1. health and fitness
2. disease
3. cancer

UT Southwestern
Harold C. Simmons
UT SOUTHWESTERN MEDICAL CENTER
HA R O L D C. SCancer
I M M O NCenter
S CO M P R E H E N S I V E CA NC E R C E N T E R
Comprehensive
Annual Report 2012
momentum
momentum
table of contents
4
12
2
Director’s Message
4
Feature: MOMENTUM
8
New Cancer Center Members
17
12 Chemistry and Cancer
18 Feature: GLIOMA
22 Development and Cancer
26
28 Feature: BREAST CANCER
32 Cancer Cell Networks
32
38 Constructing the Future:
A New University Hospital
40 Experimental Therapeutics of Cancer
44
46 Feature: SABR
50 Lung Cancer
38
56 Feature: HEPATOCELLULAR CANCER
60 Population Science and Cancer Control
66 Moncrief Cancer Institute
67 Profile: W. Phil Evans, M.D.
60
68 Numbers at a Glance
49
70 Cancer Center Members
at a glance
74 Senior Leadership
ACCRUAL TO CLINICAL ONCOLOGY TRIALS, 2006-12
By Trial Type
Non-Interventional
Interventional
69
2012
970
303
571
2011
945
374
2010
523
303
2009
826
433
230
663
399
2008
640
241
361
2007
538
177
199
2006
356
157
0
2
Total
667
200
400
ACCRUAL TO CLINICAL ONCOLOGY TRIALS, 2006-12
By Trial Type
Industrial
External Peer Review
600
National Group
800
Institutional
1000
Total
945
826
800
1000
970
director’s message
Harold C. Simmons Comprehensive Cancer Center
James K.V. Willson, M.D.
As an incubator for scientific and medical innovation, UT Southwestern has long been more than the
sum of its parts. Visionary leadership, substantial community support, and core commitments to basic
research and clinical excellence all have contributed to catapulting the University to eminence.
These components of UT Southwestern’s success also have been vital in building the Harold C.
Simmons Comprehensive Cancer Center into a powerful engine of discovery. That engine, in turn, is now
helping propel the University to new pinnacles of achievement.
The Cancer Center’s designation from the National Cancer Institute (NCI)—a mark of all-around
excellence—and its growing infrastructure of knowledge and resources have made UT Southwestern a
destination institution for cancer research. This is increasingly reflected in the University’s core leadership. Recent infusions of talent include some of the nation’s preeminent scientists and physicians, whose
work reflects a dedication to the Cancer Center’s mission. Among the additions are the new Director of the
Center for the Genetics of Host Defense, Bruce Beutler, M.D., a Nobel Laureate; Chair of Pathology, James
Malter, M.D.; Director of Pediatric Hematology/Oncology, Stephen Skapek, M.D.; Director of the Children’s
Medical Center Research Institute at UT Southwestern, Sean Morrison, Ph.D.; Chair of Radiology, Neil
Rofsky, M.D.; and Vice Chair of Radiology, Robert Lenkinski, Ph.D. The University is also benefiting from
an expanding corps of skilled young cancer investigators, the scientific pacesetters of the future.
UT Southwestern’s impact on the future will be further magnified by the vigorous development
of its Cancer Biology Training Program, which became a doctoral degree-granting program in 2009,
reflecting the breadth and intricacies of the cancer research field. Extramural funding supports 45 slots
in the integrated predoctoral and postdoctoral training program, which has 65 students and 47 faculty
members. The program fosters multidisciplinary innovation and leadership in formulating basic scientific
questions about cancer, in collaborating with investigators who help translate those findings for clinical
use, and in tailoring research programs to address real-world challenges.
Ongoing T32 funding totaling $2.7 million for training from the NCI, plus a 2010 grant of
almost $2.9 million from the Cancer Prevention and Research Institute of Texas (CPRIT), is helping
the University mold that next generation of cancer pioneers. At the same time, through their broad
support of the Cancer Center, the NCI and CPRIT enhance other educational and research capabilities
throughout UT Southwestern.
As a “matrix” cancer center, where discoveries in one area are put to use in a range of disciplines,
Simmons is a model for dynamic interactions reaching across the University. A new, comprehensive
scientific program within the Cancer Center focuses solely on lung cancer and exploits the University’s
long-held expertise in that area. Other multidisciplinary initiatives are creating novel research platforms in
areas such as brain cancer, building momentum for possible breakthroughs. Additional synergistic endeavors explore, for instance, nuclear receptor expression profiles in cancer, innate immunity, and DNA repair
mechanisms. These and other remarkable projects are natural outgrowths of research strategies devised by
the Cancer Center’s growing roster of scientific programs.
The Center is also pushing forward and outward into the community, building and improving
laboratories to disseminate discoveries related to cancer prevention and detection, especially among the
medically underserved. A new, NCI-funded community partnership called PROSPR, for example, is
exploring how best to ensure regular colon cancer screenings. Meanwhile, a robust cancer genetics
program is reaching out to ensure that patients and families with an elevated hereditary risk of colon
and uterine cancers, and those with gene mutations linked to breast and ovarian cancers, are alerted and
closely monitored.
Such wheels of progress promise to generate advances for decades to come. Those advances will improve
the state of science not just in the Simmons Cancer Center, or even more broadly at UT Southwestern,
but throughout Texas and the nation.
James K.V. Willson, M.D., Director
The Lisa K. Simmons Distinguished Chair in Comprehensive Oncology
2
3
Feature: MOMENTUM
DRIVING DISCOVERY
SUBSTANCE IN MOTION
NCI designation extends the
Cancer Center’s reach—and its
grasp. But the milestone also
stands as evidence of how fast
and how far cancer care and
research in North Texas have
come in just the last decade,
after senior University leaders
set their sights on developing a “matrix” cancer center,
where research findings in one
discipline are disseminated and
implemented broadly.
In particular, the NCI recognition marks the fruition of the
vision set forth by Dr. Willson
after he arrived in September
2004: to grow faculty and staff
strategically, forge multidisciplinary teams, and tap a wealth
of University technologies and
other resources to ensure
scientific excellence and the
seamless delivery of the latest
care. Among the factors that the
NCI considered was the Cancer
Center’s ability to maximize
institutional resources devoted
to cancer research and to make
the most of collaborations
among experts in diverse fields.
