yeung AR, Liauw SL, Amdur RJ, Mancuso AA, Hinerman RW, Morris
CG, Villaret DB, Werning JW, Mendenhall WM. Lymph node-positive
head and neck cancer treated with definitive radiotherapy: can treatment
response determine the extent of neck dissection?. Cancer 112(5):1076-82,
2008.
MacMahon, Heber MD
* Li F, Engelmann R, Metz CE, Doi K, MacMahon H. Lung cancers
missed on chest radiographs: results obtained with a commercial
computer-aided detection program. Radiology 246(1):273-80, 2008.
* MacMahon H, Li F, Engelmann R, Roberts R, Armato S. Dual energy
subtraction and temporal subtraction chest radiography. J Thorac
Imaging 23(2):77-85, 2008.
* Li F, Engelmann R, Doi K, MacMahon H. Improved detection of small
lung cancers with dual-energy subtraction chest radiography. AJR Am J
Roentgenol 190(4):886-91, 2008.
Advanced
Imaging
* Horsch K, Giger ML, Metz CE. Prevalence scaling: applications to an
intelligent workstation for the diagnosis of breast cancer. Acad Radiol
15(11):1446-57, 2008.
* Kumazawa S, Muramatsu C, Li Q, Li F, Shiraishi J, Caligiuri P,
Schmidt RA, MacMahon H, Doi K. An investigation of radiologists’
perception of lesion similarity: observations with paired breast masses
on mammograms and paired lung nodules on CT images. Acad Radiol
15(7):887-94, 2008.
* Armato SG 3rd, Roberts RY, Kocherginsky M, Aberle DR, Kazerooni
EA, Macmahon H, van Beek EJ, Yankelevitz D, McLennan G, McNittGray MF, Meyer CR, Reeves AP, Caligiuri P, Quint LE, Sundaram B, Croft
BY, Clarke LP. Assessment of radiologist performance in the detection
of lung nodules: dependence on the definition of “truth”. Acad Radiol
16(1):28-38, 2009.
* Li F, Engelmann R, Doi K, Macmahon H. True Detection Versus
“Accidental” Detection of Small Lung Cancer by a Computer-Aided
Detection (CAD) Program on Chest Radiographs. J Digit Imaging, 2009.
Metz, Charles PhD
Hillis SL, Berbaum KS, Metz CE. Recent developments in the DorfmanBerbaum-Metz procedure for multireader ROC study analysis. Acad
Radiol 15(5):647-61, 2008.
* Horsch K, Giger ML, Metz CE. Potential effect of different radiologist
reporting methods on studies showing benefit of CAD. Acad Radiol
15(2):139-52, 2008.
La Riviere, Patrick PhD
* Li F, Engelmann R, Metz CE, Doi K, MacMahon H. Lung cancers
missed on chest radiographs: results obtained with a commercial
computer-aided detection program. Radiology 246(1):273-80, 2008.
La Riviere PJ, Vargas P. Correction for resolution nonuniformities caused
by anode angulation in computed tomography. IEEE Trans Med Imaging
27(9):1333-41, 2008.
* Horsch K, Giger ML, Metz CE. Prevalence scaling: applications to an
intelligent workstation for the diagnosis of breast cancer. Acad Radiol
15(11):1446-57, 2008.
Liauw, Stanley MD
Newstead, Gillian MB, ChB
# Liauw SL, Minsky BD. The use of capecitabine in the combined-modality
therapy for rectal cancer. Clin Colorectal Cancer 7(2):99-104, 2008.
* Jansen SA, Fan X, Karczmar GS, Abe H, Schmidt RA, Newstead GM.
Differentiation between benign and malignant breast lesions detected by.
Magn Reson Med 59(4):747-54, 2008.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
95
* Jansen SA, Fan X, Karczmar GS, Abe H, Schmidt RA, Giger M, Newstead
GM. DCEMRI of breast lesions: is kinetic analysis equally effective for both
mass and nonmass-like enhancement?. Med Phys 35(7):3102-9, 2008.
* # Jansen SA, Conzen SD, Fan X, Krausz T, Zamora M, Foxley S, River
J, Newstead GM, Karczmar GS. Detection of in situ mammary cancer in
a transgenic mouse model: in vitro and in vivo MRI studies demonstrate
histopathologic correlation. Phys Med Biol 53(19):5481-93, 2008.
* Abe H, Schmidt RA, Kulkarni K, Sennett CA, Mueller JS, Newstead GM.
Axillary Lymph Nodes Suspicious for Breast Cancer Metastasis: Sampling with
US-guided 14-Gauge Core-Needle Biopsy--Clinical Experience in 100 Patients.
Radiology 250(1):41-9, 2009.
* # Al-Hallaq HA, Mell LK, Bradley JA, Chen LF, Ali AN, Weichselbaum RR,
Newstead GM, Chmura SJ. Magnetic resonance imaging identifies multifocal
and multicentric disease in breast cancer patients who are eligible for partial
breast irradiation. Cancer 113(9):2408-14, 2008.
Nishikawa, Robert PhD
Reiser I, Nishikawa RM, Edwards AV, Kopans DB, Schmidt RA, Papaioannou
J, Moore RH. Automated detection of microcalcification clusters for digital
breast tomosynthesis using projection data only: a preliminary study. Med Phys
35(4):1486-93, 2008.
Nishikawa RM, Acharyya S, Gatsonis C, Pisano ED, Cole EB, Marques
HS, D’Orsi CJ, Farria DM, Kanal KM, Mahoney MC, Rebner M, Staiger
MJ. Comparison of soft-copy and hard-copy reading for full-field digital
mammography. Radiology 251(1):41-9, 2009.
Oto, Aytekin MD
* # Yang C, Karczmar GS, Medved M, Oto A, Zamora M, Stadler WM.
Reproducibility assessment of a multiple reference tissue method for
quantitative dynamic contrast enhanced-MRI analysis. Magn Reson Med
61(4):851-9, 2009.
* Oto A, Zhu F, Kulkarni K, Karczmar GS, Turner JR, Rubin D. Evaluation of
diffusion-weighted MR imaging for detection of bowel inflammation in patients
with Crohn’s disease. Acad Radiol 16(5):597-603, 2009.
Lewis JR, Te HS, Gehlbach B, Oto A, Chennat J, Mohanty SR. A case of
biliopleural fistula in a patient with hepatocellular carcinoma. Nat Rev
Gastroenterol Hepatol 6(4):248-51, 2009.
Oto A, Ernst R, Ghulmiyyah L, Hughes D, Saade G, Chaljub G. The role of MR
cholangiopancreatography in the evaluation of pregnant patients with acute
pancreaticobiliary disease. Br J Radiol 82(976):279-85, 2009.
Pan, Xiaochun PhD
* Cho S, Xia D, Pelizzari CA, Pan X. Exact reconstruction of volumetric images
in reverse helical cone-beam CT. Med Phys 35(7):3030-40, 2008.
Sidky EY, Pan X. Image reconstruction in circular cone-beam computed
tomography by constrained, total-variation minimization. Phys Med Biol
53(17):4777-807, 2008.
LaRoque SJ, Sidky EY, Pan X. Accurate image reconstruction from few-view
and limited-angle data in diffraction tomography. J Opt Soc Am A Opt Image
Sci Vis 25(7):1772-82, 2008.
Cho S, Pearson E, Pelizzari CA, Pan X. Region-of-interest image reconstruction
with intensity weighting in circular cone-beam CT for image-guided radiation
therapy. Med Phys 36(4):1184-92, 2009.
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Pelizzari, Charles PhD
* Cho S, Xia D, Pelizzari CA, Pan X. Exact reconstruction of volumetric images
in reverse helical cone-beam CT. Med Phys 35(7):3030-40, 2008.
* Elas M, Bell R, Hleihel D, Barth ED, McFaul C, Haney CR, Bielanska J,
Pustelny K, Ahn KH, Pelizzari CA, Kocherginsky M, Halpern HJ. Electron
paramagnetic resonance oxygen image hypoxic fraction plus radiation dose
strongly correlates with tumor cure in FSa fibrosarcomas. Int J Radiat Oncol
Biol Phys 71(2):542-9, 2008.
Aristophanous M, Penney BC, Pelizzari CA. The development and testing
of a digital PET phantom for the evaluation of tumor volume segmentation
techniques. Med Phys 35(7):3331-42, 2008.
# Altman MB, Vesper BJ, Smith BD, Stinauer MA, Pelizzari CA, Aydogan B,
Reft CS, Radosevich JA, Chmura SJ, Roeske JC. Characterization of a novel
phantom for three-dimensional in vitro cell experiments. Phys Med Biol
54(5):N75-82, 2009.
Sennett, Charlene MD
* Abe H, Schmidt RA, Kulkarni K, Sennett CA, Mueller JS, Newstead GM.
Axillary Lymph Nodes Suspicious for Breast Cancer Metastasis: Sampling with
US-guided 14-Gauge Core-Needle Biopsy--Clinical Experience in 100 Patients.
Radiology 250(1):41-9, 2009.
* Drukker K, Gruszauskas NP, Sennett CA, Giger ML. Breast US computeraided diagnosis workstation: performance with a large clinical diagnostic
population. Radiology 248(2):392-7, 2008.
* Gruszauskas NP, Drukker K, Giger ML, Sennett CA, Pesce LL. Performance
of breast ultrasound computer-aided diagnosis: dependence on image selection.
Acad Radiol 15(10):1234-45, 2008.
* Li H, Giger ML, Yuan Y, Chen W, Horsch K, Lan L, Jamieson AR, Sennett CA,
Jansen SA. Evaluation of computer-aided diagnosis on a large clinical full-field
digital mammographic dataset. Acad Radiol 15(11):1437-45, 2008.
* Yuan Y, Giger ML, Li H, Sennett C. Correlative feature analysis on FFDM.
Med Phys 35(12):5490-500, 2008.
Suzuki, Kenji PhD
* Suzuki K, Yoshida H, Nappi J, Armato SG 3rd, Dachman AH. Mixture of
expert 3D massive-training ANNs for reduction of multiple types of false
positives in CAD for detection of polyps in CT colonography. Med Phys
35(2):694-703, 2008.
Selected Major Grants and Awards
The Advanced Imaging Program has a funding base of $8,320,181 in annual total costs (current as of July 2009). This sum includes
$3,311,886 in NCI funding and $3,320,764 in other NIH funding. Due to space constraints, only new awards presented since
January 1, 2008 with funding of $100,000 or more in annual total costs are listed here.
Title
Start Date
End
Date
Annual
Total Cost
Class
Funding Agency
Halpern, Howard
Very Low Frequency EPR Imaging for
in Vivo Physiology
8/1/2008
5/31/2013
$1,333,707
P41
National Institute of
Biological Imaging and
Bioengineering
Giger, Maryellen
Optimization of Computer-Aided
Diagnosis (CAD) Output in Breast
Imaging
6/15/2006
5/31/2011
$407,744
R21
National Cancer Institute
Jiang, Yulei
Computer-Aided Diagnosis of Breast
Lesions in Mammograms
7/11/2008
6/30/2009
$302,891
R56
National Cancer Institute
La Riviere, Patrick
Tailored Algorithms for Non-Contrast
Computed Tomography Using
Sinogram Restoration
9/24/2008
7/31/2013
$270,049
R01
National Cancer Institute
Chen, Chin-Tu
Hybrid MicroSPECT/MicroCT for
Quantitative Imaging
3/1/2008
2/28/2010
$250,000
S10
National Center for
Research Resources
Kao, Chien-Min
Maximal Information Utilizing in
TOF-PET for Reducing Scatter
3/1/2009
2/28/2011
$192,445
R21
National Cancer Institute
Karczmar, Gregory
High Spectral, Spatial, Temporal
Resolution MRI
10/1/2008
9/30/2009
$192,000
N/A
North American Philips
Corporation
Giger, Maryellen
Intergrated Multi Modality Image
Based Markers of Breast Density and
Structure in Assessing Breast Cancer
Risk at the University of Chicago
8/1/2008
7/31/2011
$191,000
FG02
Department of Energy
La Riviere, Patrick
Molecular Probes and Techniques for
Optoacoustic Imaging of Proteases
7/1/2008
6/30/2012
$175,000
08
Karczmar, Gregory
Pre-Clincal Development of MRI\
Guided HIFU Marking for Lesion
Visualization
9/30/2008
9/29/2009
$141,000
N/A
North American Philips
Corporation
Oto, Aytekin
Optimization of Prostate MRI
4/1/2008
4/1/2009
$101,000
N/A
Philips Medical Systems
Advanced
Imaging
Investigator
American Cancer Society
UCCRC SCIEN T IFI C R EPO R T 20 0 9
97
P ro g r a m 6
Cancer Risk and Prevention
Human fibroblasts expressing two different forms of the BLM helicase. One cell line (top two panels) expresses the normal protein (BLM+)
and the other cell line (bottom two panels) expresses a form of BLM (SM-BLM) mutated at two sumoylation sites important for its regulation.
These cell lines were stained with antibodies to the single-stranded DNA binding protein RPA (blue stain) and the RAD51 recombinase (red stain).
BLM is identified by green fluorescence. All three proteins are important in DNA repair. After treatment of cells with the DNA damaging agent
hydroxyurea, “repair foci” form that contain concentrations of DNA repair proteins. In BLM+ cells, there are many foci that contain all three proteins
(BLM, RPA, and RAD51); however, in SM-BLM cells, although there are many foci that contain both BLM and RPA, the repair foci do not contain
RAD51 recombinase. Consequently, the regulatory mutations in BLM impair the movement to or retention of RAD51 in repair foci.
(Image by N. Ellis and K. Ouyang)
Research is focused on high-risk individuals defined by
genetics, exposure, and/or other vulnerabilities or disparities
based on race/ethnicity or access to health care.
Overview & Goals
The overall objectives of the Cancer Risk and
biomarkers for early detection of cancer; (3) to
Prevention Program are to understand the
identify genetic, physiological, and bio-behavioral
genetic, psychological, behavioral, and socio-
bases of cancer risk and prevention; and (4) to
environmental basis of cancer and to translate
solidify an organized outreach research effort in
and disseminate these cancer control research
the Southside Chicago neighborhoods to enhance
efforts in our community. The program consists
participation and utilization of University of
of 40 members from 12 departments and two
Chicago research, education, and clinical services,
University Divisions (Biological Sciences,
thereby reducing the disparities in cancer and
Social Sciences). Research is focused on high-
other health outcomes and their modifiable
risk individuals defined by genetics, exposure
determinants in the community.
(behavior, environmental), and/or other
vulnerabilities (e.g., older age) or disparities
The primary scientific goals of the Program are
(1) to elucidate the genetic and environmental
Cancer Risk
& Prevention
based on race/ethnicity or access to health care.
Program Leaders:
basis, as well as the mechanisms of progression,
for common cancers (breast, ovarian, colorectal,
prostate, lung, skin, and blood), and to translate
this new knowledge into clinical and public
health practices; (2) to develop animal models
Brian Chiu, PhD
for chemoprevention studies and develop
Andrea King, PhD
UCCRC SCIEN T IFI C R EPO R T 20 0 9
99
Members
100
Investigator*
Rank
Department
Habibul Ahsan MD
Professor
Health Studies
Anirban Basu PhD
Assistant Professor
Medicine
Marc Bissonnette MD
Associate Professor
Medicine
Eugene Chang MD
Professor
Medicine
Brian Chiu PhD
Associate Professor
Health Studies
Rena Conti PhD
Instructor
Pediatrics
Nancy Cox PhD
Professor
Medicine
William Dale MD,PhD
Assistant Professor
Medicine
Soma Das PhD
Associate Professor
Human Genetics
Harriet de Wit PhD
Professor
Psychiatry
Anna Di Rienzo PhD
Professor
Human Genetics
James Dignam PhD
Associate Professor
Health Studies
Nathan Ellis PhD
Associate Professor
Medicine
Sarah Gehlert PhD
Professor
Psychology
David Grdina PhD
Professor
Radiation and Cellular Oncology
William Green PhD
Associate Professor
Neurobiology
Tara Henderson MD,MPH
Assistant Professor
Pediatrics
Susan Hong MD,MPH
Assistant Professor
Medicine
Dezheng Huo MD, PhD
Assistant Professor
Health Studies
Nora Jaskowiak MD
Assistant Professor
Surgery
Karen Kim MD
Associate Professor
Medicine
Andrea King PhD
Associate Professor
Psychiatry
Rick Kittles PhD
Associate Professor
Medicine
Sonia Kupfer MD
Instructor
Medicine
Diane Lauderdale PhD
Associate Professor
Health Studies
Yan Chun Li PhD
Associate Professor
Medicine
Stacy Lindau MD
Assistant Professor
OB/GYN
Christopher Masi MD, PhD
Assistant Professor
Medicine
Martha McClintock PhD
Professor
Pyschology
Daniel McGeHee PhD
Associate Professor
Anesthesia/Critical Care
David Meltzer MD, PhD
Associate Professor
Medicine
Eneida Mendonca MD, PhD
Associate Professor
Pediatrics
Olufunmilayo Olopade MBBS
Professor
Medicine
Blase Polite MD
Assistant Professor
Medicine
David Rubin MD
Associate Professor
Medicine
Lisa Sanchez-Johnsen PhD
Assistant Professor
Psychiatry
Lisa Shah MD, MA
Instructor
Medicine
Marion Verp MD
Associate Professor
OB/GYN
Paul Vezina PhD
Professor
Psychiatry
Irving Waxman MD
Professor
Medicine
UCCRC SCIEN T IFI C R EPO R T 20 0 9
* Reflects all Program membership during 2008-2009
Featured Faculty Research Summaries†
The Cancer Risk and Prevention Program conducts a broad scope of
research that encompasses basic studies of carcinogenesis, preclinical and
clinical translational research, behavioral and epidemiological studies,
as well as population-based genetic research. Investigators focus their
work on research themes that reflect the scientific goals of the Program as
highlighted below.
Theme: Genetic and Environmental Basis for Cancer
Olufunmilayo Olopade, MBBS
Professor of Medicine
Dr. Olopade’s multidisciplinary research team is working
to advance research on the prevention, early detection,
and treatment of breast cancer, specifically focusing on the
interplay of genes and environment in the development
of triple-negative breast cancer, which tends to be more
aggressive, less responsive to treatment, and more likely
to strike young women and those of African ancestry. The
team is working to identify and characterize genes relevant
Dr. Olufunmilayo Olopade
to tumor progression, determine their role in inherited
susceptibility, and perform genetic epidemiologic analyses
translatable to clinical practice. The laboratory is also focused on understanding epigenetic mechanisms underlying
abnormal gene expression, including aberrant CpG-island-promoter methylation of specific tumor suppressor
genes, global changes in genomic DNA methylation, and alterations in histone modification (deacetylation and
The ultimate goal of Dr. Olopade’s research is to develop more effective and less harmful methods to prevent, screen,
and treat breast cancer in all women. The specific aims are to 1) identify and elucidate the genetic and environmental
factors that influence breast cancer progression; 2) improve tools used for breast cancer diagnosis; and 3) develop
Cancer Risk
& Prevention
methylation).
new personalized therapies that specifically target tumors.
Recent findings in the laboratory have revealed differences in tumor biology, with Africans and African Americans
having poorly-differentiated tumors that lack estrogen receptor expression and present in advanced stages. These
biological differences lead to cancers that are more difficult to diagnose and treat, leading to poorer health outcomes.
Thus, the findings suggest that disparities in cancer epidemiology are in part due to genetic differences among racial/
ethnic populations.
Rick Kittles, PhD
Associate Professor of Medicine
Dr. Kittles’ overall research focus is to formally evaluate genetic mechanisms involved in complex diseases. His
work entails understanding how genetic variation is structured across human populations and how that variation
contributes to inter-individual variation in disease susceptibility. His interests also include biological and sociocultural issues related to “Race” and health disparities.
Recent findings in Dr. Kittles’ laboratory indicate that chromosome band 8q24.1 harbors four independent regions
of susceptibility to prostate cancer (Pca). These regions on 8q24 span over 2 million base pairs (Mb) and constitute a
gene desert, containing only four known transcription units and no apparent microRNA genes. Three of the regions
cluster in a distal 8q24.1 region from 128.15 Mb to 128.65 Mb, which is itself 200 kb proximal to the MYC gene. The
laboratory is currently trying to decipher the specific functional changes that occur in this region of DNA that lead
† Note: Due to space constraints, only a small representative sample of Program members is presented here.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
101
to prostate cancer. The work has major implications given that this region will likely be a target for drug development or risk
assessment.
The Kittles laboratory has been at the forefront of the development of ancestry-informative genetic markers, admixture mapping
theory, and applications for disease gene mapping in admixed populations, such as African Americans and Hispanics. Recently,
Dr. Kittles’ laboratory and collaborators at Wayne State University completed an admixture mapping study for prostate cancer
susceptibility genes in AAs. The team found significant evidence of association with Pca on chromosomes 5q35 and 7q31 and
confirmed the previous ancestry linkages on 8q24.1. Fine mapping with greater ancestry informative marker density in these
regions is needed to narrow the defined locus and better target candidate gene.
Dr. Kittles firmly believes that genetics will play a major role in early detection and risk assessment for Pca, especially for AA
men given their higher risk compared to European Americans (EAs). High-risk men have been found to have Pca detected at
low PSA values, even <2.5 ng/mL. Determining which high-risk men should have prostate biopsies at low PSA values is crucial
to early detection and avoid unnecessary biopsies. Dr. Kittles and colleagues at Fox Chase Cancer Center investigated the
concept of “race-specific” PSA by determining if baseline PSA differed by self-reported race or was associated with genetic
markers of west African (WA) ancestry based on a panel of 100 previously validated ancestry informative markers in AA men.
The team tested if differences in PSA predictive ability for Pca were due to variation in WA ancestry and found a trend for higher
prediction for PCA at any given PSA in the range of 1.5-4.0 ng/mL with increasing genetic WA ancestry. The clinical implication
of this analysis is that an AA man with high levels of WA ancestry (>80%) may have a biopsy recommendation at a PSA of 3.0
versus another AA man with a similar PSA value but lower WA ancestry (<50%).
The laboratory also has a strong interest in understanding the role vitamin D plays in prostate and colon cancer. Many
epidemiologic studies link serum vitamin D levels to breast, colon and prostate cancer; however, no clear consensus exists on
its role. The Kittles group is currently involved in a population-based study of AA and EA men to examine how much serum 25(OH) vitamin levels vary, and if it is modified by genetic and environmental factors, such as ultraviolet radiation exposure, skin
color, diet and genes involved in Vitamin D synthesis, metabolism and action.
Brian Chiu, PhD
Associate Professor of Health Studies
Dr. Chiu’s research focuses on identifying genetic makeup and environmental exposures that influence risk of hematopoietic
cancers, particularly non-Hodgkin lymphoma (NHL) and multiple myeloma, as well as identifying potential prevention
strategies for reducing racial/ethnic disparities in the incidence and progression of hematopoietic cancers.
Dr. Chiu is currently the PI of a large population-based study funded by the NCI to classify subgroups of non-Hodgkin
lymphoma (NHL) according to patterns of chromosomal aberrations. This study includes approximately 1,400 patients of NHL
and 3,200 controls (demographically similar patients who do not have NHL) to identify specific molecular pathways for which
certain environmental factors might be associated with the risk of developing NHL. Dr. Chiu and his team recently reported
that pesticide exposure is associated with a higher risk of NHL that exhibits the t(14;18)(q32;q21) chromosomal translocation,
but not t(14;18)-negative NHL. They also reported that a family history of hematopoietic cancer was associated with a twofold higher risk for both t(14;18)-positive and t(14;18)-negative NHL. In addition, they published the first study suggesting that
the diet-NHL association may differ according to the presence or absence of the t(14;18). By classifying NHL into potential
prognostic subgroups at the molecular level, their work points to a new avenue of research on NHL that could potentially
provide new insights into the pathogenesis of NHL.
Recent analysis of the data, from a population-based case-control study of 387 cases with newly diagnosed NHL and 535 controls
conducted by Dr. Chiu and colleagues, indicates that lifestyles and behaviors may affect the likelihood of developing NHL.
They found that a higher intake of green leafy vegetables and cruciferous vegetables was associated with a lower risk of NHL.
In addition, participants with NHL were more likely to report fewer hours of sun exposure than controls. They also found that
individuals who were obese (body mass index ≥30.0 kg/m2) had approximately 40 percent higher risk of NHL than people who
were normal weight. The risk was particularly higher for those who were class II obese or obese at ages 40-49 years. To follow up
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UCCRC SCIEN T IFI C R EPO R T 20 0 9
on these new leads, Dr. Chiu and colleagues are developing a large bio-repository of blood and tissue samples from patients
with lymphoma and multiple myeloma at the University of Chicago that will be annotated not only with treatment and
outcome information, but also with molecular characteristics and extensive epidemiologic data. A strong emphasis will be
placed on the detection of factors for racial/ethnic disparities in hematopoietic cancers.
Because NHL includes more than 20 histologic and clinicopathologic subtypes, a long period of time is required to conduct
studies at a single institution with enough patients to yield the statistical power necessary to identify factors associated with
risk for rare subtypes of NHL. To address this issue, Dr. Chiu is collaborating with researchers around the world to pool
data across studies, including the International Lymphoma Epidemiology Consortium (InterLymph) and the International
Multiple Myeloma Consortium. For example, in a recent pooled analysis of 29,423 participants in the United States, Europe,
and Australia, the InterLymph Consortium reported that Sjögren syndrome and Systemic lupus erythematosus are associated
with a higher risk of marginal zone lymphoma and diffuse large B-cell lymphoma, whereas celiac disease and psoriasis
are associated with a higher risk of T-cell lymphoma. As part of another worldwide collaboration, Dr. Chiu and colleagues
are developing a new consortium that will collect data from several Eastern Asian cities and countries. He will specifically
oversee the work at the Taiwan study site. This new consortium will provide a great opportunity to investigate environmental
and genetic risk factors for lymphoma in different populations.
Theme: Models for Chemoprevention and Biomarker Identification
Habibul Ahsan, MD
Professor of Health Studies, Medicine, and Human Genetics
Dr. Ahsan’s research interests focus on studying the interrelationships between environmental and genomic factors in
cancer and exploiting information on these relationships at
a population level for developing and evaluating prevention
interventions in humans. The research integrates environmental,
Cancer Risk
& Prevention
nutritional, and life-style factors with measures of host factors
and molecular genomics (involving DNA, RNA and protein
variations) to understand the etiology, pathogenesis, prognosis,
and prevention of cancer and other disorders of national and
international public health significance.
Ongoing NIH-funded major research projects include: 1) a
Pathology image analysis in the UCCRC’s Human Tissue
Resource Center.
genome-wide association study of early-onset breast cancer
among 6,000 cases and controls; 2) a prospective cohort study of 20,000 men and women in Bangladesh to investigate the
cancer risk from arsenic exposure; 3) genetic susceptibility to arsenic-related skin tumors among 3,000 cases and controls;
and 4) a randomized trial of vitamin E and selenium among 6,000 arsenic-exposed patients for the prevention of cancers and
deaths.
Dr. Ahsan conducted a series of observational, pilot randomized chemoprevention trials (RCTs) and molecular studies,
which led to a large skin tumor chemoprevention RCT for antioxidants. His team showed that arsenic is positively associated
with oxidative stress biomarkers, including urinary 8-OHdG and F2-isoprostane, and plasma protein carbonyl, sICAM and
sVCAM. His group was also the first to develop and validate a food frequency questionnaire (FFQ) for assessing the diet
of South Asian populations, which revealed that dietary intakes of antioxidants reduce risk of arsenical skin tumors. The
measurement of blood selenium levels indicated a strong, protective effect of selenium on risk of premalignant skin lesions. In
a parallel RCT, Dr. Ahsan’s team showed a clear enhancement of urinary arsenic excretion after selenium supplementation.
The beneficial effects of selenium were further supported by molecular studies, in which the team demonstrated that arsenic
exposure leads to aberrant expression of specific oxidative stress- and inflammation-related genes. In an independent study,
UCCRC SCIEN T IFI C R EPO R T 20 0 9
103
Dr. Ahsan’s team showed that selenium supplementation can revert these specific gene expressions and that arsenic causes
global DNA hypermethylation, whereas in the same individuals, selenium leads to DNA hypomethylation.
Based on these studies, a large chemoprevention RCT was established to evaluate the effects selenium and vitamin E
supplementation on prevention of skin tumorigenesis among 6000 study participants. While this 10-year trial is currently
underway, findings are likely to demonstrate important data on cancer chemoprevention. Dr. Ahsan is also involved in a series
of observational, molecular, and short-term RCTs to establish folate as an effective agent in promoting excretion of arsenic from
the body. However, unlike selenium and vitamin E, folate is unlikely to offer any long-term chemoprevention effect for cancer
once arsenic exposure is removed and, thus, may not be suitable as a long-term chemoprevention modality.
In addition, Dr. Ahsan and colleagues are studying genetic and other host determinants of cancer risk and survival, especially
for breast cancer. In a recent study, they showed that women carrying certain hormone-related genes are at higher risk of breast
cancer and found that placental genetic profile is predictive of post-pregnancy breast cancer risk, suggesting that offspring’s and
mating partner’s genotypes are predictive of risk. Dr. Ahsan’s team has also examined genomic losses and gains in breast cancer
and identified novel loci. Currently, they are extending these investigations to understand genome level sequence variations as
well as loss or gain of genes in 3,000 women with early-onset breast cancer and in an equal number of age-matched controls.
These findings will be followed by investigations of the same set of genomic determinants in relation to breast cancer survival.
Marc Bissonnette, MD
Associate Professor of Medicine
Epidermal growth factor receptors (EGFR) and their ligands are overexpressed in colon cancer. Dr. Bissonnette’s team has
shown that EGFR blockade inhibits experimental colonic carcinogenesis, and clinical studies have demonstrated efficacy of anti
EGFR antibodies in combination with cytotoxic chemotherapy for metastatic human colon cancer. The overall objective of the
Bissonnette laboratory is to understand the roles of EGFR in colonic carcinogenesis and develop chemopreventive strategies.
Azoxymethane (AOM) and azoxymethane/dextran sulfate sodium (AOM/DSS) carcinogen models are employed using mice
with up- or down-regulated EGFR signaling cascades to elucidate growth factor pathways in sporadic and inflammatory human
colon cancer. In the AOM and AOM/DSS models, the laboratory demonstrated that EGFR and its ligands are up-regulated in
dysplastic aberrant crypt foci, the earliest detectable premalignant lesion in colonic carcinogenesis. Furthermore, EGFR signals
are required for later stages of tumor progression.
Environmental factors, especially dietary constituents, contribute substantially to the risk of sporadic human colon cancer.
Recent studies in the laboratory indicated that tumor promotion by Western style dietary fat also requires EGFR signals. This
effect appears to involve increases in cyclooxygenase-2 (Cox-2) in the tumor stroma. Cox-2 is the rate-limiting enzyme in
biosynthesis of prostanoids that drive proliferation, angiogenesis, and cell survival. The Bissonnette group is currently dissecting
the roles of stromal fibroblast and epithelial EGFR to understand their contributions to Cox-2 regulation in tumorigenesis. In
contrast to tumor promoting effects of Western style dietary fat, other naturally-occurring dietary constituents, such as green
tea, curcumin and vitamin D3, exhibit chemopreventive activity against colon cancer. These substances also inhibit EGFR
signals, but the role of EGFR inhibition in their anti-cancer effects has not been elucidated. This previously unknown interaction
of EGFR and diet could potentially be exploited using such naturally occurring agents to reduce the diet-associated colon cancer
risk for insulin-dependent diabetes and obesity. Furthermore, development of more effective chemopreventive analogues, based
perhaps upon their EGFR inhibitory profile, might provide improved strategies to prevent this often-fatal disease.
Specific aims in the laboratory include 1) dissection of the roles of epithelial cell and fibroblast EGFR in colonic neoplastic
transformation; 2) identification of targets regulated by miR-143 and miR-145 in colonic tumorigenesis; 3) studies to uncover
the connections between diet and EGFR in colonic tumor promotion; 4) elucidation of the roles of EGFR in tumor invasion and
metastasis, as the laboratory showed that loss of EGFR in stromal cells greatly attenuated colon cancer tumor xenograft growth;
and 5) deciphering vitamin D-VDR pathways that inhibit diet-induced inflammation and colon cancer development.
The laboratory has also recently discovered a novel and potentially important role for EGFR in regulating microRNA in colonic
tumorigenesis. These small non-coding RNA regulate messenger RNA stability or translation and are involved in a wide range
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of normal and malignant processes. Putative tumor suppressors, such as miR-143 and miR-145, are down-regulated in colon
cancer. In the AOM/DSS model, this down-regulation requires EGFR. Consistent with these findings, the laboratory showed
that EGFR negatively regulates these miRNA in cell culture. Conversely, when miR-143 and miR-145 were transfected into
colon cancer cells, these miRNA inhibited EGFR-induced proliferation. Thus, tumor-promoting effects of EGFR appear to be
mediated at least in part by down-regulating miR-143 and miR-145. Studies are in progress to understand how EGFR regulates
these miRNA and what targets mediate their effects.
Nathan Ellis, PhD
Associate Professor of Medicine
The overall research focus of the Ellis laboratory is the study of genomic instability and its relationship to colorectal cancer
(CRC) susceptibility. Germline mutations and somatic genetic changes in DNA repair genes are causally linked to hereditary
CRC cancer syndromes and carcinogenesis, respectively, demonstrating that the maintenance of genomic integrity plays a
crucial role in cancer susceptibility. The laboratory employs candidate gene and genome-wide association studies to identify
cancer risk genes and carries out DNA sequencing studies to pinpoint and analyze culprit mutations. These genetic analyses
are combined with functional analyses to determine how genetic alterations alter repair function and cause increased cancer
susceptibility.
A particular strength of Dr. Ellis’s laboratory is the capacity to perform comparative genetic studies in different human
populations to assess the impact on cancer risk. The patient base at The University of Chicago includes a large contingent
of African Americans (AA), which offers a more genetically diverse perspective than other populations and results in an
increased power to localize genetic risk factors to smaller regions. In addition, heterogeneity in genetic risk factors has
proven useful in elucidating risk factor functions, especially those of low frequency. The Ellis laboratory also examines
AA-specific factors in CRC incidence to shed light on the causes of health disparities in this population. A consortium of
CRC investigators at major Chicago hospitals, who are pooling biological specimens, clinical data, and research expertise to
The Ellis laboratory studies genetic risk factors in CRC through the identification of high-interest DNA repair genes from
published genome-wide association and other biological studies. By searching HapMap and public sequence databases, single
nucleotide polymorphisms (SNPs) in the high-interest genes are analyzed, identifying tagging SNPs so that a systematic
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enhance these comparative studies, has been established.
analysis of all genetic variation can be conducted. Next, the frequencies of these genetic polymorphisms are compared in
cases versus controls in a large cohort from the University of Chicago to identify associations that potentially increase CRC
risk. Putative risk factors are replicated in additional case-control cohorts, and regions that contain putative risk factors
are subjected to deep sequence analysis. Further genotype analysis is performed to pinpoint candidate causal sequence
alterations. The causal sequence alterations in cell culture systems are then studied to determine their effects on DNA repair
function and genomic integrity.
The laboratory performed a systematic SNP analysis of genes in the base excision repair (BER) pathway, which removes
oxidative and other damages from DNA, and found a strong association between a pair of contiguous SNPs in XRCC1 and AA
CRC cases. The same SNPs were not associated with CRC in European Americans, nor were previously studied amino acid
substitutions in XRCC1 found to be associated with CRC in either population. Bioinformatic analysis has identified important
regulatory sequences in the region containing these two SNPs, which is now the focus of deep sequence analysis.
In multiple genome-wide association studies, a series of small regions in a two million base pair segment of chromosome
8q24.1 have been associated with prostate, colorectal, breast, and ovarian cancer. In collaboration with Dr. Rick Kittles, the
laboratory has linked SNPs in a DNA repair gene called MMS21 with CRC, which intersects with functional studies of the
BLM gene involved in homologous recombination repair. The Ellis laboratory is currently sequencing the MMS21 region to
fully explore alterations that are associated with genetic risk, develop cell culture models for studying the role of MMS21 in
homologous recombination repair, and assay BLM functions. These models will eventually be used to dissect culprit sequence
alterations and elucidate the molecular mechanisms by which they confer increased genetic risk.
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Theme: Psychological and Bio-Behavioral Basis of Cancer Risk and Prevention
Martha McClintock, PhD
Professor of Pyschology
Dr. McClintock studies the reciprocal interactions between social
behavior and psychological states. Because behavior and biological
mechanisms are reciprocally linked, Dr. McClintock’s research
centers on the behavioral control of endocrinology, immunology
and disease, in addition to the hormonal and neuroendocrine
mechanisms of behavior. Current interests in the laboratory focus
on breast cancer, working with both animal and parallel clinical
processes in humans.
In collaboration with Dr. Suzanne Conzen (Cell Signaling and Gene
Regulation Program), the laboratory discovered that social isolation
Development of a fingerstick blood spot technique,
a minimally invasive method for obtaining biological
information in population-based cancer risk research.
(Image by S. Lindau)
increases the risk of malignant mammary tumors, accelerates
aging and shortens the lifespan in both rat and transgenic mouse
models. These results demonstrate that social isolation regulates gene expression. Through additional work with the Center
for Interdisciplinary Health Disparities Research, Dr. McClintock is applying this basic research to understand the dramatic
health disparity in mortality between African-American women and women of Northern European ancestry with breast cancer.
In addition, Dr. McClintock collaborates with Center colleagues, Drs. Gehlert and Olopade, in conducting translational health
disparities research among African-American women, in the communities surrounding the University of Chicago, who have
breast cancer and are at greater risk for high mortality. The goal of this research is to identify social and psychological factors
that underlie the dramatic health disparity in Chicago, utilizing the insights gained to reduce risk in all women.