So far during Dr. Willson’s
tenure, more than 70 top cancer
specialists have been recruited
to the University to expand
existing, nationally recognized
programs or to develop new,
complementary ones. One such
prestigious recruit was Cancer
Center Deputy Director Joan
Schiller, M.D., a widely known
F o r S i m m o n s C a n c e r C e n t e r, d e s i g n a t i o n a m o n g t h e n a t i o n ’s e l i t e
institutions is a key milestone along a road of remarkable progress.
At UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center, a combination of substance and kinetics fuels
CUTTINGEDGECAREANDRESEARCHs3UBSTANCEAT3IMMONSCOMESINMANYFORMS!DEPTHANDBREADTHOFSCIENTIlCEXPERTISE
INFRASTRUCTURE THAT SUPPORTS CREATIVITY AND COLLABORATION ABUNDANT TECHNICAL AS WELL AS HUMAN RESOURCES AND GENEROUS
COMMUNITY SUPPORT s 0UTTING ALL THAT IN MOTION IS THE CREATIVE GENIUS CURIOSITY AND PASSION OF 3IMMONS SCIENTISTS
educators, and clinicians. At an unprecedented rate, Simmons is combining rich institutional and community resources with
INTELLECTUALAGILITYTOHELPTRANSFORMCANCERCAREIN$ALLASIN4EXASACROSSTHECOUNTRYANDAROUNDTHEWORLDs!STHEEQUATION
GOESMASSTIMESVELOCITYEQUALSMOMENTUM!NDTHE#ANCER#ENTERISONAROLLs#ONSIDERTHEANNOUNCEMENTTHAT
the Simmons Cancer Center had earned National Cancer Institute designation, a mark of elite status held only by the nation’s
top-tier cancer centers. Simmons is the sole site in North Texas—a region encompassing more than 6 million people—ever
to earn the prestigious federal recognition. Additional federal resources that accompany the designation will propel progRESSEVENFURTHERs4HE.#)ACCOLADEˆWHICHACKNOWLEDGESLEADERSHIPINRESEARCHCLINICALCAREANDEDUCATIONˆREmECTS
UT Southwestern’s institutional commitment to innovation and collaboration, investment in advanced technologies, and
RECRUITMENT OF TOPmIGHT RESEARCHERS AND CLINICIANS s -OREOVER .#) DESIGNATION HERALDS A NEW ERA FOR CANCER CARE IN
North Texas, says Cancer Center Director James K.V. Willson, M.D. “UT Southwestern has built a cancer center that not
only offers outstanding clinical care, but also brings the latest in science and technology to the treatment of every patient.
All of our patients and their families benefit directly from a wealth of expertise and can rest assured that they are receiving the
most advanced and comprehensive care available.”
Joan Schiller, M.D., Professor and
Chief, Hematology/Oncology
Chihuly glass sculpture in the lobby
of the Seay Biomedical Building.
4
lung cancer expert who joined
UT Southwestern in 2006 as
Chief of Hematology/Oncology, and who is Co-Leader of
the Center’s new Lung Cancer
Scientific Program.
“In the past five years, opportunities to do creative and
cutting-edge research have
grown exponentially,” Dr. Schiller
says. “New and existing collaborations across disciplines
are leading to exciting discoveries in a host of areas, including
lung cancer drug discovery and
clinical trials.”
Meanwhile, a slate of recent,
high-profile recruits to the
University (pages 8-11) adds
weight to core areas of research
at the Cancer Center—and
provides impetus for new areas
of investigation.
DFW AND BEYOND
As the only NCI-designated
cancer center for a large swath
of the South Central United
States, Simmons is situated
to be an anchor for care not
only for the Dallas-Fort Worth
region—with nearly 6.4 million
residents, the nation’s fourthlargest metropolitan area—but
also for residents of 47 rural
counties in northeast Texas and
a vast expanse of rural counties
westward. The Center’s reach
also extends to the neighboring
states of Oklahoma, Arkansas,
and Louisiana, none of which
have designated cancer centers.
At the same time, Texas itself
has become an epicenter for
progress in the fight against
cancer. A 2007 statewide ballot
initiative dedicated, over the
course of a decade, $3 billion in
public funds to cancer research
and prevention, leading to the
creation of an extraordinary
agency, the Cancer Prevention
and Research Institute of Texas
(CPRIT). CPRIT promotes the full
range of research—from basic
and translational science to clinical applications—and provides
funds through multiple, peerreviewed avenues, including program grants, support for research
infrastructure and new recruits,
multi-investigator awards, and
grants for commercialization and
cancer prevention.
UT Southwestern is a leader
in terms of awards granted by
CPRIT. In all, $190.6 million has
been devoted by CPRIT to cancer projects at UT Southwestern,
including some $18 million in
new grants in the latest round
of awards.
Investigators working in an
array of promising areas have
been newly recruited to UT
Southwestern with the aid of
CPRIT funds. For instance,
Hamid Mirzaei, Ph.D., and
Yonghao Yu, Ph.D., are developing mass spectrometry
technologies to shed new light
on the molecular workings of
cancer cells. Sean Morrison,
Ph.D., is investigating how stem
cell function is regulated normally and is hijacked by cancer
cells to promote the growth and
spread of tumors. Josh Mendell,
M.D., Ph.D., is defining the
roles in tumor development and
suppression of small molecules
of genetic material known as
microRNAs. And Robert Lenkinski, Ph.D., is strengthening
the role of imaging in clinical and
translational studies.
CPRIT funds are also serving
as a catapult for discovery far
into the future, by enabling the
recruitment of exceptional young
cancer investigators to first-time,
tenure-track faculty positions.
Other resources are also fueling the Cancer Center’s engines
of progress. For instance, as of
2012, NCI annual research funding for Center members totaled
$28.2 million.
The Center’s overall annual
extramural research funding,
as of December 31, 2012, was
$138.2 million—and is more
than double what it was just six
years ago.