In a life span study, the McClintock laboratory examined how the social environment regulates spontaneous mammary tumor
development and malignancy in genetically-prone Sprague-Dawley rats by randomly assigning animals to live either alone or
in groups of five female rats. Mammary tumor burden among social isolates increased to eighty-four times that of age-matched
controls, as did tumor malignancy. Specifically, social isolates showed a 3.3 relative risk for observed ductal carcinoma in
situ and invasive ductal carcinoma, the most common early breast cancers in women. Importantly, isolation did not extend
ovarian function in late middle age; in fact, isolated animals were exposed to lower levels of estrogen and progesterone in the
middle-age period of mammary tumor growth while tumor estrogen and progesterone receptor status remained unchanged.
Isolates, however, did develop significant dysregulation of corticosterone responses to everyday stressors manifest before tumor
development in early adulthood, and enduring across the lifespan. Among isolates, corticosterone recovery from an acute
stressor was highly attenuated and associated with increased progression of mammary tumors. In addition to being stress and
tumor prone, an array of behavioral measures demonstrated that socially isolated females possess an anxious, fearful, and
vigilant phenotype.
This animal model of spontaneous breast cancer provides a framework for studying the interaction of social neglect with genetic
risk to identify mechanisms whereby psychosocial stressors increase malignancy and growth of breast cancer. Specifically, as
part of the National Social Life Health and Aging Project (NSHAP), Dr. McClintock is examining psychosocial mechanisms
of malignant disease, reconceptualizing health during aging to include mental health and social context. In a sample of 3,000
people between the ages of 57 and 85, selected to be demographically representative of the United States, reproductive cancers
are the second most prevalent cancers, with skin cancer being the most common. In a nude mouse model of skin cancer, social
isolation in the face of recurring stressors accelerated the progression of skin cancers following UV radiation. The social and
psychological risk factors of both reproductive and skin cancers will be further studied in the second wave of the NSHAP, in
which the sample will be expanded to 4,500 by including partners of the original participants. Genetic and stress measures will
be obtained, in addition to the original biomeasures, including medical histories, psychological profiles and social structures.
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Harriet de Wit, PhD
Professor of Psychiatry
The Human Behavioral Pharmacology Laboratory (HBPL), directed by Dr. de Wit, studies the causes and consequences of
recreational drug use, including cancer-related drugs such as tobacco and alcohol. Causes of drug use include factors such
as personality, genetics, stress, and behavioral dimensions, such as sensitivity to reward or insensitivity to punishment. The
laboratory studies these risk factors as predictors of individuals’ responses to low doses of a drug, which, in turn, can predict
risk for future use. Drugs of abuse have complex effects on behavior, including effects on mood states, decision-making,
and cognition that can lead to repeated, or hazardous, use of the drugs. These drug effects are studied under controlled
conditions to identify risk factors for repeated or hazardous use. One important aim of the research is to identify brain mechanisms that mediate the behavioral effects of drugs. In
collaboration with Dr. Abe Palmer of the Department of Human Genetics, the laboratory is studying variations in the
genes that encode proteins involved in neurotransmitter functions, in relation to the behavioral responses to acute drug
administration. For example, the deWit team has shown that polymorphisms in genes encoding aspects of dopamine
receptor function are associated with variations in the behavioral effects of d-amphetamine. That is, some of the interindividual differences in acute responses to a stimulant drug can be explained by variation in the targets of the drug’s action.
These variations may also affect future risk for using the drug in a hazardous or excessive manner.
Another aim of the research is to study the relationships between stress and drug use. Stress is thought to increase the
risk for drug use, and drug use, in turn, may affect an individual’s responses to stress. In collaboration with Drs. Andrea
King, Ajna Hamidovic and Emma Childs, of the Department of Psychiatry and Behavioral Neuroscience, the laboratory is
studying stress responses in young adults as predictors of cigarette smoking. In one study that was supported by the UCCRC,
the team is testing whether behavioral and physiological responses to an acute social stressor (a public speaking task)
predicts progression from occasional smoking to regular smoking over a 6 month period. In other studies, the laboratory is
together, these studies will improve the current understanding of complex interactions between stress and drug use, and how
stress may increase risk for future drug use.
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investigating the effects of acute stress on responses to drugs, and the effects of drugs on responses to acute stress. Taken
In a further study, the de Wit laboratory is studying factors involved in relapse to smoking. Drug users, including smokers,
remain at risk for relapse long after the drug’s effects have subsided, and most drug users who are able to quit ultimately
relapse. Relapse is thought to be related to conditioned, drug-related cues, but it is not known how reactions to these cues
change with time. Recent studies with animal models of relapse suggest that cues become more, rather than less, effective
with longer periods of abstinence. In collaboration with researchers at the National Institute on Drug Abuse Intramural
Research Program, the laboratory is studying craving elicited by smoking-related cues in smokers who abstain for 7, 14 or 35
days to study the time course of cue-induced cravings. This study will provide important information about how drug-related
cravings change over the course of extended periods of abstinence from smoking.
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Daniel McGehee, PhD
Associate Professor of Anesthesia/Critical Care
The primary goal of the research in Dr. McGehee’s laboratory is understanding the cellular mechanisms underlying nicotine
addiction. Nicotine is the principal neuroactive component of tobacco, and addiction to tobacco products is one of the main
causes of preventable illness and premature death in this country. Tobacco use is associated with remarkably high prevalence of
multiple forms of cancer.
Using electrophysiological recording methods in rat brain slices, the laboratory is testing synaptic transmission and plasticity
within brain reward circuitry. The brain areas being investigated include the midbrain dopamine system, its afferent inputs,
and efferent projection sites. The aims of Dr. McGehee’s research are to assess the impact of both acute and long-term nicotine
exposure on synaptic strength in the ventral tegmental area, nucleus accumbens, and brainstem cholinergic centers. With
support from the UCCRC, the laboratory has recently begun to investigate the impact of co-administration of nicotine and
ethanol, as these drugs are the most commonly abused substances in our society with a high degree of co-morbidity. In this
regard, the McGehee team is testing the interaction of ethanol with nicotinic receptors in these brain areas. Preliminary
results indicate profound enhancement of nicotinic responses in VTA, but significant suppression in the brainstem cholinergic
centers. This line of research may lead to novel treatments for both nicotine and ethanol abuse.
The most recently published work investigated the impact of nicotine and opiate drugs on dopamine release in the nucleus
accumbens and dorsal striatum. A profound overlap of the effects of these two classes of addictive drugs was observed on
dopamine release dynamics. The data suggest a common mechanism in rewarding effects of these drugs, again suggesting
possible treatment strategies.
Theme: Community Outreach to Reduce Health Disparities
Karen Kim, MD
Associate Professor of Medicine
Dr. Kim is nationally recognized as an advocate for reducing
health disparities and equal access to health care for Asian
Americans and is the cofounder of the Asian Cancer
Prevention Organization. Specifically, Dr. Kim’s research
interest focuses on community based interventions directed at
improving access to cancer screening in minority populations.
Research is focused on two specific cancers, hepatocellular
carcinoma and colorectal cancer. Her interest in hepatitis B
induced liver cancer is part of a recently Centers for Disease
Dr. Rick Kittles
Control-funded program which addresses awareness and
cultural competent messaging to improve hepatitis B screening in Asian Americans. Asian Americans have the highest rates of
hepatocellular cancer worldwide as a direct result of chronic infection with hepatitis B. Dr. Kim’s research utilizes a lay health
educator model in several Chicago Asian communities, including Chinese, Korean, Vietnamese, Laotian, and Cambodian
immigrant communities to improve awareness and screening for hepatitis B to decrease the liver cancer burden in these high
risk and underserved communities. Prevalence rates for chronic hepatitis B infection vary significantly between ethnic specific
communities with rates as high as 13.5% in Chinese communities, and as low as 4.6% in Korean communities. These efforts have
resulted in increased funding to address the need to disaggregate the Asian American community health data to understand
the health disparities better in minority communities. Dr. Kim is part of a community-wide research program to collect local
health indices for cancer screening in order to inform policy and public health leaders about the need for programs directed
toward these culturally- and linguistically-isolated communities.
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Dr. Kim’s second area of research interest addresses disparities in colorectal cancer in African Americans. Despite the
higher incidence of colorectal cancer in African Americans, studies addressing interventions specifically targeting cancer
prevention are lacking. Low Vitamin D levels have been hypothesized to be associated with increased mortality from
colorectal cancer, and epidemiological studies show that African Americans are at greatest risk for reduced vitamin D levels.
Therefore, chemoprevention trials using vitamin D may have a greater impact on African Americans than other populations.
Unfortunately, national clinical trials using vitamin D have low African American enrollment. Dr. Kim’s research, funded
by the American Cancer Society and the UCCRC, studies the feasibility of vitamin D chemoprevention on polyp prevention
in African Americans. Preliminary results have shown recruitment rates of 80% with 35% enrollment. Ongoing work to
understand barriers to minority enrollment in clinical trials continue to be a priority. Dr. Kim hopes to expand this work
into a multi-center study in the near future.
Lisa Sanchez-Johnsen, PhD
Assistant Professor of Psychiatry
Dr. Lisa Sánchez-Johnsen is the Director of both the Multicultural Health Research Program and the Latino Health
Research Program in the Department of Psychiatry & Behavioral Neuroscience. She has extensive experience in community
participatory research and has served as the chair of several community advisory boards for Latino health in Illinois and
Hawaii. As part of Dr. Sánchez’s research studies, she has active involvement in Hispanic/Latino Health Community
Advisory Boards, which are instrumental in developing and implementing those studies. Her areas of interest include
conducting cancer prevention research with underserved ethnic minority groups, such as Latinos, African Americans, and
Asians. She is currently conducting clinic and community-based and culturally competent cancer risk reduction assessments
and interventions in the areas of obesity, physical activity, body image, and smoking.
As part of Dr. Sánchez’s K01 award and her U of C Health Disparities Research grant, she is pilot-testing a communitybased obesity and secondhand smoke education intervention with 40 Latina women. The specific aims of her K01 study are
intervention in 40 overweight Latinas using a community-based participatory framework; 2) estimate the effectiveness of
this intervention on weight loss, healthy body image, healthy eating, physical activity; and secondhand smoke education; and
3) develop and adapt measures of diet, physical activity, body image, and tobacco use to be culturally proficient for Latinas,
and compare their reliability and validity. In the first phase, she completed quantitative and qualitative interviews with 20
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to: 1) test the acceptability and feasibility of a 6-week culturally-proficient diet, physical activity, body image, and tobacco
women to test the acceptability of the questionnaires and to guide the development of the intervention. In the second phase,
she is conducting a culture-based diet, physical activity, body image, and tobacco intervention for overweight Latina females,
using a community-based participatory research framework.
Dr. Sánchez’s early research revealed that Blacks consumed more calories and percent calories from fat than Latinas, whereas
Latinas consumed more fiber and calories from carbohydrates and protein than Blacks. Latinas also preferred a thinner
body and had a greater body image discrepancy than Blacks. Blacks were also more sedentary than Latinas. These findings
highlighted the need to explore cultural variables underlying ethnicity, as it relates to diet, physical activity, and body image,
so that culture-based community obesity interventions can be developed. To address this need, Dr. Sánchez is conducting
an NCI R21 study (to explore the role of four cultural variables (acculturation, acculturative stress, ethnic identity, and
cultural values) that may help to explain the ethnic disparities in correlates of overweight/obesity (diet, physical activity,
and body image) among Mexican and Puerto Rican women. The research will also identify logistical/practical and cultural
considerations regarding the development of diet, physical activity, and body image interventions for overweight Mexican and
Puerto Rican women. Results will be used to develop tailored and targeted interventions that address diet, physical activity,
and body image in overweight Mexican and Puerto Rican women of various acculturation levels.
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Sarah Gehlert, PhD
Professor of the School for Social Service Administration
Dr. Sarah Gehlert is the Principal Investigator of the Center for Interdisciplinary Health Disparities Research (CIHDR), funded
by an initiative of the National Cancer Institute, National Institute of Environmental Health Sciences, Office of Social and
Behavioral Research, and National Institute of Aging. The CIHDR aims to 1) bring together scientists from inside and outside
the University and members of the community to inform the CIHDR’s scientific agenda; 2) increase interest in population
health and health disparities among scientists and students from various disciplines and from community members; and 3)
disseminate findings to as wide an audience as possible, including members of vulnerable populations, community-based
organizations and agencies, and scientific investigators inside and outside the University.
Dr. Gehlert also leads one of CIHDR’s four interdependent and mutually-informative research projects entitled “Social
environment, stress, and health.” In its first year of operation, the project conducted 49 community-based participatory focus
groups in South Side Chicago neighborhood areas to understand how residents conceptualize breast cancer and its treatment
and how accurately psychosocial constructs and measures used in other CIHDR projects captured residents’ life experiences.
Dr. Gehlert contributed towards two publications that resulted from focus group activities, involving community epidemiology
of breast cancer risk and perceptions of breast cancer and its treatment among African-American women and men.
The project shares a central research question with CIHDR projects by Drs. Fumni Olopade, Martha McClintock, and Suzanne
Conzen (Cell Signaling and Gene Regulation Program), namely how factors in women’s social environments contribute to the
African American and white disparity in breast cancer mortality in the United States. Informed by the focus group data and
experiences, the Gehlert laboratory staff worked with African American women newly diagnosed with breast cancer living on
Chicago’s South Side to address two additional specific aims: 1) to utilize the informed and modified instruments along with
biological/genetic- and neighborhood/community-level variables to understand the relationships between social, behavioral,
and biological factors in the etiology of breast cancer among African-American women (compared to white women); and 2)
to develop recommendations to inform health care policy, practice, and education around breast cancer. Women are followed
for 1.5 years, and data is collected inside the home (perceived discrimination, social network living arrangements, depression)
and in a four-block area around each woman’s home to assess built environment and publically-available data on crime,
socioeconomic status, etc. geo-coded to each woman’s address. As a result, the team outlined a multi-level model of breast
cancer, and in collaboration with the Principal Investigators of the other eight centers funded by the same initiative, outlined
their shared model of how disparities develop.
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Additional Program Highlights*
Research
•• Community-Based Smoking Cessation to Reduce African American Health Disparities. Andrea King, PhD, Lisa
Sánchez-Johnsen, PhD, and colleagues developed an intensive group-based smoking cessation intervention program and
provided transdermal nicotine patches to urban low- and middle income African American smokers to reduce health
disparities in access and comfort with tobacco interventions. Results showed the majority of participants completed the
intervention, adhered to patch and approximately one-third had quit smoking by the end of treatment. Predictors of success
in treatment included patch adherence, utilization of the cognitive-behavioral skills in the program, and lower negative
effect. The research team concluded that more studies are warranted to examine targeted treatment elements and individual
difference factors to enhance cessation outcomes in African American smokers (King et al., Journal National Med Assoc
100:208-217, 2008).
•• Prediction of BRCA Mutations Using the BRCAPRO Model in Clinic-Based African American, Hispanic, and Other
Minority Families in the United States. BRCAPRO, a BRCA1/BRCA2 mutation carrier prediction model, was developed on
the basis of studies in individuals of Ashkenazi Jewish and European ancestry. Olufunmilayo Olopade, MBBS, and Dezheng
Huo, MD, PhD evaluated the performance of the BRCAPRO model among clinic-based minority families and assessed the
clinical utility of mutation status of probands (the first individual tested in a family) in the recommendation of BRCA1/
BRCA2 mutation testing for other at-risk family members. The findings support the use of BRCAPRO in pretest BRCA1/
BRCA2 mutation prediction among minority families in clinical settings, but there is room for improvement in ethnic
groups other than Hispanics. Knowledge of the mutation status of the proband provides additional predictive value, which
may guide genetic counselors in recommending BRCA1/BRCA2 testing of additional relatives when a proband has tested
negative (Huo et al., J Clin Oncol 10;27(8):1184-1190, 2009).
racial differences in clinical outcomes in the setting of two large cooperative group randomized clinical trials. The study
cohort consisted of 787 white and 195 African American patients with metastatic breast cancer enrolled in two successive
Cancer and Leukemia Group B (CALGB) trials using taxanes in the metastatic setting. African Americans with metastatic
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•• Racial differences in clinical outcomes from metastatic breast cancer. Blaise Polite, MD, and his colleagues examined
breast cancer have an increased hazard of death compared with whites despite the receipt of similar per-protocol treatment,
but experience no differences in time to treatment failure or overall response to therapy. More direct and robust measures
of comorbidities, and perhaps other factors, such as receipt of subsequent therapy could help further explain the observed
survival difference (Polite et al., J Clin Oncol 26(16):2659-2665, 2008).
•• Population Specific GSTM1 Copy Number Variation. As one of the major
glutathione conjugation enzymes, GSTM1 detoxifies a number of drugs and
xenobiotics. Through a genome-wide association study, Nancy Cox, PhD,
Soma Das, PhD, and M. Eileen Dolan, PhD (Clinical and Experimental
Therapuetics Program) identified a significant association between HapMap
SNP rs366631 and GSTM1 expression. HapMap rs366631 is a pseudo-SNP
that can be used as a GSTM1 deletion marker. Both the pseudo-SNP allele
frequency and GSTM1 upstream region copy number variation show
population-specific patterns between Caucasian and African samples
(Huang et al., Hum Mol Genet 18(2):366-372, 2009).
Dr. Tara Henderson
* Due to space constraints, only a small representative sample of Program highlights is presented here.
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Selected New Funding
•• Lisa Sanchez-Johnsen, PhD, was the recipient of a National Cancer Institute R21 award to examine the role of four
cultural variables (acculturation, acculturative stress, ethnic identity, and cultural values) that may help to explain the
ethnic disparities in levels of obesity within the Hispanic/Latino community. The findings from this study will aid in
assessing the role of ethnicity and culture in obesity-related variables, and identify some of the cultural factors that should
be accounted for when developing obesity interventions for Mexicans and Puerto Ricans.
•• Harriet Dewit, PhD, in collaboration with Cecilia Hillard, MD, Professor at the Medical College of Wisconsin, was the
recipient of a National Institutes for Health R21 award to test the theory that gender differences in the effects of stress on
endocannabinoid (eCB) signaling contribute to the gender differences in susceptibility to certain psychiatric disorders.
Data from this study will help to clarify the differential vulnerabilities of women and men to certain disorders, substance
abuse in particular.
•• Tara Henderson, MD, MPH, and her colleagues, with funding from a National Cancer Institute K07 award, are examining
the long-term health of childhood cancer survivors, a high risk group for both early deaths and subsequent illnesses due
to second cancers. Dr. Henderson is developing a four-year training program to examine the long-term trends that affect
this group, and also research methods for examining the clinical outcomes, health beliefs and behaviors of a targeted
group of women who developed breast cancer following chest radiation for a pediatric cancer.
•• Andrea King, PhD, was awarded an R01 grant from the National Institutes of Health to study the factors associated with
alcohol stimulation and sedation in binge drinkers. Data from this study will determine the relative contributions of
sensitivity to stimulant-like alcohol effects, tolerance to sedative-like effects, and objective responses to future drinking
patterns over time. Such information may have an important impact on the early identification of at-risk drinkers and the
factors underlying hazardous drinking practices to improve prevention, education, and early intervention efforts.
•• Eugene Chang, MD, was the recipient of an R21 award from the National Center for Human Genome Research to develop
technologies for the discovery of novel human colonic mucosal-associated microbes. Current methods are likely to dilute
and distort sampling of the enteric microbiome, and are likely to miss underrepresented species that may have direct
bearing on human health and disease. This study is anticipated to produce new and improved non-cultivation-based
technologies that will facilitate genomic sequencing and metagenomic analysis of previously uncharacterized members of
the human enteric microbiome.
•• Dezheng Huo, MD, PhD, received R03 funding from the National Cancer Institute to characterize breast cancer
subtypes using an integrative genetic and epidemiologic approach. The study aims to determine the pattern of loss of
heterozygosity and copy number alterations between subtypes and to examine germline determinants. The results
will improve the prevention and treatment of breast cancer by identifying genetic variants predisposing individuals to
different subtypes of the disease.
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New Faculty Recruitments and UCCRC Members
Brian Chiu, PhD is a cancer epidemiologist whose research focuses on integrating advanced molecular techniques with
traditional epidemiologic methods to examine host and environmental factors that influence the etiology of hematopoietic
cancers. Dr. Chiu’s research includes the examination of lifestyle, environmental, and genetic factors that contribute to the
pathogenesis of non-Hodgkin lymphoma to identify potential prevention strategies.
Susan Hong, MD, MPH, is an internist with an interest in cancer survivorship. Dr. Hong has developed a women’s health
curriculum for the internal medicine residents, which has been integrated into the residency program. Dr. Hong has established
a Cancer Survivorship Clinic with an initial focus on breast cancer survivors. In addition to providing clinical services, this
clinic provides the structure for the expansion of survivorship research.
Dezheng Huo, MD, PhD is a statistician and cancer epidemiologist with broad biostatistical research interests including the
etiology and prevention of cancer in underserved and under-studied populations. Dr. Huo is currently studying polymorphisms
and reproductive factors in breast cancer risk among Africans; the incidence of breast cancer subtypes across ethnic groups in
the U.S.; and genetic, environmental, and lifestyle factors that influence the risk for breast cancer subtypes.
Sonia Kupfer, MD was recruited as an Instructor in the Department of Medicine. Dr. Kupfer performs genetic association
studies in colorectal cancer with a special focus on African Americans.
Eneida Mendonca, MD, PhD is a member of the Computation Institute of the University of Chicago and Argonne National
Laboratory. Dr. Mendonca uses mining and retrieval technologies to improve the diagnosis and treatment of pediatric cancer.
Her current interests focus on using computational methods and informatics to analyze biomedical data in order to build an
infrastructure to support pediatric oncology research. Dr. Mendonca is also interested in exploring long-term health issues and
Lisa Shah, MD, MA is an Instructor in the Department of Medicine whose interests include hospital-based smoking cessation
interventions, preventive health care, and quality improvement.
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elucidating decision-making processes associated with pediatric cancer treatment and survivorship.
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Selected Publications
* : Intraprogrammatic Collaboration
# : Interprogrammatic Collaboration
* # Tao Y, Hart J, Lichtenstein L, Joseph L, Ciancio M, Hu S, Chang EB,
Bissonnette M. Inducible Heat Shock Protein70 Prevents Multifocal Flat
Dysplastic Lesions and Invasive Tumors in an Inflammatory Model of Colon
Cancer. Carcinogenesis 30(1):175-82, 2009.
* Hu S, Zhu X, Triggs JR, Tao Y, Wang Y, Lichtenstein L, Bissonnette M,
Musch MW, Chang EB. Inflammation-induced, 3’UTR-dependent translational
inhibition of Hsp70 mRNA impairs intestinal homeostasis. Am J Physiol
Gastrointest Liver Physiol 296(5):G1003-11, 2009.
Ahsan, Habibul MD
* Argos M, Kibriya MG, Jasmine F, Olopade OI, Su T, Hibshoosh H, Ahsan H.
Genomewide scan for loss of heterozygosity and chromosomal amplification in
breast carcinoma using single-nucleotide polymorphism arrays. Cancer Genet
Cytogenet 182(2):69-74, 2008.
* Huo D, Adebamowo CA, Ogundiran TO, Akang EE, Campbell O,
Adenipekun A, Cummings S, Fackenthal J, Ademuyiwa F, Ahsan H, Olopade
OI. Parity and breastfeeding are protective against breast cancer in Nigerian
women. Br J Cancer 98(5):992-6, 2008.
Kaklamani VG, Wisinski KB, Sadim M, Gulden C, Do A, Offit K, Baron JA,
Ahsan H, Mantzoros C, Pasche B. Variants of the adiponectin (ADIPOQ) and
adiponectin receptor 1 (ADIPOR1) genes and colorectal cancer risk. JAMA
300(13):1523-31, 2008.
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the intestinal mucosal barrier. Am J Physiol Gastrointest Liver Physiol
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Wang Q, Li YC, Wang J, Kong J, Qi Y, Quigg RJ, Li X. miR-17-92 cluster
accelerates adipocyte differentiation by negatively regulating tumor-suppressor
Rb2/p130. Proc Natl Acad Sci U S A 105(8):2889-94, 2008.
Musch MW, Li YC, Chang EB. Angiotensin II directly regulates intestinal
epithelial NHE3 in Caco2BBE cells. BMC Physiol 9:5, 2009.
Lindau, Stacy MD
Curlin FA, Dinner SN, Lindau ST. Of more than one mind: obstetriciangynecologists’ approaches to morally controversial decisions in sexual and
reproductive healthcare. J Clin Ethics 19(1):11-21, discussion 22-3, 2008.
Lindau ST, Tetteh AS, Kasza K, Gilliam M. What schools teach our patients
about sex: content, quality, and influences on sex education. Obstet Gynecol
111(2 Pt 1):256-66, 2008.
* Lindau ST, Hoffmann JN, Lundeen K, Jaszczak A, McClintock MK, Jordan
JA. Vaginal Self-Swab Specimen Collection in a Home-Based Survey of Older
Women: Methods and Applications. J Gerontol B Psychol Sci Soc Sci, 2009.
Lindau ST, Drum ML, Gaumer E, Surawska H, Jordan JA. Prevalence of highrisk human papillomavirus among older women. Obstet Gynecol 112(5):979-89,
2008.
Masi, Christopher MD, PhD
* Masi CM, Gehlert S. Perceptions of breast cancer treatment among AfricanAmerican women and men: implications for interventions. J Gen Intern Med
24(3):408-14, 2009.
McClintock, Martha PhD
* Gehlert S, Sohmer D, Sacks T, Mininger C, McClintock M, Olopade O.
Targeting health disparities: a model linking upstream determinants to
downstream interventions. Health Aff (Millwood) 27(2):339-49, 2008.
Yee JR, Cavigelli SA, Delgado B, McClintock MK. Reciprocal Affiliation Among
Adolescent Rats During a Mild Group Stressor Predicts Mammary Tumors and
Lifespan. Psychosom Med 70(9):1050-9, 2008.
McClintock MK. Human aromas, pheromones and vasanas: effects on
fertility, sexuality and emotions. Aroma Research 10: 72-77, 2009.
Gehlert S, Murray A, Sohmer D, McClintock MK, Conzen SD, and
Olopade F. The importance of transdisciplinary collaborations for
understanding and resolving health disparities. Journal of Health and
Social Policy, 2009 (in press).
Hermes GL, Delgado B, Tsakalis M, Tretiakova M, Cavigelli SA, Krausz T,
Conzen SD, and McClintock MK. Social Isolation dysregulates endocrine
and behavioral stress responses while increasing the malignant burden
of spontaneous mammary tumors. Proc Natl Acad Sci U S A, 2009 (in
press).
McClintock MK, Gehlert S, Conzen SD, Olopade F, and Krausz T.
Overcoming Health Disparities: The Power of a Transdisciplinary
Approach to Environmental Regulation of Gene Expression. Royal
Society of Canada, 2009 (in press).
McGeHee, Daniel PhD
Britt JP, McGehee DS. Presynaptic opioid and nicotinic receptor
modulation of dopamine overflow in the nucleus accumbens. J Neurosci
28(7):1672-81, 2008.
Campioni M, Xu M, McGehee DS. Stress-Induced Changes in Nucleus
Accumbens Glutamate Synaptic Plasticity. J Neurophysiol 101(6):3192-8,
2009.
Meltzer, David MD, PhD
Meltzer D. Response to “Future costs and the future of cost-effectiveness
analysis”. J Health Econ 27(4):822-5, 2008.
* # Conti RM, Meltzer DO, Ratain MJ. Nonprofit biomedical companies.
Clin Pharmacol Ther 84(2):194-7, 2008.
Abbo ED, Sobotka S, Meltzer DO. Patient preferences in instructional
advance directives. J Palliat Med 11(4):555-62, 2008.
Braithwaite RS, Meltzer DO, King JT Jr, Leslie D, Roberts MS. What does
the value of modern medicine say about the $50,000 per quality-adjusted
life-year decision rule?. Med Care 46(4):349-56, 2008.
Cancer Risk
& Prevention
King G, Yerger VB, Whembolua GL, Bendel RB, Kittles R, Moolchan ET. Link
between facultative melanin and tobacco use among African Americans.
Pharmacol Biochem Behav 92(4):589-96, 2009.
Howard DH, Meltzer D, Kollman C, Maiers M, Logan B, Gragert L,
Setterholm M, Horowitz MM. Use of cost-effectiveness analysis to
determine inventory size for a national cord blood bank. Med Decis
Making 28(2):243-53, 2008.
* Yin W, Basu A, Zhang JX, Rabbani A, Meltzer DO, Alexander GC. The
effect of the Medicare Part D prescription benefit on drug utilization and
expenditures. Ann Intern Med 148(3):169-77, 2008.
* Dale W, Basu A, Elstein A, Meltzer D. Predicting utility ratings for
joint health States from single health States in prostate cancer: empirical
testing of 3 alternative theories. Med Decis Making 28(1):102-12, 2008.
* Basu A, Dale W, Elstein A, Meltzer D. A linear index for predicting
joint health-states utilities from single health-states utilities. Health Econ
18(4):403-19, 2009.
Walton SM, Schumock GT, Lee KV, Alexander GC, Meltzer D, Stafford
RS. Prioritizing Future Research on Off-Label Prescribing: Results of a
Quantitative Evaluation. Pharmacotherapy 28(12):1443-1452, 2008.
Mendonca, Eneida MD, PhD
# Sam LT, Mendonca EA, Li J, Blake J, Friedman C, Lussier YA.
PhenoGO: an integrated resource for the multiscale mining of clinical
and biological data. BMC Bioinformatics 10 Suppl 2:S8, 2009.
Hermes GL, McClintock MK. Isolation and the timing of mammary gland
development, gonadarche, and ovarian senescence: implications for mammary
tumor burden. Dev Psychobiol 50(4):353-60, 2008.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
117
Olopade, Olufunmilayo MBBS
Sanchez-Johnsen, Lisa PhD
* Bradbury AR, Ibe CN, Dignam JJ, Cummings SA, Verp M, White MA,
Artioli G, Dudlicek L, Olopade OI. Uptake and timing of bilateral prophylactic
salpingo-oophorectomy among BRCA1 and BRCA2 mutation carriers. Genet
Med 10(3):161-6, 2008.
* King A, Sanchez-Johnsen L, Van Orman S, Cao D, Matthews A. A pilot
community-based intensive smoking cessation intervention in African
Americans: feasibility, acceptability and early outcome indicators. J Natl Med
Assoc 100(2):208-17, 2008.
* Huo D, Kim HJ, Adebamowo CA, Ogundiran TO, Akang EE, Campbell O,
Adenipekun A, Niu Q, Sveen L, Fackenthal JD, Fackenthal DL, Das S, Cox
N, Rienzo AD, Olopade OI. Genetic polymorphisms in uridine diphosphoglucuronosyltransferase 1A1 and breast cancer risk in Africans. Breast Cancer
Res Treat 110(2):367-76, 2008.
Sanchez-Johnsen LA, Hogan K, Wilkens LR, Fitzgibbon ML. Correlates of
problematic eating behaviors in less acculturated Latinas. Eat Behav 9(2):181-9,
2008.
* Huo D, Adebamowo CA, Ogundiran TO, Akang EE, Campbell O,
Adenipekun A, Cummings S, Fackenthal J, Ademuyiwa F, Ahsan H, Olopade
OI. Parity and breastfeeding are protective against breast cancer in Nigerian
women. Br J Cancer 98(5):992-6, 2008.
* Garner CP, Ding YC, John EM, Ingles SA, Olopade OI, Huo D, Adebamowo
C, Ogundiran T, Neuhausen SL. Genetic variation in IGFBP2 and IGFBP5 is
associated with breast cancer in populations of African descent. Hum Genet
123(3):247-55, 2008.
* Huo D, Senie RT, Daly M, Buys SS, Cummings S, Ogutha J, Hope K, Olopade
OI. Prediction of BRCA Mutations Using the BRCAPRO Model in Clinic-Based
African American, Hispanic, and Other Minority Families in the United States.
J Clin Oncol 27(8):1184-90, 2009.
* # Olopade OI, Grushko TA, Nanda R, Huo D. Advances in breast cancer:
pathways to personalized medicine. Clin Cancer Res 14(24):7988-99, 2008.
Xu J, Huo D, Chen Y, Nwachukwu C, Collins C, Rowell J, Slamon DJ, Olopade
OI. CpG island methylation affects accessibility of the proximal BRCA1
promoter to transcription factors. Breast Cancer Res Treat, 2009.
Polite, Blase MD
# Polite BN, Cirrincione C, Fleming GF, Berry DA, Seidman A, Muss H, Norton
L, Shapiro C, Bakri K, Marcom K, Lake D, Schwartz JH, Hudis C, Winer EP.
Racial differences in clinical outcomes from metastatic breast cancer: a pooled
analysis of CALGB 9342 and 9840--Cancer and Leukemia Group B. J Clin
Oncol 26(16):2659-65, 2008.
Rubin, David MD
# Nathanson JW, Yadron NE, Farnan J, Kinnear S, Hart J, Rubin DT. p53
mutations are associated with dysplasia and progression of dysplasia in patients
with Crohn’s disease. Dig Dis Sci 53(2):474-80, 2008.
Rubin DT. An Updated Approach to Dysplasia in IBD. J Gastrointest Surg
12(12):2153-6, 2008.
Nathanson JW, Zisman TL, Julian C, McCaffrey S, Rubin DT. Identification
of patients at increased risk for colorectal cancer in an open access endoscopy
center. J Clin Gastroenterol 42(9):1025-31, 2008.
# Weber CR, Nalle SC, Tretiakova M, Rubin DT, Turner JR. Claudin-1 and
claudin-2 expression is elevated in inflammatory bowel disease and may
contribute to early neoplastic transformation. Lab Invest 88(10):1110-20, 2008.
* Calderwood AH, Huo D, Rubin DT. Association between colorectal cancer
and urologic cancers. Arch Intern Med 168(9):1003-9, 2008.
Zisman TL, Rubin DT. Colorectal cancer and dysplasia in inflammatory bowel
disease. World J Gastroenterol 14(17):2662-9, 2008.
Rubin DT, Cruz-Correa MR, Gasche C, Jass JR, Lichtenstein GR,
Montgomery EA, Riddell RH, Rutter MD, Ullman TA, Velayos FS, Itzkowitz
S. Colorectal cancer prevention in inflammatory bowel disease and the role
of 5-aminosalicylic acid: a clinical review and update. Inflamm Bowel Dis
14(2):265-74, 2008.
118
UCCRC SCIEN T IFI C R EPO R T 20 0 9
Verp, Marion MD
* Bradbury AR, Ibe CN, Dignam JJ, Cummings SA, Verp M, White MA,
Artioli G, Dudlicek L, Olopade OI. Uptake and timing of bilateral prophylactic
salpingo-oophorectomy among BRCA1 and BRCA2 mutation carriers. Genet
Med 10(3):161-6, 2008.
Vezina, Paul PhD
Vezina P, Leyton M. Conditioned cues and the expression of sensitization in
animals and humans. Neuropharmacology 56: 160-168, 2009
Waxman, Irving MD
# Konda VJ, Ross AS, Ferguson MK, Hart JA, Lin S, Naylor K, Noffsinger A,
Posner MC, Dye C, Cislo B, Stearns L, Waxman I. Is the risk of concomitant
invasive esophageal cancer in high-grade dysplasia in Barrett’s esophagus
overestimated?. Clin Gastroenterol Hepatol 6(2):159-64, 2008.
de Tejada AH, Chennat J, Miller F, Stricker T, Matthews J, Waxman I.
Endoscopic and EUS features of groove pancreatitis masquerading as a
pancreatic neoplasm. Gastrointest Endosc 68(4):796-8, 2008.
Ross A, Mehdizadeh S, Tokar J, Leighton JA, Kamal A, Chen A, Schembre D,
Chen G, Binmoeller K, Kozarek R, Waxman I, Dye C, Gerson L, Harrison ME,
Haluszka O, Lo S, Semrad C. Double balloon enteroscopy detects small bowel
mass lesions missed by capsule endoscopy. Dig Dis Sci 53(8):2140-3, 2008.
Selected Major Grants and Awards
The Cancer Risk and Prevention Program has a funding base of $17,841,935 in annual total costs (current as of July 2009). This sum
includes $4,221,965 in NCI funding and $8,082,978 in other NIH funding. Due to space constraints, only new awards presented since
Investigator
Title
Start Date
End
Date
Annual
Total Cost
Class
Funding Agency
King, Andrea
Alcohol Stimulation and Sedation in
Binge Drinkers
1/1/2009
12/31/2013
$671,587
R01
National Institutes of Health
Basu, Anirban
A Comprehensive Probabilistic-MicroSimulation Model to Assess CostEffectiveness
9/23/2008
5/31/2013
$568,535
R01
National Institute of Mental
Health
Olopade,
Olufunmilayo
Dr. Ralph and Marian Falk Center for
Clinical Cancer Genetics
1/1/2008
12/31/2010
$500,000
N/A
Falk Foundation
Chang, Eugene
Cytoprotective Role of Heat Shock
Proteins in IBD
4/1/2008
1/31/2013
$310,838
R37
Nat. Inst. of Diabetes &
Digestive & Kidney Diseases
Green, William
The Neuronal Alpha-Bungarotoxin
Binding Site
8/1/2008
7/31/2009
$307,646
R56
National Inst. of
Neurological Disorders and
Stroke
Olopade,
Olufunmilayo
Developing an Infrastructure to
Conduct Clinical Breast Cancer Trials
in Resource Poor Nations such as
Nigeria
10/1/2008
9/30/2009
$250,000
N/A
Breast Cancer Research
Foundation
Olopade,
Olufunmilayo
Targeting the Fanconi Anemia-BRCA1
Pathway in Breast Cancer
10/1/2008
9/30/2009
$250,000
N/A
Breast Cancer Research
Foundation
Olopade,
Olufunmilayo
National Women's Cancer Research
Alliance (NWCRA)
5/1/2008
4/30/2009
$250,000
N/A
The Entertainment Industry
Foundation
Polite, Blase
A Phase III Randomized Double
Blind STudy of Sunitinib Vs Placebo
in Patients w/Progressive Advanced/
Metastatic Well Differentiated
Pancreatic Islet Cell Tumors
9/8/2008
9/7/2010
$193,465
N/A
Pfizer, Inc.