5
Simmons Cancer Center
POWERED BY ITS PEOPLE
At Simmons, six complementary scientific programs—
Chemistry and Cancer (pages
12-17), Development and
Cancer (pages 22-27), Cancer
Cell Networks (pages 32-37),
Experimental Therapeutics of
Cancer (pages 40-45), Lung
Cancer (pages 50-55), and
Population Science and Cancer
Control (pages 60-65)—serve as
vehicles for discovery. But within
those programs, it’s people who
drive growth and progress.
The Center’s 238 members
are affiliated with 40 departments or centers across
UT Southwestern and represent
a wealth of opportunity to blend
basic knowledge with translational and clinical pursuits. Ninety-six
of the Center’s members are in
basic science departments, while
142 are in clinical departments.
Cancer Center members published 311 scholarly articles in
2012, of which 34 percent were
collaborative articles written by
two or more members across
scientific programs.
“One of the most enabling
CONSEQUENCESOFTHISINITIATIVE
is the uniting of physicians and
basic scientists pursuing common goals for disease intervention,” says Michael White, Ph.D.,
Professor of Cell Biology and
the Cancer Center’s Associate Director for Basic Science.
“These ‘dream teams’ are where
the next wave of innovative advances will be coming from.”
6
Fruitful collaborations abound
at Simmons. For example,
years of work by biochemists Kevin Gardner, Ph.D., and
Richard Bruick, Ph.D., on a
master regulator molecule called
HIF-2—which tumors hijack to
help them grow—is opening
doors to potential therapeutic
targets (page 14). Research on
nuclear hormone receptors spearheaded by Pharmacology Chair
David Mangelsdorf, Ph.D., with
key contributions from Professor and lung cancer specialist
John Minna, M.D., is revealing
patterns of activity that relate to
narrower gene expression profiles
relevant to cancer (page 44). And
teamwork by molecular biologist
David Boothman, Ph.D., and
biomedical engineer Jinming
Gao, Ph.D., is showing not just
how an agent known as betalapachone kills cancer cells in a
remarkable way, but how to identify appropriate cancers to target
and, crucially, how to effectively
deliver the agent in nano-sized
vehicles (page 42). All these collaborations, and others, enlist an
array of talent from throughout
the Cancer Center—and across
the University.
This constant bustle of progress at Simmons takes place in
the midst of a thriving academic and medical institution.
UT Southwestern ranked first
among major universities for the
impact of published research in
clinical medicine, and in biology
and biochemistry, in a 2010
Science Watch report—making
the University the only institution to receive a top ranking
in more than one of six areas
of biological sciences. A new,
12-story, $186 million research
tower—expanding office and
lab space for faculty as well as
educational opportunities for
graduate students—opened on
the North Campus in late 2010.
And in December 2011, Bruce
A. Beutler, M.D., a Cancer
Center member and director of
the new Center for the Genetics
of Host Defense, became the
University’s fifth Nobel Prize
winner, recognized in physiology or medicine for his work
elucidating innate immunity.
In 2010 and 2011, UT Southwestern earned the designation
of “Best Hospital” among more
than 100 hospitals in the DallasFort Worth region according to
U.S. News and World Report.
Meanwhile, scheduled to open
in late 2014 is the state-ofthe-art $800 million, 12-story,
460-bed William P. Clements
Jr. University Hospital, now
under construction (page 38).
Also in 2014, UT Southwestern
physicians will be practicing in
another cutting-edge facility: a
$1.3 billion, 862-adult-bed new
Parkland Memorial Hospital.
PROGRESS FOR PATIENTS
-OMENTUMISREmECTEDIN
many milestones of achievement.
But at Simmons, the march of
progress is perhaps best measured in the Center’s impact on
patients. Consider the wide range
of cutting-edge therapies offered
under the auspices of the brandnew Lung Cancer Program:
Someone who has early-stage
lung cancer might receive care
from physicians in the University’s
new Division of Thoracic Surgery,
headed by Kemp Kernstine,
M.D., Ph.D., an expert in surgical
management of cancers of the
lung and esophagus as well
as mesothelioma.
If the patient were too frail for
surgery, other effective options are available. A treatment
approach pioneered by Robert
Timmerman, M.D., and colleagues at UT Southwestern has
made highly concentrated doses
of radiotherapy not only viable
for fragile patients with lung
cancer, but also as successful a
treatment as surgery (page 46).
Cancer Center scientists
have also teamed up to launch
an unprecedented effort to perform state-of-the-art analysis of
the genetic makeup of patients’
lung tumors and to test that
malignant tissue for vulnerability to any of about 220,000
substances and thousands of
small interfering RNAs, which
impact gene activity (page 52).
The effort, built on UT Southwestern’s status as a national
leader in translational lung cancer research, will yield crucial
clues to effective, individualized
treatment approaches. Currently, patients’ non–small cell lung
tumors can be tested for more
than two dozen genetic mutations, with the goal of offering
available targeted therapies—
some of which can be obtained
only in clinical trials—that are
most likely to kill the cancer.
At the same time, Simmons
radiation oncologists are working to generate new radiation
technologies for lung cancer
that improve therapy effectiveness while reducing toxicity.
Other goals of the project are
to advance capabilities in tracking tumor motion and changes
during radiotherapy, and to
develop MRI and PET imaging
TECHNIQUESTOHELPPHYSICIANS
better predict patient outcomes
in lung cancer.
Breast cancer patients,
meanwhile, are benefiting from
ADVANCEDIMAGINGTECHNIQUES
some in the clinic and some
still in the research stages, as
well as from active outreach
by geneticists to help find relatives who might be at risk for
disease (page 28). Liver cancer
patients are receiving comprehensive treatment—from all the
SPECIALISTSTHEYNEEDˆQUICKLY
and efficiently with the opening
of the Cancer Center’s new
heptatocellular carcinoma clinic
(page 56). And physicians who
treat patients with glioblastoma, working with colleagues
in the basic sciences, are shedding new light on the processes that help feed these deadly
brain tumors (page 18).
Simmons Cancer Center is
bringing more and more such
science to patients every day.
In 2011, more than 5,000 new
patients were treated at the
Cancer Center, with breast cancer patients (661) and prostate
cancer patients (636) leading
the list. Meanwhile, the total
number of patients enrolled annually in all clinical trials at Simmons has more than doubled
since 2006, with more than half
of those patients in interventional trials, receiving some form
of treatment (page 68). The
number of patients in institutional trials—those generated by
Cancer Center members and
based on UT Southwestern
scientific discoveries—has
increased more than threefold
during that same period.