Chang, Eugene
Technologies for the Discovery of
Novel Human Colonic MucosalAssociated Microbes
9/26/2008
7/31/2010
$187,640
R21
National Center For Human
Genome Research
Mendonca, Eneida
Answering Information Needs in
Workflow
4/1/2008
3/31/2010
$182,739
R01
National Institutes of Health
Chang, Eugene
Short Term Training: Health
Professional Students
5/1/2008
4/30/2013
$181,129
T35
National Institutes of Health
Meltzer, David
Research and Mentoring in CostEffectiveness and Hospital-Based Elder
Care
6/1/2008
$174,352
K24
National Institute on Aging
Sanchez-Johnsen,
Lisa
Latinos, Culture, and Obesity
7/21/2008
6/30/2010
$173,250
R21
National Cancer Institute
Henderson, Tara
Health Beliefs and Behavior:
Cohort Studies in Pediatric Cancer
Survivorship
9/17/2008
8/31/2012
$129,600
K07
National Cancer Institute
Shah, Lisa
A Missed Opportunity: Exploring
Barriers to Quit in Hospitalized
Smokers
8/15/2008
8/14/2010
$125,000
N/A
American Cancer Society,
Illinois
Dale, William
Decision Making in Older Men
Starting Androgen Ablation for
Prostate Cancer
9/1/2008
8/31/2010
$123,484
N/A
American Cancer Society,
Illinois
Li, Yan Chun
Cardiovascular Effects of
Doxercalciferol
2/3/2009
2/2/2010
$121,800
N/A
Genzyme Corporation
Kim, Karen
Vitamin D Intervention in Polyp
Recurrence in African Americans - A
Pilot Study
7/1/2008
6/30/2009
$100,000
N/A
American Cancer Society,
Illinois
Polite, Blase
Understanding Racial Disparities in
Chemotherapy Receipt
7/1/2008
6/30/2010
$100,000
N/A
American Society of Clinical
Oncology
UCCRC SCIEN T IFI C R EPO R T 20 0 9
Cancer Risk
& Prevention
January 1, 2008 with funding of $100,000 or more in annual total costs are listed here.
119
Clinical Trials Activity
Dr. Alessandro Fichera with a patient
The UCCRC has sustained a vigorous clinical research
program for many years, and has long been recognized
for its strength in basic and clinical research.
Clinical Trials Activity
Most recently, these activities are been expanded
and translational endpoints, sequencing of
to population research including epidemiology
multidisciplinary treatment, transplantation,
and prevention trials. The tight and dynamic
organ preservation, and treatment intensification
linkages connecting our basic scientists with
as strategies to increase cure rates and response.
our enhanced team of translational and clinical
Within the past few years, there has been a
researchers have led to major contributions to
remarkable increase in tangible benchmarks, such
early-phase clinical trials and drug development.
as multi-investigator, multi-disciplinary grants, as
The integration of population researchers
well as investigator-initiated clinical trials.
is taking these trials to the population and
community level.
UCCRC therapeutic clinical trials are
conceived and conducted by multidisciplinary
teams, each comprised of a group of clinical
investigators representing Medical Oncology,
Radiation Oncology, Pathology, Biostatistics,
Clincal Trials
Activity
and appropriate surgical specialties. All of our
research programs conduct clinical research.
These clinical efforts focus on studies of new
drugs (cytotoxic or cytostatic) with clinical
UCCRC SCIEN T IFI C R EPO R T 20 0 9
121
The clinical trials activity of the UCCRC is managed through the Cancer Clinical Trials Office (CCTO). The CCTO
provides oversight and quality control for these studies through the provision of policies and procedures, by centralizing
regulatory and reporting functions, supervision of staff, auditing, and tracking of these activities with a centralized database.
The overall objective of the CCTO is to provide the infrastructure to support successful cancer clinical research across
departments within the University, as well as through national cooperative groups. CCTO services and areas of operation
can be divided into four distinct but somewhat overlapping areas: (1) regulatory affairs; (2) affiliate institution coordination
and oversight; (3) protocol tracking and management; and (4) quality control.
Our drug development program is unique in the Chicago metropolitan area, and among the largest in the United States.
Patients travel from throughout the world to be evaluated for enrollment in Phase I and Phase II trials of novel anticancer
agents. Annually, between 12001400 patients are enrolled on clinical trials, with 800-1000 entered on therapeutic trials.
Clinical trials span the gamut from preclinical development to investigator-initiated Phase I clinical trials to Phase II trials
in the regional Phase II network to Phase III studies within CALGB. Many trials also incorporate correlative laboratory
studies which include pharmacokinetic studies, genotyping studies, population pharmacology and pharmacogenetics, and
measurement of biomarker endpoints. In 2008, clinical trials enrollment included 1005 patients to 200 therapeutic protocols;
548 patients were treated on 101 Phase II protocols, and 180 patients were treated on 26 Phase I studies.
In 2008, regulatory managers in the CCTO opened 98 new protocols and were responsible for ongoing regulatory activities
of an additional 351studies already open to enrollment, as well as the regulatory activities (e.g., IRB continuing renewals,
amendments, safety reports) for 357 studies closed to enrollment, but not terminated with the IRB. These trials represent
over 50 principal investigators from multiple departments (Medicine, Radiology, Radiation and Cellular Oncology, Surgery,
Pediatrics, and Obstetrics and Gynecology
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UCCRC SCIEN T IFI C R EPO R T 20 0 9
Number of therapeutic protocols (N=344*) and patient accrual (N=1005 by sponsor in 2008)
Total No. Trials
No. Investigator
Initiated
No. of Pts
Enrolled
Institutional
36 (11%)
27
307 (31%)
NCI
45 (13%)
19
229 (22%)
Cooperative Group
122 (35%)
2
139 (14%)
Industry
141 (41%)
6
330 (33%)
344
54 (16%)
1005
Study Sponsor
Total
*Note that of the 344 trials open to accrual in 2008, approximately 16% were investigator-initiated. In addition, more than 50% of our accrual to
therapeutic protocols is to NCI and institutional studies that are largely investigator-initiated.
The UCCRC and CCTO have been instrumental in the success of several major grants and contracts including the Phase I
Grant: Phase I Clinical Trials of Anticancer Agents, the Phase II Contract: Novel Therapeutics, the CALGB grant, and the Breast
Cancer SPORE, which was awarded in the fall of 2006. The most recent Phase II contract (2006) added the Medical University
of South Carolina as an academic partner; approximately 200 patients are enrolled on Phase II contract studies annually. The
Clincal Trials
Activity
CCTO continues to support the clinical trials activity associated with these programs.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
123
Shared Resources
Dr. Vytas Bindokas imaging tumor cell nuclear morphology, using the
live-cell optimized Olympus DSU spinning disk confocal system with a
high-sensitivity EM-CCD camera, in the UCCRC’s Integrated Microscopy Facility.
Multiple levels of scientific and administrative oversight
ensure the continued delivery of optimal state-of-the-art
technologies to meet the needs of the research community.
Overview
The University of Chicago Biological Sciences
Division (BSD) provides shared technologies
through 23 Core Facilities, which aim to
support research and serve as educational
resources for the University of Chicago. The
Core Facilities serve as centralized centers
of expertise and provide UCCRC researchers
access to a comprehensive set of technical
resources, which offer advanced services to
support vital translational research, and facilitate
the interaction of researchers and clinicians
from different disciplines. Multiple levels of
Cytometry Facility, Genomics Core Facility,
the continued delivery of optimal state-of-
Human Immunologic Monitoring Core, Human
the-art technologies to meet the needs of the
Tissue Resource Center, Integrated Microscopy
research community. Thirteen of these shared
Facility, Immunohistochemistry Facility,
facilities are supported by the UCCRC. These
Magnetic Resonance Imaging and Spectroscopy
facilities are integrated with the other Core
Facility, Pharmacology Core Facility, Scientific
Facilities and include the Biostatistics Core
Image Reconstruction and Analysis Facility, and
Facility, Cancer Clinical Trials Office, Frank
Transgenic Mouse and Embryonic Stem Cell
W. Fitch Monoclonal Antibody Facility, Flow
Facility.
Shared
Resources
scientific and administrative oversight ensure
UCCRC SCIEN T IFI C R EPO R T 20 0 9
125
Biostatistics Core Facility
Scientific Director: Ronald Thisted, PhD
Technical Director: Theodore Karrison, PhD
Website: http://health.bsd.uchicago.edu/Page.aspx?Page=BiostatLab
The Biostatistics Core Facility provides collaborative statistical support to investigators for the design, conduct, and analysis
of clinical trials, observational and population-based studies, and basic science research projects.
The services provided include:
•• Collaboration with investigators in the formulation of study design and data
analysis plans, including sample-size and power calculations;
•• Assistance in the development, execution, and statistical analyses of investigator-initiated
phase I, phase II, and phase III clinical trials and correlative/translational studies;
•• Collaboration in the design and analysis of prospective and retrospective observational
studies, basic science research projects, and animal experiments;
•• Collaboration with investigators on the preparation of manuscripts for publication;
•• Assistance in new grant submissions, including U01, P01, R01, R21, and SPORE grants;
•• Participation in the review of clinical protocols through membership on the Clinical Trials Review Committee; and
•• Participation in the teaching and training of investigators in fundamental
statistical concepts, study design, and clinical trials methodology.
Cancer Clinical Trials Office
Scientific Director: Marcy A. List, PhD
Technical Director: Connie Skosey, RN, CCRP
Website: http://uccrc.uchicago.edu/researchers/core_ccto.html
The Cancer Clinical Trials Office (CCTO) provides oversight and quality control for clinical trials activity at the UCCRC
by centralizing regulatory and reporting functions. The overall objective of the CCTO is to provide the infrastructure to
support successful clinical research across departments.
The services provided are categorized under the following key functions:
•• Regulatory Affairs: Provide centralized regulatory management for the conduct of all cancer clinical trials at the
University of Chicago regardless of sponsor, department, or type of study, including the completion of required
forms and submission to the Clinical Trials Review Committee (CTRC), the Institutional Review Board (IRB),
and other required committees (e.g., Institutional Biosafety Committee); annual renewals to the IRB and the
Scientific and Accrual Monitoring Committee of the UCCRC; and investigational new drug submissions.
•• Affiliate Institution Coordination and Oversight: Provide infrastructure for the participation of
affiliate institutions enrolling patients on trials at the UCCRC (including CALGB affiliate institutions,
Phase II NCI contract affiliate institutions, and additional ad hoc affiliates participating in selected
studies); coordinate all study-related communications; serve as the point of patient registration
for some programs; and review operations to ensure compliance with federal regulations. •• Protocol Tracking, Management: Provide a centralized location and database (Velos eResearch) for
tracking protocol-specific data (including study teams, protocol status, and patient registration);
provide web-based direct access (e.g., in clinics) to current consent forms, protocols, and investigational
brochures; and report generation with respect to both clinical data and study status information.
•• Quality Control: Provide training of regulatory managers across departments; support continuing education;
train nurses, data managers, faculty and fellows in the use of Velos eResearch; oversee designated data and
safety monitoring activities (e.g., severe adverse event tracking, coordination of High-Risk Protocol Conference
HRPC); coordinate the audit program; and develop and implement Standard Operating Procedures.
126
UCCRC SCIEN T IFI C R EPO R T 20 0 9
Frank W. Fitch Monoclonal Antibody Facility
Scientific Director: Anne Sperling, PhD
Technical Director: Carol McShan
Website: http://fitchantibodies.bsd.uchicago.edu
The Frank W. Fitch Monoclonal Antibody Facility provides a wide range of services focusing on the generation and production
of monoclonal antibodies. The overall objective of the Facility is to provide investigators with comprehensive hybridoma and
protein production services. The services provided include:
•• Production of novel monoclonal antibodies, including complete immunization, fusion, and ELISA screening services;
•• Custom and routine culturing of antibody producing cell lines, including thawing of
cryopreserved cell lines, subcloning, routine culture, and cryopreservation;
•• Customized ELISA services, including performance of standard assays and development of custom assays;
•• Antibody purification, conjugation, and isotype determination;
•• Ascites fluid production and large-scale protein production using Hollow Fiber Bioreactor (HFB) technology; and
•• Supply of commonly used antibodies.
Flow Cytometry Facility
Scientific Director: Anne Sperling, PhD
Technical Director: Ryan Duggan
Website: http://ucflow.bsd.uchicago.edu
The Flow Cytometry Facility provides access to state-of-the-art technology and quantitative analytical approaches to measure
molecular and cellular function. The Facility is designed to meet the wide-spread needs for specialized cytologic analysis
by providing instrumentation for cell sorting and bench-top analysis of subcellular components using multiparametric
fluorescence detection technology.
The services provided include:
•• Bench-top analyses ranging from simple protein expression assays using
fluorescent reporters to highly complex 9-color functional assay;
•• Cell sorting at bulk rates of 30,000 cells per second or in microtiter format;
•• Development of novel fluorescence-based detection assays and applications;
•• Education and training in use and application of all instrumentation and software analysis programs within the Facility.
Genomics Core Facility
Shared
Resources
•• Data analysis; and
Scientific Director: T. Conrad Gilliam, PhD.
Technical Directors: William J. Buikema, PhD, Rafael Gama, PhD, and Barry Allen, PhD
Websites: http://cancer-seqbase.uchicago.edu; http://fgf.bsd.uchicago.edu; http://brdfhelp.uchicago.edu
The Genomics Core Facility provides, via its three Subcores (DNA Sequencing and
Genotyping, Functional Genomics Facility, and Biomedical Research Development
Facility), state-of-the-art microarray, DNA sequencing, and genotyping platforms
with specialized databases for storing, managing, and manipulating both clinical
information and diverse types of genetic and genomic data. The Facility is aimed
towards both biomedical researchers who are generally unfamiliar with whole genome
and bioinformatics approaches, as well as experts seeking sophisticated hardware,
software, programming, or database solutions, or seeking to facilitate interdisciplinary
UCCRC SCIEN T IFI C R EPO R T 20 0 9
127
collaborations. The Facility maintains the latest copies of all major genomic databases, thus allowing investigators to perform
all genomic and bioinformatics analyses at the highest possible speeds.
The services provided include:
•• Plasmid preparation, DNA sequencing, and genotyping analysis;
•• Fragment assembly and primer walking;
•• Archival data storage and technical consultations for DNA preparation and interpretation of results;
•• Genome-scale gene expression profiling and screening of protein-DNA interactions, DNA copy number
variations, chromosomal deletions, splicing variants, and novel transcribed sequences;
•• Validation of differential gene/miRNA expression;
•• Antibody protein array profiling and protein-protein interaction array hybridizations;
•• Customized services include slide scanning, RNA extraction, RNA quality evaluation, and RNA/DNA quantification;
•• Software tutorials and microarray data analysis; and
•• Comprehensive mirrored genomic databases, bioinformatic software applications, and custom genomic database design.
Human Immunologic Monitoring Facility
Scientific Director: Thomas F. Gajewski, MD, PhD
Technical Director: Yuanyuan Zha, PhD
Web Site: http://him.bsd.uchicago.edu
The Human Immunologic Monitoring (HIM) Facility provides service to clinical cancer
investigators to measure immunologic endpoints and other pharmacodynamic parameters
in subjects participating in clinical trials. The Facility serves as a specialized laboratory
to perform scientific analyses that include: 1) Evaluating changes in immune response
parameters in response to immunotherapeutic interventions; 2) Monitoring biologic effects
of other pharmacologic agents using lymphocytes or other hematopoietic cell subsets as a
surrogate tissue; and 3) Interfacing with the cGMP Facility to carry out the preparation of
clinical-grade products, such as cancer vaccines, for administration to patients.
The services provided include:
•• Preparation of peptide-based cancer vaccines;
•• IFN-γ ELISPOT and peptide/tetramer analysis;
•• Flow cytometry for specific T cell subsets and activation markers;
•• mRNA isolation and analysis of gene expression profiling data in the tumor microenvironment;
•• ELISA assays for angiogenesis factors; and
•• Western blot analysis for specific signal transduction intermediates.
Human Tissue Resource Center
Scientific Director: Mark Lingen, DDS, PhD
Technical Director: Leslie Martin
Website: http://pathcore.bsd.uchicago.edu
The Human Tissue Resource Center (HTRC) provides investigators a centralized
infrastructure to optimize the efficiency and costs related to research involving human
biospecimens. The HTRC is comprised of three integrated components: Biospecimen
Bank (BSB), Laser Capture Microdissection (LCM), and Pathology Image Analysis
(PIA). Currently, the HTRC provides services for the collection of clinically-annotated
human tissues and provides collaborative support and services for procuring, processing,
dispersing, and assessing all types of biospecimens.
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The Services provided include:
•• Centralized tissue banking for organ, saliva, urine, blood, plasma, serum, and other tissue derivatives;
•• Pathological verification and analysis of tissue samples;
•• Consultation and technical support in the construction and analyses of custom tissue microarrays;
•• Histological services including routine tissue formalin fixation, processing, paraffin
embedding, microtomy, H&E staining, and immunostaining;
•• Identification, localization, and microdissection of targeted cell populations (from human and animal tissue sources);
•• Extraction of DNA and/or RNA from dissected tissues; and
•• Quantitative image analysis of immunohistochemistry on conventional and tissue microarray
sections, including tissue scoring, rare event detection, microvascular density counting,
ploidy analysis, integrated optical density analysis, and tissue microarray scoring.
Integrated Microscopy Facility
Scientific Director: Benjamin Glick, PhD
Technical Directors: Shirley Bond, MA, Christine Labno, PhD, and Vytas Bindokas, PhD
Web Site: http://digital.bsd.uchicago.edu
The Integrated Microscopy Facility functions as a supervised, user-based core by providing
state-of-the-art microscopy imaging capabilities to investigators through microscopy
instrumentation, image analysis tools, and expert training and assistance. The Facility
strives to provide high-quality optics and equipment that most labs do not possess, including
confocal and state-of-the-art two-photon spectral microscopes. Available techniques
provided by the Facility include classic color histological stain imaging, contrast generation
in unstained cells, and fluorescence technologies that allow for applications ranging from
localization of multiple targets to readouts of biochemical or physiologic parameters in either
fixed or living preparations.
The services provided include:
•• Light microscopes with brightfield and fluorescence optics, including high-end objectives and technologies (color,
phase contrast, DIC, multi-parameter fluorescence including multi-ratio imaging and laser-based TIRFM);
•• Digital image capture: high-resolution B/W and color CCD cameras, high-sensitivity CCDs, and high-speed EMCCD;
•• Confocal microscopy including two-photon spectral systems (highresolution, high- sensitivity, and high-speed image capture);
•• Support for live sample maintenance and imaging;
Shared
Resources
•• New product demonstrations and user training on microscopes and software;
•• Data analysis, storage, back-up, oversight, and maintenance; and
•• Assistance with technique/technology development.
Immunohistochemistry Facility
Scientific Director: Anthony Montag, MD
Technical Director: Terry Shihong Li, MD
Website: http://ihccf.uchicago.edu/index.htm
The Immunohistochemistry Facility provides support for basic research in cellular structure/function, as well as
translational research in clinical applications and molecular medicine. The Facility aims to provide routine histologic and
immunohistochemical services in a timely manner using cutting-edge technology and expertise, evaluate and develop new
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The services provided include:
•• Routine histological services including tissue preparation,
processing, sectioning, and H&E staining;
•• Specialized tissue sectioning (preparation of 20 serial sections on a single slide);
•• Immunohistochemical services including enzymatic amplification methods
and detection systems using conventional and fluorescence microscopy;
•• Development of staining methods for novel antibodies, including the
identification of appropriate post-sectioning fixatives, antigen retrieval
methods, buffers, enzymatic pretreatment, and antibody titration;
•• Repository of control tissue for investigator use;
•• Development of in situ hybridization assays; and
•• Technical support for protocols on all aspects of tissue antigen detection.
Magnetic Resonance Imaging and Spectroscopy Facility
Scientific Director: Brian Roman, PhD and Greg Karczmar, PhD
Technical Director: Xiaobing Fan, PhD
Web Site: http://mris.bsd.uchicago.edu
The Magnetic Resonance Imaging and Spectroscopy (MRIS) Facility provides magnetic resonance
imaging for studies of both animal models of cancer and clinical research involving human
subjects. The measurements provided include very high resolution anatomic images, images
of hemodynamic parameters such as perfusion rate and capillary permeability, imaging tumor
oxygenation and changes in oxygenation. In addition, the scanners can provide metabolic
measurements with MR spectroscopy and MR spectroscopic imaging.
The services provided include:
•• Scans of tissues, cells, animal models of cancer, and patients to provide information
on, for example, detailed 3D anatomy, blood volume, energy metabolism, changes in
tumor oxygenation during therapy, calcium dynamics, and pancreatic function;
•• fMRI measurements of brain activation;
•• Development and testing of new contrast agents and imaging methods;
•• Data analysis and consultation; and
•• Veterinary services, including the preparation of animals for MRI experiments, anesthesia and
respiration, physiological monitoring, catheter implantation, and tumor implantation.
Pharmacology Core Facility
Scientific Director: M. Eileen Dolan, PhD
Technical Directors: Jacqueline Ramirez, MS and Shannon Delaney, MS
Web Site: http://pharmacology.bsd.uchicago.edu
The Pharmacology Core Facility evaluates pharmacokinetic, pharmacodynamic, and
pharmacogenetic parameters in conjunction with clinical trials. The Facility is comprised of an
Analytical Core and a Biochemical Core. The Analytical Core is responsible for assays of various
pharmacological targets, the development of pharmacological assays of anti-cancer agents and
their metabolites, and the analysis of drug and metabolite concentrations in biological fluids. The
Biochemical Core is responsible for the assessment of markers for drug resistance and measurement
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The services provided include:
•• Analysis of drug levels in biological fluids (whole blood, plasma, urine);
•• Sample transportation and storage;
•• Plasma and lymphocyte isolation from whole blood;
•• DNA and RNA Isolation; and
•• Assessment of markers for drug resistance.
Scientific Image Reconstruction and Analysis Facility
Scientific Director: Robert M. Nishikawa, PhD
Technical Director: Chun Wei Chan, MS
Website: http://osrf.bsd.uchicago.edu/facilities/svif.html
The Scientific Image Reconstruction and Analysis Facility (SIRAF) provides three essential
services for medical imaging, including a high performance computer cluster, direct archival
capabilities, and software to facilitate the development of databases. The SIRAF allows
researchers to have free access to all computers and services and supports image acquisition,
construction of databases, reconstruction techniques, image analysis (including computeraided diagnosis), and technology assessment. The Facility supports basic research involving
modeling and simulations, applied research involving the development of new image
analysis methods, research that requires patient information by aiding in the collection of
anonymized data, and the development of grid-based technologies. The services provided include:
•• Free-access to a high speed computer system and specialized software packages;
•• Centralized archiving for storage of large databases;
•• HIPAA-compliant access to patient images and associated medical records stored
in the Picture Archive and Communication System (PACS); and
•• Access to grid computing.
Transgenic Mouse and Embryonic Stem Cell Facility
The Transgenic Mouse and Embryonic Stem Cell Facility provides investigators with genetically-manipulated mice through
transgenic technology or embryonic stem cell manipulation. The Facility provides a comprehensive set of technical services, has
a fully operational gene targeting service and offers an annual course in Mouse Handling and Breeding. In addition, the Facility
is in the process of establishing gene construction services. Shared
Resources
Scientific Director: Kathleen Millen, PhD
Technical Director: Linda Degenstein
Website: http://transgenic.bsd.uchicago.edu
The services provided include:
•• Transgenic mouse production from founder through F1 Stage;
•• ES cell technology mouse production (e.g., knockouts, knockins, conditional knockouts);
•• ES cell line development and gene targeting and culturing;
•• Mouse embryonic fibroblast (MEF) cell production and embryo rederivation;
•• Various breeding services and genetically engineered mouse model line maintenance; and
•• DNA preparation from ES cell lines for the construction of gene targeting constructs.
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Other Resources and Centers
Patient and Community Resources
The UCCRC has developed a broad range of resources to provide cancer
information to the public. These include the UCCRC website, print
publications, the Cancer Resource Center, the Cancer Risk Clinic, the
Upper Aerodigestive Malignancies Clinic, and the Community Engagement
Centering on Solutions program. Through education, the UCCRC aims
to save lives through the prevention and control of cancer, and enhance its
clinical trials program through increased public awareness.
Website and Print Publications
The UCCRC website (http://uccrc.uchicago.
The UCCRC also informs the public about
edu) features a “For Patients” section that
advances in cancer diagnosis and treatment
provides general cancer information. The
through media outreach and the distribution of
public can access numerous links to online
various publications. A quarterly newsletter and
resources concerning general and specific
an annual report are circulated to approximately
cancer information, cancer publications,
5,000 patients and friends of the UCCRC. These
patient resources and support groups, and
publications provide readers with updated UCCRC
cancer survivorship. In addition, the UCCRC
information on new research developments,
website provides a cancer glossary, a calendar
patient care services, and active clinical trials.
of events for patients and their families, a
The UCCRC also sends email publications that
current listing of active UCCRC clinical trials,
highlight related media articles to UCCRC
and designated contacts for patient referrals.
members, staff, and donors approximately every
The site is integrated with the University of
2 weeks. In addition, a monthly e-mail newsletter
Chicago Medical Center website, which provides
informs UCCRC members about its latest
information on clinical services, appointment
developments and activities.
(http://www.uchospitals.edu). The UCCRC
has completely rewritten the website and has
launched a total redesign to make it more
user-friendly. The new design will include an
expansive section on UCCRC programs for the
community and the general public.
The UCCRC also works closely with the UCMC’s
Office of Media Affairs to discuss news of interest
to the media and general public, help respond to
media inquiries, and ultimately inform the public
of cancer-related activities. This close working
relationship has led to an increased focus on
cancer-related issues in the media. Approximately
32% of all press releases distributed by the Medical
Center in 2008 were directly related to cancer. For
Other Resources
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services, and a searchable directory of physicians
the first five months of 2009, 33% of press releases
were related to cancer.
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Cancer Resource Center
The UCCRC offers a unique resource to patients and their families to facilitate their access to counseling and reliable cancerrelated information. The Cancer Resource Center, in existence since 1997, operates in partnership with the American Cancer
Society and is currently located in the main lobby of the Duchossois Center for Advanced Medicine outpatient facility. The
Center is staffed by a certified health education specialist and a licensed clinical social worker who help patients and their
families obtain comprehensive cancer information, including facts about specific types of cancer, education on treatment and
pain management, and information about innovative clinical trials and how they can participate. The Center offers support
groups for caregivers and patients with breast, head and neck, oral, and lung cancer. A new partnership with Gilda’s Club
Chicago also offers patients on-site access to a wide variety of activities, including additional support/networking groups,
healing arts and movement workshops, and various educational programs. The Center also offers assistance with financial
grant applications and medical insurance, referrals for social and support services (housekeeping, home healthcare, child
care, medical equipment, and other support services), and patient navigation services, including transportation to and from
cancer-related appointments (travel vouchers, discounted lodging, etc). Outreach activities include meeting with patients in
the clinic, coordinating weekly volunteer opportunities, and supplying monthly cancer awareness literature.
Outreach and delivery of these special services to cancer patients has increased dramatically over the past several years. In
2008, Cancer Resource Center staff had face-to-face informational meetings with approximately 2,100 patients and provided
special services to an additional 2,633 patients (815 new patients, 1,818 return patients). The Center provided transportation
assistance for more than 1,000 Chicago Transit Authority rides, gas covering 35,000 miles of travel, and 2,500 hospital
parking passes. Additionally, the Center facilitated financial assistance with medications for pain and nausea, nutrition
supplies, and home healthcare items.
Cancer Risk Clinic
The Cancer Risk Clinic, established in 1992 with an initial seed grant from the UCCRC, is a comprehensive cancer risk
assessment and prevention program dedicated to helping individuals with a high risk of cancer. The Clinic is directed by
Dr. Funmi Olopade, MBBS, and staffed by a team of genetic counselors, a research nurse, a clinical psychologist, a medical
geneticist, and a medical oncologist who work with these individuals to provide genetic counseling, education about cancer
risk and prevention, and personalized risk reduction strategies. These strategies include systematic monitoring or screening
for early detection, implementation of life-style changes including diet and exercise, and the use of cancer prevention
procedures or drugs. The clinic records annual visits of more than 450 new patients and has a database of more than 4,000
individuals who were evaluated for inherited susceptibility to different cancers. The clinic also has an active community
outreach program, which has led to an increase in the number and diversity of patients evaluated for cancer risk, and thus
available for research studies. Resources in the Cancer Risk Clinic have been invaluable to the translational research efforts of
investigators both at the University and other collaborating institutions.
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Upper Aerodigestive Cancer Risk Clinic
The Upper Aerodigestive Cancer Risk Clinic opened in 2007 and is co-directed by Dr. Kyle Hogarth, MD, and Ravi Salgia,
MD, PhD. The Clinic offers a multidisciplinary approach to prevent, diagnosis, and treat individuals at high risk for the
development or recurrence of cancers of the upper aerodigestive tract, including lung cancer, esophageal cancer, head and
neck cancer, mesothelioma, and other rare malignancies. An expert team comprised of specialists in cancer, pulmonary
medicine, psychiatry, and substance abuse, work collaboratively with patients to provide individualized care, including cancer
screening, early detection services, risk reduction and prevention plans, and comprehensive treatment. Treatments are aimed
at preventing or ending high-risk behaviors. These may include counseling and medication to help patients overcome tobacco
addiction, counseling and therapy for depression, stress management, and relapse prevention plans. Through the Frances
Lederer Aerodigestive Cancer Research Program, researchers are investigating the use of earlier diagnosis methods, including
the testing of family members of patients for genetic markers that may indicate high risk. The Clinic is aiming to eventually
create risk profiles that will facilitate the design of individualized prevention and improved screening plans for at-risk patients.
Community Lectures.
The UCCRC has developed an ongoing community lecture series to provide members, nurses, and social workers with forums to
educate the public and address concerns regarding lung cancer. Sponsored by the UCCRC, the Hematology/Oncology Thoracic
Oncology Research Program, and the Respiratory Health Association of Metropolitan Chicago, this lecture series has been held
annually every November since 2006. The lectures focus on lung cancer diagnosis, patient resources, treatments, and research.
A new lung cancer networking group was established in response to the lecture series. The group meets once per month to
enable lung cancer patients, as well as their family members and friends, to share their experiences and information.
Community Engagement Centering on Solutions
The Community Engagement Centering on Solutions (CECOS) Program was developed by the UCCRC in 2007 to expand
its community outreach. The program represents a comprehensive effort to enhance public awareness of cancer prevention,
early cancer detection and control, and the role of genetics in cancer. Led by Rick Kittles, PhD, the Associate Director for
Diversity and Community Relations at the UCCRC, the program develops collaborative partnerships with the surrounding
community and its leaders to promote health and prevent disease. Specifically, CECOS develops sustained relationships
between Chicago’s Southside community and the UCCRC to increase local awareness of the latest advances in cancer research,
provide information related to cancer issues and treatment options, and communicate the benefits of participating in cancer
clinical trials and other UCCRC research studies. The program seeks to increase the participation of underserved communities
in these studies through education. To accomplish these goals, CECOS provides a central source of information for all UCCRC
community-focused programming, including health, educational, volunteerism, and service programming; engages faculty and
staff in conducting cancer research in the community; trains UCCRC members in the relevance of biomedical research and
enables the development of skills required to disseminate this knowledge to the community; and helps community members
share ideas about cancer and address fears pertaining to clinical trials. CECOS also organizes workshops and conferences
within the Southside community to disseminate information on cancer advances, clinical trials, research trends, and the value
and perspectives between the community and the UCCRC that will translate into sound, culturally-appropriate, and relevant
research.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
Other Resources
& Centers
of understanding family history in assessing cancer risk. These activities ensure a meaningful bidirectional exchange of ideas
135
CECOS has successfully developed and delivered one successful healthcare initiative per quarter in the Southside
community since its inception. Initiatives in 2008 included the Brother to Brother: Breaking the Barriers to Good
Health workshop for discussing men’s health and related cancer issues, the Save Our Sister: Sharing Strategies for
Survival workshop for raising awareness of breast cancer rates among the African American community, the Lungs
for Life: Facing the Challenge of Lung Cancer Together workshop for disseminating information on lung cancer risk
reduction, and the Annual Nutrition Knowledge Bowl, a competition involving students from six Chicago-area high
schools designed to raise awareness of nutrition and its role in preventing cancer. A video on the Nutrition Bowl was
aired on CATV in June 2009. High-school participants in this program are continuing to help CECOS spread the
word about the importance of healthy eating as Nutrition Bowl Ambassadors. In 2009, CECOS organized the Our
Daughters, Our Duty: The Facts about HPV and Cancer, a town hall meeting to discuss how community members can
protect themselves and their families from cervical cancer. The program has also developed unique partnerships with
Chicago Public Schools, Kennedy-King College, and the other City Colleges of Chicago.
In response to public demand, many of CECOS’s efforts focus on the relationship between cancer and poor nutrition.
An example of these activities is the partnership with the
Bronzeville Farmers’ Market. Every Sunday throughout the summer of 2008, CECOS members staffed a tent at the
market to distribute informational material on cancer and nutrition. In the spring of 2009, CECOS launched a new
initiative to provide nutrition tours at local grocers. The team provided on-site nutritional information and led a tour
through Farmers Best Market, the only African American-owned supermarket in Illinois. In May of 2009, CECOS held
a focus group with school teachers involved in the Nutrition Bowl to facilitate the improved design and expansion of
future nutritional events, including the 2009 Nutrition Bowl (to be held in the winter).
In addition to the activities offered by the Cancer Resource Center and CECOS, the UCCRC, UCMC Office of
Community Affairs, and the Center of Interdisciplinary Health Disparities Research (CIHDR; see Highlights – Research
Initiatives for details) have built positive relationships with political leaders, churches, community organizations,
support groups, and other hospitals in order to develop and participate in community events. Community outreach
programs and initiatives include the Smoking Cessation Program (C-STOP); a Community Fitness Program that
addresses various health topics; monthly educational sessions held downtown at the Whole Foods grocery store on
various topics; community workshops and forums offering cancer risk assessments, osteoporosis screenings, self breast
exam demonstrations, smoking cessation classes, and nutrition information; and public education and lecture series.
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Education
UCCRC members participate in a variety of training programs and educational opportunities. Unique departmental
committees are responsible for graduate and post-graduate training in a variety of disciplines related cancer, including the
Cancer Biology; Clinical Pharmacology and Pharmacogenomics; Genetics, Genomics, & Systems Biology; Immunology;
Molecular Biology; Medical Physics; and Molecular Metabolism and Nutrition Committees. Many UCCRC members are
involved in one or more of these training programs, many of which are supported by NIH training grants. The UCCRC also
offers fellowship training programs in Surgical Oncology, Radiation Oncology, and Pediatric Oncology. All UCCRC members
participate in a variety of seminar series, journal clubs, and program and departmental retreats, which are instrumental in
fostering a variety of inter- and intrapro grammatic research collaborations.
Committee on Cancer Biology
The Committee on Cancer Biology administers a multidisciplinary graduate training program to bestow a PhD in Cancer
Biology. The Committee is directed by Geoffrey Greene, PhD, and supported by a training grant from the NCI. The program
has a full curriculum and focuses on several areas of cancer biology, including apoptosis, cancer cytogenetics, cell cycle,
chromosome damage/repair, drug resistance, hormone action, metastatic progression, cell signaling, and tumor biology/
immunology. The Committee facilitates the exchange of information and ideas, and fosters interactions between basic,
translational, and clinical researchers.
Committee on Clinical Pharmacology and Pharmacogenomics
The Committee on Clinical Pharmacology and Pharmacogenomics administers a 2-year post-graduate training program,
accredited by the American Board of Clinical Pharmacology and supported by an NIH training grant, for MDs, PhDs and
PharmDs. The Committee is led by Dr. Mark Ratain and consists of faculty from various departments. The goal of the program
is to train individuals in various subspecialties of clinical pharmacology, including principles of therapeutics, molecular
pharmacology, and pharmacogenomics. The program offers training through various didactic exercises, seminars, and research
projects.
Committee on Medical Physics
The Committee on Medical Physics offers research training leading to a MS or PhD degree. The program, led by Dr. Maryellen
Giger and supported by an interdisciplinary NIH training grant, applies the principles of the physical sciences to biomedicine.
The Committee includes members of the UCCRC Advanced Imaging Program and faculty from the Departments of Radiology,
and Radiation and Cellular Oncology. Areas of focus include, for example, diagnostic radiography, magnetic resonance imaging
and spectroscopy, computer-aided diagnosis and quantitative image analysis, electron paramagnetic resonance imaging, nuclear
medicine imaging, and computer applications in radiation therapy.
The Committee on GGSB offers a PhD program that combines training in modern genetic analysis with genetic-based methods
for investigating clinical and basic science questions in the context of physiological, developmental, and evolutionary systems.
The program, under the leadership of Douglas Bishop, PhD, is supported by an NIH training grant and consists of faculty from
Other Resources
& Centers
Committee on Genetics, Genomics, & Systems Biology (GGSB)
16 different departments and represents a broad interdisciplinary approach to teaching and research. Strengths of the program
include gene expression and developmental genetics, chromosome organization and behavior, population and evolutionary
genetics, and genetics of human disease with an emphasis on genetic alterations in cancer.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
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Committee on Immunology
The Committee on Immunology provides multidisciplinary training towards a PhD degree in fundamental immunology
and approaches to understanding immunological diseases. The program has been continuously-funded by NIH training
grants for over 30 years and represents one of the oldest and most prestigious immunology programs in the country. The
Committee, under the direction of Harinder Singh, PhD, integrates the basic biological sciences with the clinical sciences
to effectively develop new approaches for the diagnosis and treatment of various immune diseases and cancer. Areas of
basic and applied immunology research include autoimmunity; hematopoiesis, lymphoid and myeloid development; T-cell
differentiation; signal transduction in lymphoid development and activation; and tumor immunity.