Moreover, care is extending
beyond treating malignancies.
Novel screening and prevention
efforts are under way with the
safety-net hospitals in Dallas
and Tarrant counties, and a recent five-year, $6.3 million grant
from the NCI has established
the Parkland-UT Southwestern
PROSPR Center, one of three
key national sites focusing on
colorectal cancer screening
(page 62). Also transforming
cancer care in North Texas is an
innovative multicounty, community-based survivorship program
(page 64) offered through the
UT Southwestern Simmons
Cancer Center’s Moncrief
Cancer Institute in Fort Worth.
“Moncrief Cancer Institute is
making a difference in preventing cancer, and for patients who
have cancer, especially in medically underserved populations,”
says Keith Argenbright, M.D.,
Medical Director of the Institute.
Such dedication to patient
care and research at Simmons
is proving to be an irresistible
force that can steadily move
what once seemed immovable:
the plague of cancer.
Michael White, Ph.D., Professor, Cell Biology
7
MAKING THEIR MOVES
UT Southwestern and the Simmons
Cancer Center have attracted
talented scientists and physicians
from top institutions across the
U.S., including these recent recruits:
BRUCE BEUTLER, M.D.
Director, Center for the Genetics of Host Defense
Professor, Immunology
Regental Professor
Raymond and Ellen Willie Distinguished Chair
in Cancer Research in Honor of Laverne and
Raymond Willie, Sr.
Dr. Beutler—formerly Chairman of the Department of Genetics at Scripps Research Institute
in La Jolla, Calif.—shared the 2011 Nobel Prize
in Physiology or Medicine for his discovery of an
important family of receptors, known as Toll-like
receptors, that recognize disease-causing agents
ANDTRIGGERAPOWERFULINmAMMATORYRESPONSE
He also isolated mouse tumor necrosis factor
and was the first to recognize it as a key mediaTOROFTHEINmAMMATORYRESPONSE(ISlNDINGS
are fundamental to scientific understanding of
innate immunity and are significant to research in
cancer development. Dr. Beutler’s current work
uses germline mutagenesis and careful analysis of
relevant phenotypes to explore the detailed molecular mechanisms underlying innate immunity. In
2008, he was elected to the National Academy of
Sciences and was named to the Institute of Medicine. He has received numerous awards besides
the Nobel, including the Robert Koch Prize in
2004, the Gran Prix Charles-Léopold Mayer from
the Académie des Sciences in France in 2006, the
Balzan Prize in 2007, the Albany Medical Center
Prize in Medicine and Biomedical Research in
2009, the University of Chicago Professional
Achievement Citation in 2010, and the Shaw Prize
in 2011. Dr. Beutler started his scientific career at
UT Southwestern as an internal medicine intern
and neurology resident. He also served as a UT
Southwestern faculty member from 1986 to 2000,
during which he made the Nobel-winning finding.
8
ARTHUR E. FRANKEL, M.D.
Professor, Internal Medicine
Phase I Program Leader
Dr. Frankel—formerly Professor and head of
Hematology/Oncology at Texas A&M Medical
School—has expertise in investigative cancer drug
development and early-phase clinical studies.
He has synthesized and/or performed preclinical
testing of eight recombinant targeted immunotoxin
protein drugs for cancer and chronic cancer pain.
He has also been principal investigator for more
than a dozen first-in-man clinical studies for both
hematologic and solid tumor malignancies. At UT
Southwestern, Dr. Frankel is leading the phase I
clinical trials unit. He has more than 200 peerreviewed publications, serves as editor-in-chief of
Clinical Pharmacology: Advances and Applications, and is on the editorial board of Leukemia
Research, Molecular Cancer Therapeutics, and
Clinical Cancer Research.
DAVID H. JOHNSON, M.D.
Chair, Internal Medicine
Donald W. Seldin Distinguished Chair
in Internal Medicine
CPRIT Established Investigator
Dr. Johnson—formerly director of Hematology/
Oncology at Vanderbilt University Medical Center
in Nashville, Tenn., and deputy director of its
Vanderbilt-Ingram Cancer Center—brings a
wealth of cancer expertise and leadership to the
University. His focus on patients with lung cancer
(including clinical trials, serum proteomics in detection, and genetic determinants of risk and outcome)
enhances the Simmons Cancer Center’s already
leading-edge lung cancer program. Dr. Johnson
was president in 2005 of the American Society of
Clinical Oncology, and is a member and Chair-Elect
of the Board of Directors of the American Board of
Internal Medicine. He is also active in committee
leadership for organizations, including the National
Cancer Institute and LiveSTRONG.
KEMP KERNSTINE, M.D., PH.D.
Chair, Thoracic Surgery
Robert Tucker Hayes Foundation
Distinguished Chair in Cardiothoracic Surgery
Dr. Kernstine—who previously was director of the
Lung Cancer and Thoracic Oncology Program
at the City of Hope National Medical Center in
Duarte, Calif.—is Chair of the University’s new
Division of Thoracic Surgery in the Department of
Cardiovascular and Thoracic Surgery. Dr. Kernstine
specializes in surgical management of benign and
malignant diseases in the chest in both children
and adults, with a strong interest in the clinical
and physiological impact of minimally invasive
and robotic surgery. He also focuses on surgical
evaluation and treatment of lung and esophageal
cancers, mesothelioma, and thymic cancers. He
has been active in the launch and management
of investigator-initiated and cooperative-group
clinical trials involving patients with early and locally
advanced thoracic malignancies. He has served in
committee leadership positions for entities including
the Southwest Oncology Group and the Society of
Thoracic Surgeons.
ERIK KNUDSEN, PH.D.
Professor of Pathology
Dr. Charles T. Ashworth Professorship
in Pathology
UT Translational STARS Award
Dr. Knudsen—formerly Professor of Cancer
Biology and Deputy Director of Basic Science at
Thomas Jefferson University’s Kimmel Cancer
Center in Philadelphia—has expertise in cancer
genetics, tumor suppressors, and cellular stress
responses. Dr. Knudsen’s research focuses on
cell cycle regulation and the functional role of the
retinoblastoma (Rb) tumor suppressor in disease
progression and response to cancer therapy. In
collaboration with Dr. Agnes Witkiewicz and other
colleagues, he has identified novel biomarkers
indicative of prognosis and therapeutic response in
breast cancer—including a recent finding that loss
of the Rb protein in triple negative breast cancer is
associated with better response to chemotherapy
and longer overall survival. Dr. Knudsen is an
editorial board member for the American Journal
of Pathology, Genes & Cancer, and PLOS ONE.
ROBERT E. LENKINSKI, PH.D.
Vice Chair, Radiology
Charles A. and Elizabeth Ann Sanders Chair
in Translational Research
Jan and Bob Pickens Distinguished Professor
in Medical Science, in Memory of Jerry Knight
Rymer and Annette Brannon Rymer and Mr. and
Mrs. W.L. Pickens
CPRIT Missing Link
Dr. Lenkinski—former Professor of Radiology
at Harvard Medical School and Vice Chief of
Radiology at Beth Israel Deaconess Medical
Center—advances scientific understanding of
cancer in part by forging key collaborations with
basic scientists and clinicians to further the development of novel magnetic resonance (MR) approaches. Dr. Lenkinski’s own research involves
the development, validation, and application
of MR spectroscopic and multinuclear imaging
methods, and how information provided by these
TECHNIQUESCANHELPDIAGNOSESTAGEANDTREAT
diseases such as brain, breast, and prostate
cancers. He also focuses on development of
MR-based molecular imaging agents, including
lanthanide-based chelates for the imaging of
micro-calcifications in human breast cancer.
W. LEE KRAUS, PH.D.
Director, Cecil H. and Ida Green Center
for Reproductive Biology Sciences
Cecil H. and Ida Green Distinguished Chair
in Reproductive Biology Sciences
Dr. Kraus—formerly a Professor of Molecular Biology
and Genetics at Cornell University in Ithaca, N.Y., and
Professor of Pharmacology at Weill Cornell Medical College in New York—is setting an agenda to
enhance basic research in reproduction and development at the Green Center, with a special emphasis on
CUTTINGEDGETECHNIQUESINGENOMICSBIOINFORMATICS
and computational biology. The goal is to shed light
on the normal functioning of cells in the reproductive tract and elsewhere as well as on how errant
processes in these cells give rise to diseases such as
cancer. Dr. Kraus’ work examines signaling and gene
regulation in the nucleus by small molecules, such as
estrogen, and how such processes go awry in condiTIONSINCLUDINGBREASTCANCERANDINmAMMATION
9
melding the Cancer Center’s advanced imaging expertise with disease-focused translational
research and is spearheading the center’s drive
for certification as an NCI Center for Quantitative
Imaging Excellence.
an associate editor for the American Journal of
Gastroenterology. He serves on the American
Gastroenterology Association Leadership Council
and is a founding member of the International
Liver Cancer Association.
JAMES S. MALTER, M.D.
Professor and Chair, Department of Pathology
Senator Betty and Dr. Andy Andujar
Distinguished Chairmanship of Pathology
Dr. Malter—formerly Professor of Pathology and
Laboratory Medicine at the University of Wisconsin School of Medicine and Public Health and
Associate Director for Biological Sciences of the
Waisman Center for Developmental Disabilities at
the University of Wisconsin-Madison—is an internationally acclaimed pathologist with specific exPERTISEININmAMMATORYSIGNALINGANDIMMUNEAND
neuronal cell function. Dr. Malter has distinguished
himself by his ability to merge basic and clinical
sciences in pathology in a creative fashion and
to great effect. The results of his research studies
have been presented in more than 100 scientific
publications. Dr. Malter serves on editorial advisory
boards for the Journal of Experimental Medicine
and Science Signaling.
JORGE A. MARRERO, M.D., M.S.
Professor, Internal Medicine
Chief, Clinical Hepatology
Medical Director, Liver Transplantation
Dr. Marrero—formerly the Director of the Multidisciplinary Liver Tumor Program at the University
of Michigan Comprehensive Cancer Center—is
a renowned expert on hepatocellular carcinoma
(HCC) and liver transplantation. His accomplishments include devising a strategy for validating
BIOMARKERSFOREARLYDETECTIONOF(##WORKING
to identify several potential novel serum biomarkERSFOREARLYDETECTIONDEVELOPINGTHEDIAGNOSTIC
criteria adopted by several international societIESFOR(##DIAGNOSISANDHELPINGTOESTABLISH
tumor burden, liver function, and performance
status as widely used prognostic and tumor
staging measures. Dr. Marrero is a member of
the National Comprehensive Cancer Network’s
Hepatobiliary Committee, an editorial board
member for the journal Disease Markers, and
10
SEAN MORRISON, PH.D.
Director, Children’s Medical Center Research
Institute at UT Southwestern
Mary McDermott Cook Chair in Pediatric Genetics
Howard Hughes Medical Institute Investigator
CPRIT Established Investigator
JOSH MENDELL, M.D., PH.D.
Professor, Molecular Biology
CPRIT Scholar in Cancer Research
CPRIT Rising Star
Dr. Mendell—formerly an Associate Professor of
Pediatrics, and Molecular Biology and Genetics,
at Johns Hopkins University’s McKusick-Nathans
Institute of Genetic Medicine—focuses his work
on a class of small regulatory ribonucleic acids
known as microRNAs. These molecules play esSENTIALROLESINNORMALPHYSIOLOGYANDFREQUENTLY
are aberrant in human diseases such as cancer.
His goal is to unravel exactly how microRNAs,
which sometimes promote tumor development
and sometimes suppress it, contribute to malignancies. Work led by Dr. Mendell has demonstrated, in a mouse model, that replenishing
microRNAs in liver tumors can kill the tumor cells
(see page 22). Among Dr. Mendell’s accolades
are a 2009 Howard Hughes Medical Institute
Early Career Scientist Award, and the 2010
Outstanding Achievement in Cancer Research
Award from the American Association for
Cancer Research.