Committee on Molecular Metabolism and Nutrition (CMMN)
The Committee on MMN is an interactive research program, supported by an NIH training grant, that offers
interdisciplinary doctoral training in the molecular basis of biological processes related to nutritional status, metabolic
homeostasis, and human disease. Led by Chistopher Rhodes, PhD, the program focuses on metabolism and metabolic
diseases including, for example, diabetes and obesity, using biochemical, clinical, physiological, cell, and molecular biological
approaches. The Committee works closely with the Digestive Disease Research Core Center and Kovler Diabetes Center at
the University of Chicago.
Department of Health Studies
The Department of Health Studies, chaired by Ronald Thisted, PhD, is a cross-disciplinary program that studies the
environmental and organizational factors that influence the health of human populations through biostatistics, epidemiology,
and health services research. The Department offers a Masters of Science in Health Studies for Clinical Professionals
(MSCP), and a certificate program, the Clinical Research Training Program (CRTP). The MSCP is a course of study designed
for the enhancement of doctoral-level individuals in the theory, methods, and concepts of biostatistics, epidemiology, and
health services research needed to design and carry out clinical and epidemiologic research studies. The CRTP, a NIHsupported program designed for clinicians or clinical researchers, offers formal training opportunities in areas relevant to the
design, implementation, and analysis of clinical research. In addition, the Department offers a PhD program in biostatistics,
epidemiology, and health services research based on a core curriculum in population-based health research.
MacLean Center for Clinical Medical Ethics
The MacLean Center for Clinical Medical Ethics is recognized as a leading program in the country for research and training
in medical ethics. The Center is directed by Mark Siegler, MD, and consists of several UCCRC members as well as faculty
in medicine, law, business, public policy, and social sciences. Established in 1984 with support from the family of Dorothy J.
MacLean, the Center offers both a 2-year Masters Degree and a one-year part-time fellowship program. The Masters Degree
program provides a health services research curriculum and is intended for physicians interested in pursuing an academic
career with a focus on health policy and clinical medical ethics. The one-year, part-time fellowship program offers clinicians,
not necessarily pursuing academic medicine, training in medical ethics.
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Graham School of General Studies
The University of Chicago Graham School of General Studies offers a Clinical Trials Management Certificate Program. This
post-baccalaureate program provides comprehensive training required to initiate clinical research, apply effective monitoring
methods, prepare reports, and understand regulations and good clinical practices. All staff in the Cancer Clinical Trials Office
have completed this training program, which consists of courses in clinical practices, the drug development process, statistical
concepts for clinical research, and clinical site management and monitoring.
Training Grants
UCCRC members are principal investigators of 12 NIH T32 training programs in basic and clinical research that foster and
enhance interdisciplinary interactions. These training programs cover diverse areas of cancer-related research, such as cancer
biology, immunology, molecular biology, genetics, medical oncology, clinical therapeutics, medical physics, and addictions
research.
Cancer- Relevant Training Grants
PI
Grant #
Title
5-T32-AI07090
Interdisciplinary Training Program in Immunology
Eugene Chang
5-T32-DK07074
Research Training in Digestive Diseases and Nutrition
Maryellen L. Giger
5-T32-EB02103
Research Training in Medical Physics
Benjamin Glick
5-T32-GM07183
Molecular and Cellular Biology Training Grant
Geoffrey Greene
5-T32-CA09594
Graduate Training Program in Cancer Biology
Elizabeth M. McNally
5-T32-HL07381
Cardiovascular Sciences Training Grant
David Meltzer
5-T32-AG23496
MD/PhD Program in Medicine, Social Sciences, and Aging
Olufunmilayo Olopade
5-T32-CA09566
Basic Medical Research Training in Medical Oncology
Mark J. Ratain
5-T32-GM07019
Clinical Therapeutics
Nancy B. Schwartz
5-T32-HD07009
Graduate Training in Growth and Development
Julian Solway
5-T32-HL07605
Research Training in Respiratory Biology
Paul Vezina
5-T32-DA07255
Neuropsychopharmacology Training in Drug Abuse Research
Other Resources
& Centers
Albert Bendelac
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The University of Chicago Medical Center
The University of Chicago Medical Center has been at the forefront of medicine since 1927. The Medical Center occupies over 30
buildings, which house all hospital and clinical areas of the campus as well as teaching and research space. The primary clinical
facilities of the UCCRC include the Bernard A. Mitchell Hospital, the Comer Children’s Hospital, and the outpatient clinics in
the Duchossois Center for Advanced Medicine (DCAM).
Bernard A. Mitchell Hospital
The Bernard A. Mitchell Hospital is the primary adult inpatient facility, which includes the emergency department and the
Arthur Rubloff Intensive Care Tower. More than 60 beds are dedicated to adult medical oncology. Patients who participate
in clinical pharmacology studies and require hospitalization are placed in the General
Clinical Research Center (GCRC), an NIH-funded facility with dedicated skilled nursing
and research staff for clinical research. The facility provides more than 4,000 square feet
of space for specialized research and patient care (8-bed inpatient and 3-bed outpatient
units). Additional GCRC resources include a dedicated metabolic kitchen, nutrition
unit, and a core laboratory facility offering a variety of services such as rapid routine
assays and sample processing.
Comer Children’s Hospital
The Comer Children’s Hospital, which opened in 2005, is a tertiary care teaching facility dedicated
to treating childhood diseases through patient education, care, and research. The state-of-the-are
facility provides 242,000 sq ft of space with a capacity of more than 150 beds, 25% of which are
dedicated to the treatment of children and adolescents with cancer. The facility also includes one
of the country’s largest and most advanced pediatric intensive-care units equipped to treat children
with multiple traumas and complex medical problems.
Duchossois Center for Advanced Medicine
The UCCRC’s outpatient facilities are located in the state-of-the-art DCAM facility,
which brings together most of the Medical Center’s diagnostic and outpatient treatment
services. The 550,000 sq ft facility houses outpatient clinics for medical oncology,
gynecological oncology, and radiation oncology. Resources include modern radiation
therapy facilities, contemporary chemotherapy infusion suites, and an apheresis unit.
The multidisciplinary Breast Center provides mammography services, examination and
consulting rooms, patient information, and cancer risk assessment in a single location to
serve patients with breast cancer and their families.
New Hospital Pavilion
The UCMC has made significant commitments to replacing clinical care and clinical
research space with state-of-the art facilities. In addition to the opening of the Comer
Children’s Hospital and Center for Children and Specialty Care in 2005 and 2006,
construction of the New Hospital Pavilion began in 2009. The Pavilion will be a
400,000 sq ft, $700 million facility that will provide complex specialty care, with
a focus on cancer and advanced surgery. Completion of the facility is planned for 2012.
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Dedicated Research Facilities
Ellen and Melvin Gordon Center for Integrative Science (GCIS)
The GCIS is a 430,000 sq ft building that houses 20 members of the UCCRC in stateof-the-art modular laboratories. The seven-story building, which opened in 2005,
represents one of the few collaborative research facilities in the nation that bridges
physical and biological sciences under one roof. The GCIS houses the Ben May
Department for Cancer Research, the Howard Hughes Medical Institute, the Institute
for Biohpysical Dynamics, the Department of Biochemistry and Molecular Biology, and
select laboratories of the Physical Sciences Division.
Gwen and Jules Knapp Center for Biomedical Discovery
The UCCRC is experiencing a significant expansion in facilities. Construction
of the Knapp Center for Biomedical Discovery (KCBD) has been completed with
occupancy occurring during June of 2009. The 12 story KCBD provides an additional
330,000 sq ft of research space and houses ~50 UCCRC researchers. The facility
includes a state-of-the-art vivarium; dedicated core facility space for the Genomics,
Transgenic Mouse/ES Cell, and Integrated Microscopy Facilities; and will houses
research programs from the Departments of Medicine (Section of Hematology
and Oncology) and Pediatrics (Section of Pediatric Hematology and Oncology), the UCCRC, the Ludwig Center for Metastasis
Research, and the Institute for Genomics and Systems Biology. The UCCRC has 22,000 sq ft, allowing for the recruitment
of up to 8 new faculty members. The KCBD is connected to the adjacent GCIS and Knapp Center for Molecular Medicine by
pedestrian bridges. Upon full occupancy of the KCBD, over 75 UCCRC researchers (more than 80% of all UCCRC laboratory
researchers) will be located in three inter-connected, state-of-the-art facilities. This configuration will foster more extensive
Other Resources
& Centers
interactions between researchers and enable the UCCRC to achieve strategic programmatic growth.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
141
Highlights
The Gwen and Jules Knapp Center for
Biomedical Discovery, a new UCCRC research facility.
Research Initiatives
Breast Cancer Specialized Program of Research Excellence (SPORE)
The Breast Cancer SPORE program brings together a multidisciplinary team of basic, clinical, and population science
investigators to perform innovative research using a global strategy to reduce the pain and suffering from breast cancer.
Awarded by the National Cancer Institute, the program is one of only 11 Breast SPOREs in the the United States. The
investigators represent three UCCRC Programs, including the the Cancer Risk and Prevention, Advanced Imaging, and Clinical
and Experimental Therapeutics Programs. The Breast Cancer SPORE is an integrated program that translates recent advances
in genetics to benefit women who are at risk of developing an aggressive form of breast cancer, which disproportionately affects
African American women at a young age.
The Breast Cancer SPORE is led by Dr. Fumni Olopade (Cancer Risk and Prevention Program), along with co-leaders Drs. Gini
Fleming (Clinical and Experimental Therapeutics Program), and Maryellen Giger (Advanced Imaging Program), and involves
researchers in genetics, bioinformatics, molecular biology, biophysics, and structural biology. The UCCRC integrates these
researchers with those in clinical disciplines, including epidemiology, medical oncology, surgical oncology, and radiation
oncology, to facilitate the translation of scientific advances to patients.
The SPORE consists of four translational research projects, each co-led by basic and applied investigators from the UCCRC.
Project 1 aims to develop mammography and MRI image-based markers, to assess breast density, for use alone or in
combination with other biomarkers to quantify breast cancer risk and monitor therapeutic response. In Project 2, researchers
are examining whether MR imaging with improved spectral, temporal, and spatial sampling leads to improved detection of
early breast cancer. Project 3 aims to determine whether variations in genes involved in hormone and xenobiotic metabolism
influence breast cancer risk. Finally, Project 4 aims to identify population-specific genetic variants that influence toxicity
to breast cancer chemotherapy. These projects are supported by an Analytic and Informatics Core; Biospecimen, Pathology
and Genotyping Core; and an Administration Core. These Core Facilities were built on the unique strengths of the existing
UCCRCsupported Cores.
Breast Cancer SPORE Projects and Leaders
Basic Scientist
Applied Scientist(s)
1) Imaging-based determination of
breast cancer risk
Maryellen Giger
(Advanced Imaging Program)
Gillian Newstead,
(Advanced Imaging Program)
2) Specificity of MRI with optimal
temporal, spatial, and spectral
sampling in early breast cancer
Gregory Karczmar
(Advanced Imaging Program)
3) Variation in hormone and
xenobiotic metabolizing enzyme
genes and breast cancer
Anna Di Rienzo
(Cancer Risk and Prevention Program)
Olufunmilayo Olopade (Cancer Risk
and Prevention Program)
4) Identifying population specific
variants important in toxicity to
breast cancer therapy
M. Eileen Dolan
(Clinical and Experimental
Therapeutics Program)
Mark Ratain (Clinical and
Experimental Therapeutics Program)
Gillian Newstead
(Advanced Imaging Program)
Nora Jaskowiak
(Cancer Risk and Prevention Program)
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Highlights
Project
143
Leukemia and Lymphoma Society Specialized Center of Research Grant (SCOR)
The SCOR focuses on the development of peptides and small molecules therapeutics for hematological malignancies.
Awarded by the Leukemia and Lymphoma Society, this initiative specifically aims to develop a comprehensive
multidisciplinary program that will provide a platform for the identification and testing of novel cell-permeable peptides
and small molecules for the treatment of hematological malignancies. Development of the SCOR grant was supported by
Pilot Project funding from the UCCRC. The SCOR represents a collaboration among three institutions and is led by Michael
Thirman, MD (Molecular Genetics and Hematopoiesis Program).
The central theme of the SCOR program is a common therapeutic strategy based on the targeting of protein-protein
interactions in leukemia and lymphoma, rather than focusing on a single disease entity. The program brings together a
large group of scientists to form a highly interactive group of chemists, molecular biologists, and clinicians who might not
otherwise have the opportunity to work together in a translational research program in leukemia and lymphoma. Specifically,
the program encompasses a collaborative effort involving eleven University of Chicago senior researchers as well as two
project leaders from two other NCI-designated Cancer Centers. Each project within the SCOR incorporates the use of
cell permeable peptides and small molecules as part of an integrated program to develop and optimize a novel therapeutic
platform for hematologic malignancies. The associated cores have formed an integral part of the SCOR and have provided
valuable reagents and expertise for each of the projects.
SCOR Projects and Leaders
Project
Leader
1) Targeting Transducible Anticancer Peptide
Therapeutics to Kill Tumor Cells In Vivo
Steven Dowdy
(University of California-San Diego)
2) Peptide and Small Molecule Therapeutics for
MLL-Associated Leukemia
Michael Thirman
(UCCRC - Molecular Genetics and Hematopoiesis Program)
3) Specific Anti-BCL-6 Targeted Transcription
Therapy for B-Cell Lymphomas
Ari Melnick
(Cornell University)
Core
A)Peptide Therapeutics
Leader(s)
Steve Kron and Piers Nash
(UCCRC - Cell Signaling and Gene Regulation Program)
Steven Dowdy
(University of California-San Diego)
144
B)Small Molecule Therapeutics
Geoffrey Greene and Milan Mrksich
(UCCRC - Cell Signaling and Gene Regulation Program)
C)Patient Demographics and Cell Bank
Michelle Le Beau and Richard Larson
(Molecular Genetics and Hematopoiesis Program)
D)Hematopathology
John Anastasi
(Molecular Genetics and Hematopoiesis Program)
E) Clinical Trials and Minimal Residual Disease
Monitoring
Wendy Stock
(Molecular Genetics and Hematopoiesis Program)
F) Stem Cell Processing and Purging
Koen van Besien and Amittha Wickrema
(Molecular Genetics and Hematopoiesis Program)
UCCRC SCIEN T IFI C R EPO R T 20 0 9
Center for Interdisciplinary Health Disparities Research (CIHDR)
In 2003, the UCCRC was awarded one of eight Center grants by the National Institutes of Health/National Cancer Institute
to study health disparities. The CIDHR, based at the University of Chicago’s Institute for Mind and Biology, was established
to understand population health and health disparities to eliminate group differences in health using a multi-level approach.
Over the past five years, the CIHDR has focused its efforts on understanding population differences in the incidence and
nature of breast cancer among Black and White women. Black women in the United States and West Africa develop breast
cancers that occur at a younger age and are more aggressive and lethal than those experienced by White women of Northern
European ancestry. In conjunction with these studies, the Center is also examining the occurrence of breast cancer in Nigerian
women through research conducted at the University of Ibadan. The overall goal is to increase our understanding of the social,
behavioral, and biological factors that influence health disparities so that appropriate measures may be taken to eliminate such
disparities.
The CIHDR is directed by Sarah Gehlert, PhD, the Associate Dean for Research in the School of Social Service Administration,
and co-directed by Martha McClintock, PhD, the David Lee Shillinglaw Distinguised Service Professor in Psychology (both
members of the Cancer Risk and Prevention Program). The Center draws on the diverse talents of social workers, psychologists,
physicians, and molecular geneticists to explore the causes of breast cancer in African-American women by examining both
medical and environmental factors.
The specific aims of the Center are to bring together scientists and community members who are vulnerable to adverse health
conditions to inform them of the Center’s agenda, which are to 1.) foster health disparities research from multiple levels of
analysis through shared conceptual frameworks that integrate discipline-specific theories and methods; 2.) increase interest in
health disparities among scientists, students, and community members; 3.) develop appropriate methods for the comprehensive
analysis of environmental, psychological, and genetic factors among vulnerable populations; 4.) increase existing knowledge on
social, behavioral, and biological factors that influence health disparities; and finally, 5.) disseminate these findings to vulnerable
populations, community organizations, and scientific researchers. The Center is supported by the Human Tissue Resource
Center Core, and is conducting research in four separate projects to achieve these aims.
CIHDR Projects and Leaders
Leader
1) Comparison of gene regulation in mammary tumors and ovarian
function between socially isolated and group-living rats
Martha McClintock
(Cancer Risk and Prevention Program)
2) Molecular characterization of primary breast tumors from
Nigerian and Chicago Southside women to determine if
alterations in BRCA1 contribute to breast cancer in younger
Black women; exploration of McClintock’s model in primary
tumors
Olufunmilayo Olopade
(Cancer Risk and Prevention Program)
3) Examination of culture-specific views of breast cancer and
treatment; testing of McClintock’s model in community
volunteers (using community, living, social, behavioral,
biological, and health outcomes factors)
Sarah Gehlert
(Cancer Risk and Prevention Program)
4) Examination of mammary tumor growth rate, response to
chemotherapy, and chemoprevention in animal models
Suzanne Conzen
(Cell Signaling and Gene Regulation Program)
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Highlights
Project
145
Institute for Genomics and Systems Biology (IGSB)
The IGSB was established to further the advancement of technology development for genome analysis and accelerate the
transition of basic discoveries in genome science into translational and clinical research. The Institute, which reflects
the collaborative nature between the University of Chicago and Argonne National Laboratory, focuses on genomics and
systems biology approaches to understand genome function evolution, uncover new diagnostic and therapeutic targets, and
discover new strategies for complex human diseases with a major focus on cancer. The IGSB is organized into ten areas of
investigation, including proteomics and structural genomics, computational biology and informatics, microbial systems
biology, evolutionary genomics and systems, biological engineering and technology development, cellular and genomic
networks, chemical genomics, cancer, population genomics and complex diseases, and clinical genomics.
The Institute is directed by Kevin White, PhD, (Cell Signaling and Gene Regulation Program) and draws on the expertise
of investigators from Argonne National Laboratory and more than twenty different departments in the Biological Sciences
and Physical Sciences Divisions at the University of Chicago. More than 70 researchers, many of which are members of the
UCCRC, are performing research on complex biological systems from a wide variety of experimental, computational, and
theoretical approaches. Current research initiatives include breast cancer, metabolic diseases and diabetes, and inflammatory
bowel disease. The IGSB has established two core facilities to support its research, including the Cellular Screening Center
(CSC), for high-throughput RNAi and chemical genetic screening, and the High-Throughput Genome Analysis Core (HGAC),
which features resources for ultra-high-throughput sequencing and microarray processing. The IGSB is also establishing a
Proteomics Core for high-throughput cloning and protein production facilities for antibody generation.