Dr. Morrison—renowned leader in stem cell research and former director of the Center for Stem
Cell Biology at the University of Michigan—was
recruited in collaboration with Children’s Medical
Center to lead the new Children’s Medical Center
Research Institute at UT Southwestern. Focusing on the nervous and hematopoietic (blood
cell-forming) systems, his laboratory team studies
mechanisms that regulate the self-renewal and
aging of stem cells—a type of cell that can give
rise to other, specialized cells in the body—as
well as the role these mechanisms play in cancer.
Among Dr. Morrison’s honors is recognition as a
Searle Scholar (2000), a Presidential Early Career
Award for Scientists and Engineers, the Society
for Hematology and Stem Cells’ McCulloch and
Till Award (2007), and a MERIT Award from the
National Institute on Aging.
AGNIESZKA K. WITKIEWICZ, M.D.
Associate Professor, Pathology
UT Translational STARS Award
STEPHEN X. SKAPEK, M.D.
Director, Pediatric Hematology/Oncology at
UT Southwestern
Medical Director, Center for Cancer and Blood
Disorders at Children’s Medical Center
Children’s Cancer Fund Distinguished
Professorship in Pediatric Oncology Research
Dr. Skapek—formerly of the Department of Pediatrics, Section of Hematology/Oncology and Stem
Cell Transplantation at the University of Chicago—
specializes in the care of children with malignant
solid tumors, especially soft-tissue and bone sarcomas. He is a member and Soft Tissue Sarcoma
Committee vice chair for the Children’s Oncology
Group, focusing on clinical trials of treatments for
rhabdomyosarcoma, a cancer comprising cells
that normally form skeletal muscle, and other
soft-tissue sarcomas. His laboratory research
investigates the roles that certain tumor suppressor genes play in normal development and
in childhood cancer. One focus for Dr. Skapek’s
laboratory work relates to understanding how
blood vessel growth is regulated.
Dr. Witkiewicz—formerly an Associate Professor of Anatomy, Pathology, and Cell Biology at
Thomas Jefferson University in Philadelphia and
Director of the Translational Research Core at
Jefferson’s Kimmel Cancer Center—specializes
in breast and gynecologic pathology and dermatopathology. Her research focuses on discovery
and characterization of biomarkers of prognosis
and treatment responses in breast cancer. She
is also interested in development of preclinical
models from primary tumor tissue that maintain
the in vivo interactions between tumor epithelial
cells and stromal compartment and permit modeling the therapeutic response of patient tumors
ex vivo. Her group developed a robust ex vivo
model for the analyses of breast and pancreatic
tumor tissue, which can be expanded to other
cancers (for example, lung and melanoma). She
is an editorial board member for the American
Journal of Pathology.
NEIL M. ROFSKY, M.D.
Chair, Radiology
Effie and Wofford Cain Distinguished Chair
in Diagnostic Imaging
Co-Director of Translational Research,
Advanced Imaging Research Center
Dr. Rofsky—formerly a Professor of Radiology at
Harvard Medical School and Director of Magnetic
Resonance Imaging at Beth Israel Deaconess
Medical Center—is a pioneer in the development
ANDAPPLICATIONOFMANYIMAGINGTECHNIQUES
and holds special expertise in body MRI. He
played an integral role in Harvard’s Renal Specialized Program of Research Excellence (SPORE),
developing novel MRI approaches to detect and
monitor renal cancers using high-spatial-resolution
TECHNIQUES$R2OFSKYISCONTINUINGTHATRESEARCH
including in prostate and liver cancers. He is also
11
leadership
chemistry and cancer
In their quest for cancer discoveries, chemists are searching high and low,
considering the rarified air of the mountaintops and delving into the sediments
and sponges of the sea.
AT A GLANCE
goal
To discover drug-like chemicals that
impede (or enhance) biological processes
related to the development (or inhibition)
of cancer.
approaches
From chemistry to biology—starting
with a novel natural product that damages cancer cells and discovering exactly
how it works—and from biology to chemistry—starting with an understanding of
a specific biological process related to
cancer and identifying chemicals that
influence that process.
2012 funding
TOTAL: $14.1 million
National Cancer Institute: $5.9 million
Other National Institutes of Health:
$3.3 million
Cancer Prevention and Research
Institute of Texas: $3.8 million
peer-reviewed
publications
2009-2012: 86
12
Steven McKnight, Ph.D., Chair, Biochemistry
Jef De Brabander, Ph.D., Professor, Biochemistry
Dr. McKnight has built a program interweaving
structural and discovery biology with synthetic,
medicinal, analytical, and natural products
chemistry. He has devoted much of his career to
the question of how genes are switched on and
off in higher eukaryotic cells—work recognized by his 1992 induction into the National
Academy of Sciences and his 2005 election to
the Institute of Medicine. In 2004 he received a
National Institutes of Health Director’s Pioneer
Award. Dr. McKnight holds the Sam G. Winstead and F. Andrew Bell Distinguished Chair
in Biochemistry and the Distinguished Chair in
Basic Biomedical Research.
Dr. De Brabander is a recognized expert in the
total synthesis of many complex natural products
that are toxic to cells—work for which he has
received National Cancer Institute funding and
an Alfred P. Sloan Fellowship. Dr. De Brabander
integrates his synthetic chemistry program
with molecular pharmacology, biochemistry,
and cancer biology, and he collaborates on
various projects, including the discovery of
novel small-molecule orexin receptor agonists
for the treatment of narcolepsy and antitumor
agents that target tumor-derived neural stem
cells. Dr. De Brabander is a co-founder and
member of the Scientific Advisory Board of
Dallas-based Reata Pharmaceuticals, and he
holds the Julie and Louis Beecherl, Jr. Chair in
Medical Science.
Cultures of bacteria strains from the
lab of Assistant Professor of Biochemistry
John MacMillan, Ph.D.
13
impact
Flipping a Master Switch
Nearly a decade of research yields promise in
cutting off a key cancer survival mechanism.
Fighting cancer’s many manifestations will no
doubt take a pocket full of miracles. But for
biochemists Kevin Gardner, Ph.D., and Richard Bruick, Ph.D., just one or two miracles—
in a particular molecular pocket—will do.
Drs. Gardner and Bruick are investigating the form and function of a molecule
called HIF-2, one of three “hypoxia inducible
factors” encoded within the human genome.