IGSB Initiatives and Leaders
Initiative
Leader
Kevin White
1) Breast Cancer – Assessment of the role of specific genes in breast
cancer; rapid identification of novel drug targets; screening of chemical (Cell Signaling and Gene Regulation Program)
and Ruby Dhar
libraries to develop improved, targeted therapies
146
2) Metabolic Diseases and Diabetes – Discovery of genomic variation and
expression patterns for evaluating potential outcomes of drug therapy;
drug and genome screening of insulin-secreting cells for identifying
therapies that promote insulin production
Mark Ratain
(Clinical and Experimental Therapeutics
Program)
3) Inflammatory Bowel Disease – Determination of the relationship
between specific bacteria and inflammatory bowel disease
Eugene Chang
(Cancer Risk and Prevention Program)
UCCRC SCIEN T IFI C R EPO R T 20 0 9
Ludwig Center for Metastasis Research
The Ludwig Center for Metastasis Research, which is affiliated with the UCCRC, aims to further our understanding of
metastasis and translate laboratory concepts into novel therapeutics for the prevention and treatment of metastasis. Established
in 2006 by an endowment from the Ludwig Fund (providing $2.5 million per year), the Center will be housed in the Gwen and
Jules Knapp Center for Biomedical Discovery. The Center is led by Ralph Weichselbaum, MD, the Chairman of the Department
of Radiation & Cellular Oncology (Clinical and Experimental Therapeutics Program) and Geoffrey Greene, PhD, the Vice Chair
of The Ben May Department for Cancer Research and the Associate Director Basic Sciences for the UCCRC (Cell Signaling
and Gene Regulation Program). Researchers from various disciplines, including molecular and cell biology, bioinformatics,
chemistry, genetics, imaging, and medicine collaborate to dissect the basic mechanisms of metastasis using sophisticated, stateof-the-art approaches. The Center is pursuing three specific research aims, initially targeting metastasis of breast and prostate
cancers.
Ludwig Center Aims
Aims
Description
For imaging and killing tumor cells expressing the estrogen or androgen
receptor (targeted against cancers of the breast, prostate, ovary, and lung)
2) Development of novel receptortargeted nanoparticle reagents
For selective and precise imaging and delivery of therapeutics to tumor cells
expressing the estrogen or androgen receptor (targeted against a wide array of
cancers)
3) Identification and development of
novel small molecules
For the sensitization of tumors, independent of hormone receptor status, to
ionizing radiation or chemotherapy (targeted against cancers of the breast, head
and neck, lung, ovary, and prostate)
Highlights
1) Development of radiolabeled steroid
receptor modulators
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147
Systems Biology Approach for the Study of Therapy-Related Acute Myeloid Leukemia (t-AML)
In early 2009, the Cancer Research Foundation (CRF) provided the University of Chicago with generous funding to catalyze
a multidisciplinary systems biology and genomics approach to study t-AML. An interdisciplinary team of scientists has
been assembled to use a comprehensive approach to identify individuals at risk for developing t-AML, identify genetic
susceptibility factors that are involved, and design effective prevention and treatment strategies for this disease. Therapyrelated acute myeloid leukemia is a direct result of mutational events that are induced by chemotherapy or radiotherapy
used in the treatment of primary malignancies, such as breast and colon cancer. Approximately 8-10% of all patients treated
for cancer will develop the disease, an average of 5 years after receiving treatment, and have a median survival of 8 months.
Patients who have received immunosuppressive agents for organ transplantation and the elderly are also at risk for developing
t-AML and AML.
Members of the interactive team, led by Michelle Le Beau, PhD, Director of the UCCRC and Cancer Cytogenetics Laboratory,
represent the UCCRC and the IGSB. The team has extensive research expertise in clinical oncology, hematopathology,
genetics, genomics, systems biology, computational modeling of molecular networks, and hematopoiesis. Using a systems
approach, these investigators will integrate six research projects involving high-throughput screening, stem cell biology,
pharmacogenetics, clinical trial design, and computation to understand the basic biology of t-AML. Taken together, these
projects will help researchers identify the molecular basis of the disease and lead to improved therapies, earlier detection, and
prevention strategies.
t-AML Projects and Leaders
Project
148
Team
1) Identifying the genetic signature of therapy-related
leukemias
Ken Onel, Michelle Le Beau, and Richard Larson (Molecular
Genetics and Hematopoiesis Program); Kevin White (Cell
Signaling and Gene Regulation Program); Yves Lussier (Clinical
and Experimental Therapeutics Program)
2) Understanding the leukemia stem cell
John Cunningham, Michelle Le Beau, and Harinder Singh
(Molecular Genetics and Hematopoiesis Program); Kevin White;
Yves Lussier
3) Pharmacogenetics – predicting response to therapy
Ken Onel and Sandeep Gurbuxani (Molecular Genetics and
Hematopoiesis Program); M. Eileen Dolan (Clinical and
Experimental Therapeutics Program); Yves Lussier
4) Using the leukemia stem cell to model disease
Harinder Singh, John Cunningham, Michelle Le Beau, Yves
Lussier
5) Targeted clinical trials
Richard Larson, Lucy Godley, Wendy Stock, and Olatoyosi
Odenike (Molecular Genetics and Hematopoiesis Program); M.
Eileen Dolan; Rong Huang
6) Computational biology – creating an atlas of
therapies
Yves Lussier with all team members
UCCRC SCIEN T IFI C R EPO R T 20 0 9
Selected Awards and Honors
Cell Signaling and Gene Regulation Program
Edwin Ferguson, PhD, Associate Professor of Molecular Genetics and Cell Biology, was the recipient of the University of
Chicago 2009 Llewellyn John and Harriet Manchester Quantrell Award for Excellence in Undergraduate Teaching.
Hue Luu, MD, Assistant Professor of Surgery, was the recipient of the 2009 Career Development Fellowship Award from the
Orthopaedic Research Society.
Elizabeth McNally, MD, PhD, Professor of Medicine, was elected Vice President of the American Society for Clinical
Investigation (ASCI) in 2009.
Kevin White, PhD, Professor of Human Genetics, was named by Crain’s Chicago Business as one of its “40 Under 40” in 2008,
which recognizes the area’s up-and-comers. Dr. White was the only recipient from an academic setting.
Molecular Genetics and Hematopoiesis Program
Kenneth Cohen, MD, Assistant Professor of Medicine, was the recipient of the 2009 Cancer Research Foundation Young
Investigator Award.
Barbara Kee, PhD, Associate Professor of Pathology, was the co-editor with Dr. Amittha Wickrema of the book entitled,
Molecular Basis of Hematopoiesis (2009).
Richard Larson, MD, Professor of Medicine, served as a Councilor for the 2009 American Society of Hematology Executive
Committee. Dr. Larson was also the Co-Chair of the 2009 Organizing Committee for Global Opinion Leader Summit on
CML in Paris, France and a member of the 2009 Organizing Committee for Benzene (Health Effects and Mechanisms of Bone
Marrow Toxicity) at the Technical University of Munich, Germany.
Michelle Le Beau, PhD, Professor of Medicine, was elected to the Board of Directors of the American Association of Cancer
Institutes and received the American Cancer Society Distinguished Service Award in 2008. Dr. Le Beau was also selected to
give the 2008 Distinguished Lectureship for the Lurie Comprehensive Cancer Center of Northwestern University.
Olatoyosi Odenike, MD, Assistant Professor of Medicine, is a member of the International Working Group for Myelofibrosis
Research and Treatment. Dr. Odenike is also a 2009 member of the American Society of Clinical Oncology (ASCO) Scientific
Program Committee for the Leukemia, Myelodysplasia, and Transplantation Track and will serve as the Track Leader in 2010.
Janet Rowley, MD, Professor of Medicine has received many of the nation’s most prestigious awards, and 2009 was an
extraordinary year for awards. President Barack Obama awarded her with the Presidential Medal of Freedom, the nation’s
highest civilian honor. (In 1998, President Bill Clinton presented the National Medal of Science, the nation’s highest scientific
honor, to Dr. Rowley.) She also received the 2009 Genetic Prize of the Peter and Patricia Gruber Foundation and the 2009
Association of American Cancer Institute’s distinguished Scientist Award. She was one of only six research scientists invited by
President Barack Obama to the signing of the executive order to lift the ban on embryonic stem cell research in 2009.
Amittha Wickrema, PhD, Associate Professor of Medicine, was the co-editor with Dr. Barbara Kee of Molecular Basis of
Highlights
Hematopoiesis (2009).
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Immunology and Cancer Program
Maria-Luisa Alegre, MD, PhD, Associate Professor of Medicine, received the Leif B. Sorenson Faculty Research Award from
the University of Chicago Department of Medicine in 2008. Dr. Alegre was also elected to the Board of Directors for the
Autumn Immunology Conference as a Liaison to Academia and member of the Basic Science Advisory Committee for the
American Society of Transplantation in 2009.
Albert Bendelac, MD, PhD, Professor of Pathology, was named the University of Chicago A.N. Pritzker Professor in
Pathologyin 2008.
Thomas Gajewski, MD, PhD, Associate Professor of Pathology, was elected the incoming President (2010-2012) of the
International Society for the Biologic Therapy of Cancer (iSBTc), the major translational cancer immunotherapy society.
Vu Nguyen, MD, Assistant Professor of Medicine, received the Cancer Research Foundation Young Investigator Award
in 2008, and was the recipient of the Damon Runyon Clinical Investigator Award and the American Society for Blood and
Marrow Society New Investigator Award in 2009.
Jian Zhang, MD, Assistant Professor of Medicine, was the recipient of the Career Investigator Award from the American
Lung Association in 2008.
Clinical and Experimental Therapeutics Program
Ezra Cohen, MD, Assistant Professor of Medicine, was a member of the Scientific Committee for the 7th International
Conference on Head and Neck Cancer. He is also a member of the Investigational Drug Steering Committee PI3K/Akt/
mTOR (PAM) Task Force (2008), International Thyroid Oncology Group (2009), and American Society of Clinical Oncology
Scientific Program Committee (2009). Dr. Cohen also served as a panelist at the 2009 Workshop on Oral Cancer Screening,
hosted by the American Dental Association’s Council on Scientific Affairs.
Mark Ferguson, MD, Professor of Surgery, was elected President of the International Society of Diseases of the Esophagus in
2008 and appointed to the Board of Directors for the Cardiothoracic Surgery Network (CTSNet) in 2009.
Alessandro Fichera, MD, Assistant Professor of Surgery, was nominated President of the Chicago Society of Colon and
Rectal Surgeons in 2008 and elected into the Society of University Surgeons in 2009.
Philip Hoffman, MD, Professor of Medicine, was named the 2009 Faculty Honoree by the University of Chicago Pritzker
School of Medicine class of 2009.
Edwin Kaplan, MD, Professor of Surgery, received the Oliver Cope Meritorious Achievement Award in 2009 from the
American Association of Endocrine Surgeons (AAES) for his contributions in the field of endocrine surgery as an investigator,
teacher, and clinical surgeon. This honor has only been awarded five prior times in the 30-year history of the AAES.
Theodore Karrison, PhD, Associate Professor of Health Studies, was inducted as a Fellow of the American Statistical
Association (ASA) in 2009 for his outstanding contributions to statistical methodology, collaborative research, and leadership
in the field of statistical science. The ASA Fellow designation is among the most distinctive honors in the field of statistics.
Hedy Kindler, MD, Associate Professor of Medicine, was elected President of the International Mesothelioma Interest
Group. She was also elected a member of the Board of Directors and Cadre Leader (Pancreatic Cancer) of the Cancer and
Leukemia Group B (CALGB).
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Bruce Minsky, MD, Professor of Radiation and Cellular Oncology, was the recipient of the 2008 Distinguished Alumni Award
from the Memorial Sloan Kettering Cancer Center. In 2008, he was a Visiting Professor in the Department of Radiation
Oncology at the Medical College of Wisconsin and at the Mofitt Cancer Center in Tampa, FL. He was also a Visiting Professor
at Oregon Health and Sciences University in Portland, OR and at Sirio-Lebanese Hospital in Sao Paulo, Brazil in 2009.
Mitchell Posner, MD, Professor of Surgery, is a member of the Surgical Oncology Advisory Council of the American Board of
Surgery (2009) and was nominated President-Elect of the Society of Surgical Oncology in 2009.
Kevin Roggin, MD, Assistant Professor of Surgery, was elected to the Gold Humanism Honors Society (2008) and was the
recipient of the 2008 Leonard Tow Humanism in Medicine Award. Dr. Roggin was also nominated Outstanding Faculty
Member and elected as a fellow of the Academy of Distinguished Medical Educators of the Pritzker School of Medicine in 2008.
He was listed as one of “America’s Top Surgeons” by the Consumers’ Research Council of America (2008-2009) and received the
2009 MDx Medical Patient’s Choice Award.
Richard Schilsky, MD, Professor of Medicine, was elected the President of the American Society of Clinical Oncology in 2008.
David Song, MD, Associate Professor of Surgery, was the 2008 recipient of the Arthur G. Michel Award, in recognition of being
an outstanding clinician, from the Breast Cancer Network of Strength.
Walter Stadler, MD, Professor of Medicine, was listed as one of “America’s Top Doctors” in medical oncology by Castle
Connolly in 2008.
Gary Steinberg, MD, Professor of Surgery, was appointed the Chairperson of the Scientific Advisory Board of the Bladder
Cancer Advocacy Network in 2009. He was also selected Program Chairman for the 2009 Fourth Annual Bladder Cancer Think
Tank Meeting focused on “Novel Therapeutics for Advanced Urothelial Cancer of the Bladder”.
Everett Vokes, MD, Professor of Medicine, was appointed Chairman of Medicine at the University of Chicago Medical Center
in 2009. Dr. Vokes has been recognized several times on America’s best doctor lists, including America’s Top Doctors by
Castle Connolly (most recently 2008), Best Doctors in America, and Chicago Magazine’s Top Doctors. He was also one of two
recipients of the 2008 Translational Research Professorship from the American Society of Clinical Oncology. Dr. Vokes has
served as Chair of the Cancer and Leukemia Group B (CALGB) Respiratory Committee since 2004.
Advanced Imaging Program
Stephen Archer, MD, Professor of Medicine, is the Chair of the Cardiopulmonary Critical Care Council of the American Heart
Association and was elected member of the Association of Professors of Cardiology in 2008.
Samuel Armato, PhD, Associate Professor of Radiology, was the Raine Visiting Professor at the University of Western Australia
in Perth (2009).
Richard Baron, MD, Professor of Radiology, was appointed to the Radiological Society of North America (RSNA) Board of
Directors in 2008.
Maryellen Giger, PhD, Professor of Radiology, was named President-Elect (2008), President (2009), and Chairman of the Board
Charles Metz, PhD, Professor of Radiology, received the 2008 Kurt Rossmann Award for Excellence in Teaching from students
in the University of Chicago Graduate Programs in Medical Physics, offered jointly by the Departments of Radiology and
Highlights
(2010) for the American Association of Physicists in Medicine.
Radiation and Cellular Oncology.
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Cancer Risk and Prevention Program
Anirban Basu, PhD, Assistant Professor of Medicine, was a recipient of the 2009 Bernie J. O’Brien New Investigator Award
from the International Society of Pharmacoeconomics and Outcomes Research (ISPOR). He was also chosen as the Labelle
Lecturer in Health Services Research at McMaster University, Canada, and was the winner of the Society for Medical
Decision Making (SMDM) Comparative Effectiveness Research Essay Contest in 2009.
Brian Chiu, PhD, Associate Professor of Health Studies, was inducted to the Delta Omega Honorary Society in Public
Health, Alpha Phi Chapter, in 2009.
Harriet De Wit, PhD, Professor of Psychiatry, was the 2009 recipient of the Marian W. Fischman Lectureship Award from
the College on Problems of Drug Dependence. The award recognizes the contributions of an outstanding woman scientist in
drug abuse research.
James Dignam, PhD, Associate Professor of Health Studies, will assume the position of Group Statistician and Senior
Scientific Director, Statistics and Data Management Center for the Radiation Therapy Oncology Group (RTOG) in 2009.
Founded in 1968, the RTOG is an NCI-sponsored multi-institutional international Clinical Trials Cooperative Group. While
the RTOG headquarters are located at the American College of Radiology in Philadelphia, Dr. Dignam will coordinate this
activity from the University of Chicago.
David Grdina, PhD, Professor of Radiation and Cellular Oncology, was appointed as a member of the NASA Space Radiation
Standing Review Panel and the National Council on Radiation Protection and Measurements PAC1 in 2009.
Sarah Gehlert, PhD, Professor of the School of Social Service Administration, was named to the Helen Ross Professorship in
2008.
Stacy Lindau, MD, Assistant Professor of Obstetrics and Gynecology, is the Director of the University of Chicago Program in
Integrative Sexual Medicine for Women and Girls with Cancer (2008). Dr. Lindau received the Best Poster Award in Biology at
the International Society for the Study of Women’s Sexual Health 2009 Annual Meeting. She is also a member of the National
Academy of Sciences Committee on Population, which is organizing a workshop on Collecting, Storing, Accessing, and
Protecting Social Survey Data Containing Biological Measures in 2009.
David Meltzer, MD, PhD, Associate Professor of Medicine, was elected a member of the American Society for Clinical
Investigation (ASCI) in 2008.
Olufunmilayo Olopade, MBBS, Professor of Medicine, was elected to the Institute of Medicine of the National Academies in
2008. Dr. Olopade also received the Nigerian Lawyers Association Annual Merit Award, National Medical Association Scroll
of Merit Award, and YWCA Racial Justice Award in 2008. She was named Honorary Canon by the Saint James Cathedral of
Chicago, Illinois in 2008 and received an Honorary Degree of Doctor of Science from Bowdoin College in Brunswick, Maine in
2009.
David Rubin, MD, Associate Professor of Medicine, received a fellowship in the American Gastroenterological Association and
was elected to the Nominating Committee for the American Gastroenterological Association in 2009.
Dr. Lisa Sanchez-Johnsen PhD, Assistant Professor of Psychiatry, recently received the “Distinguished Early Career
Professional” award from the National Latino Psychological Association due to her research, service, and clinical work
addressing health disparities and community based research. She also received the “Latino Leadership Citation Presidential
Award” from the American Psychological Association based on her “innovative research in developing culturally-tailored
behavioral interventions to reduce cancer related outcomes”. For the past 6 years, she has been a Health Disparities Research
Scholar with the NIH-National Center for Minority Health and Health Disparities.
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Financials
The University of Chicago Cancer Research Center
Reporting Date: 3/31/09
Funding Agency
Sum of Direct Costs
Sum of Total Costs
(Direct + Indirect)
Total Number
of Projects
ACS
$1,124,165
$1,325,000
8
NCI
$24,431,918
$34,658,783
106
NSF
$341,157
$502,424
6
Other NIH
$40,943,439
$55,650,976
159
Other Peer
$4,930,558
$6,296,547
32
Subtotal of Peer Reviewed
$71,771,237
$98,433,730
311
Industry
$10,604,635
$13,444,055
215
Other Non Peer
$10,579,303
$11,343,429
132
Subtotal of Non Peer Reviewed
$21,183,938
$24,787,484
347
Grand Total (All Projects)
$92,955,175
$122,529,210
658
Highlights
*CALGB projects ($11,306,870 Total Cost) are not included above.
UCCRC SCIEN T IFI C R EPO R T 20 0 9
153
www.uccrc.uchicago.edu
Editor: Hoyee Leong, PhD
Cover Design: Words & Pictures
Interior Design and Printing: Pixel Print Graphics