HIF-2 allows the body’s cells to thrive in
low-oxygen, or hypoxic, environments, such
as at high altitudes. “Every cell in your body
A
B
needs to be able to sense that change and
adapt,” says Dr. Bruick, Associate Professor
of Biochemistry.
HIF-2 exerts its effects by serving as a
master regulator of hundreds of genes, determining whether those genes will perform
their usual functions. But cancer cells can hijack this low-oxygen survival mechanism for
their own purposes, helping a tumor progress
even before an adequate blood supply can
develop to provide needed oxygen and
other nourishment.
Along with a related molecule called
HIF-1, HIF-2 has been implicated in the
progression of a variety of tumor types.
Human cells respond to low oxygen levels (hypoxia) using the hypoxia inducible factor, or HIF, complex (near center of diagram), assembled from two proteins:
HIF and ARNT. At normal oxygen levels, HIF is shut off by the destruction of the HIF subunit. When oxygen levels fall, the HIF subunit can accumulate in
the cell nucleus, where it binds to ARNT, forming HIF complexes. These complexes control transcription (depicted at right of diagram) of more than 100 genes
affecting the cell’s ability to adapt and respond to hypoxia. While this system is essential when it functions properly, certain conditions lead to it being continually
activated at normal oxygen levels, promoting several types of cancer. Small-molecule inhibitors of the HIF /ARNT interaction may be able to shut down HIF complexes in these cases, providing potential anti-cancer therapies.
Tucked in the “pocket” found in a part of the HIF-2 molecule called the HIF-2 PAS-B domain is a small-molecule disruptor of HIF-2. Initially identified by
nuclear magnetic resonance-based screening and optimized by on-campus medicinal chemists to improve its binding potency, this compound has paved the
way for subsequent high-throughput screening and other drug discovery efforts that have found potent inhibitors of HIF-2 function in living cells (data from T.H.
Scheuermann et al., Proc Natl. Acad Sci USA 2009;106:450.)
A
B
14
“Our research has focused more on
HIF-2 in part because we believe that some of
the unique features of HIF-2 make it particularly vulnerable to attack by drug-like small
molecules that we’re identifying in the lab,” Dr.
Bruick says. HIF-2 so far appears to be important in a very common type of kidney cancer,
clear cell renal cell carcinoma, and also may
play a role in brain cancers called glioblastomas and in non–small cell lung cancers, the
most common type of lung malignancy.
Drs. Gardner and Bruick have spent
the better part of a decade unraveling HIF-2’s
secrets. Biochemical and biophysical analyses
have revealed first and foremost that HIF-2
is a complex of two proteins that dock onto
each other. “That dimeric complex is functionally active,” says Dr. Gardner, Professor
of Biophysics and Biochemistry. “If we could
break that complex up, we would find a way
to artificially disrupt that activity.”
In further work, the researchers and
their colleagues have trimmed both proteins
down to the smallest versions required for the
complex to form, which they then produced
in bacteria and purified. After verifying that
the two partners still bound to each other
in vitro, this team of researchers worked
with the Cancer Center’s High-Throughput
Screening Shared Resource to screen a library
of about 220,000 drug-like compounds to see
which of these chemical challengers could
split the HIF-2 complex apart.
That’s where the pocket comes in. In
deciphering the atomic structure of the two
HIF-2 protein pieces, the Gardner lab had
found a rare pocket, or cavity, inside one of
the proteins—a place where, under normal
conditions, some naturally occurring compound in the cell probably binds. During
the testing against hundreds of thousands of
chemicals, that pocket proved to be the sweet
spot: Drug-like compounds that could split
the active multiprotein complex apart actually
bound to it at that site.
“Taking two proteins that normally
dock and turning on or off [the molecule] is
very challenging,” Dr. Gardner says. “But in
this case nature has given us a great foothold
that we can exploit, in the form of that pocket.” Compared with other modes of disrupting
HIF, this tactic could be useful in treating a
wide variety of tumors, the scientists believe.
It’s less likely than other, oxygen-dependent
approaches to be counteracted by tumor
defenses that can regulate HIF regardless of
the cell’s oxygen environment.
Drs. Bruick and Gardner next tapped
the expertise of John MacMillan, Ph.D., and
Uttam Tambar, Ph.D., both Assistant Professors of Biochemistry, to increase the potency
of some of the compounds that split apart
HIF-2 during the high-throughput screening.
“After that tweaking, we had small molecules
that were potent enough that we could test
them on living cells that originated from
actual human tumors—in this case, a HIFdependent renal cell carcinoma,” Dr. Bruick
says. “The molecules did what we hoped they
would do”— they bound to the HIF complex
at the site of the pocket, splitting it apart and
disrupting the function of the genes controlled by HIF-2. “You’re blocking the master
regulator,” he says, “and by blocking that
regulator you block the ability of that transcription factor to turn on its target genes.”
Those target genes are involved in wellknown avenues for cancer therapy, such as the
VEGF receptor and metabolic pathways.
“The hope would be that by targeting a master regulator like HIF you’d have the ability to
compromise not just one but several pathways
that tumor cells exploit to adapt to their
environment and progress,” Dr. Bruick says.
While Drs. Gardner and Bruick had
hypothesized early on that protein complexes like the one HIF-2 comprises would
be a potentially ready target for medicines,
“there was reasonable skepticism; this kind of
small-molecule regulation of protein-protein
complexes is inordinately complex to do,”
says Dr. Gardner. “Would HIF redundancy
make it moot? Rick and I have been taking
those questions on and wrestling them to
the ground to show that, yes, this actually
does work.”
The research was begun as part of a
National Cancer Institute program project
grant and has since been awarded funds totaling $1.8 million from the Cancer Prevention
and Research Institute of Texas.
Along with a growing list of collaborators, Drs. Gardner and Bruick continue to
tweak the most promising compounds and
investigate the workings of HIF-2 in the
context of different cancers. Experiments are
under way to see whether the compounds can
disrupt HIF-2 activity and cancer growth in
human tumors that are implanted under the
skin of mice. At the same time, tapping a library of complex natural products established
by Dr. MacMillan has suggested ways that cells
might naturally regulate the pairing of the two
HIF-2 proteins, via the molecular pocket.
Ultimately, the Gardner and Bruick
labs hope to push the concept of HIF-2
disruption into development—and create a
little therapeutic magic in that pocket.
CHEMISTRY AND CANCER
HIGH-IMPACT PUBLICATIONS
Fang M, Shen Z, Huang S, Zhao L, Chen S,
Mak TW, Wang X. The ER UDPase ENTPD5
promotes protein N-glycosylation, the Warburg
effect, and proliferation in the PTEN pathway. Cell
2010;143:711-724.
Han TW, Kato M, Xie S, Wu LC, Mirzaei H, Pei
J, Chen M, Xie Y, Allen J, Xiao G, McKnight SL.
Cell-free formation of RNA granules: bound RNAs
identify features and components of cellular assemblies. Cell 2012;149:768-779.
Kato M, Han TW, Xie S, Shi K, Du X, Wu LC,
Mirzaei H, Goldsmith EJ, Longgood J, Pei J,
Grishin NV, Frantz DE, Schneider JW, Chen S, Li
L, Sawaya MR, Eisenberg D, Tycko R, McKnight
SL. Cell-free formation of RNA granules: low
complexity sequence domains form dynamic
fibers within hydrogels. Cell 2012;149:753-767.
Partch CL, Gardner KH. Coactivators necessary
for transcriptional output of the hypoxia inducible
factor, HIF, are directly recruited by ARNT PAS-B.
Proc Natl. Acad Sci USA 2011;108:7739-7744.
Petersen SL, Peyton M, Minna JD, Wang X.
Overcoming cancer cell resistance to Smac
mimetic induced apoptosis by modulating
cIAP-2 expression. Proc Natl. Acad Sci USA
2010;107:11936-11941.
Pieper AA, Xie S, Capota E, Estill SJ, Zhong J,
Long JM, Becker GL, Huntington P, Goldman
SE, Shen CH, Capota M, Britt JK, Kotti T, Ure K,
Brat DJ, Williams NS, MacMillan KS, Naidoo J,
Melito L, Hsieh J, De Brabander J, Ready JM,
McKnight SL. Discovery of a proneurogenic,
neuroprotective chemical. Cell 2010;142:39-51.
Boldface denotes Cancer Center members in
the Chemistry and Cancer program; underline
denotes members affiliated with another scientific
program within the Cancer Center.
15
impact
Microorganisms from marine sediments are
untapped trove of potential medicines.
A
A strain of Streptomyces that produces a natural
product (chemical) that appears to interfere with a
cancer-related cellular pathway called DDR2, which
is a novel target in lung cancer.
B
A heat map reveals similarities in gene expression
between the kinase DDR2 and natural product fractions
such as SNA-048-7 (horizontal axis) using a six-gene
reporter assay (vertical axis). The data suggest that
scientists can find chemical compounds in the natural
product fractions that target the DDR2 signaling pathway.
C
One molecule now under investigation
has opened a door to potentially speeding up
that process. High-throughput screening of this
molecule, called IC50, showed substantial potency against just one of seven types of cancers
in the screen—the brain cancer glioblastoma.
IC50 is produced by a sea sediment bacteria
called micromonospora, collected off the coast
of Galveston, Texas.
Collaborating with Professor of Cell
Biology Michael White, Ph.D., and the Cancer
Cell Networks Program, the scientists have developed a platform that allows them to rapidly
generate hypotheses of what the mechanism
of action of a natural product is. The approach
takes advantage of data produced by screening cancer cell lines with both small molecules
and small interfering ribonucleic acid (RNAi).
Given that the scientists already know what each
RNAi targets, any screen of a small molecule that
generates data similar to that produced by a particular RNAi suggests that the small molecule is
impacting something in the same pathway. Using
this platform, the researchers have determined
with just one assay that IC50 is targeting a cellular pathway that is commonly flawed in cancer,
the AKT signal transduction pathway.
“John is leading the way here for a dramatic and innovative approach to natural products discovery,” Dr. White says of Dr. MacMillan.
“In one fell swoop he has bagged hundreds of
interesting chemicals with important selective
activity in cancer cells, and we are quickly honing
in on their mechanisms of action.”
The new platform has yielded predictions
of targets for about 30 of the MacMillan lab’s
natural products. For instance, in screening a
set of fractions from a Stroptomycetes bacterium, the platform suggested the anti-cancer
target was the discoidin domain receptor 2,
which is involved in a number of tumors and
appears to be a novel target in lung cancer. The
researchers approached Professor of Cell Biology Fred Grinnell, Ph.D., who has been studying the DDR2 pathway. “In a matter of a few
weeks we could show we had an inhibitor,” Dr.
MacMillan says. Moreover, the inhibitor didn’t
kill the cancer cells but interfered with their
ability to migrate, meaning it could potentially
prevent metastasis. “Any other assay we would
have done would never have found a molecule
like that,” he says.
Meanwhile, chemical detective work is
under way to investigate a series of about 20
related molecules, or analogs, of a compound
called aureol, derived from the sea sponge
Smenospongia aurea. Working with former
UT Southwestern biochemist Xiaodong Wang,
Ph.D., MacMillan and his colleagues have
discovered that aureol inhibits ENTPD5, an
enzyme that plays a role in fueling rapid cell
division in various colon cancer cell lines.
Investigations of other natural products
are also under way, even as Dr. MacMillan and
colleagues look for new organisms to tap. Ultimately, he says, the possibility of finding novel
medicines seems unbounded. “That’s what’s fun
about natural products. We’re really in the game
of discovery.”
A
B
BNIP-3
BNIP3L
ACSL5
LOXL2
NDRG1
ALDOC
SNA-015-6
DDR2
SNB-001-8
SNB-001-9
SNA-048-7
SNA-008-6
16
Dr. MacMillan collects a sponge sample 80 feet
underwater off San Salvador Island in the Bahamas.
It’s a dirty job—but one that could someday
yield a rich reward.
In a quest for better pharmaceuticals,
Assistant Professor of Biochemistry John
MacMillan, Ph.D., starts with sediment. He and
his colleagues dredge marine environments to
exploit an abundance of microorganisms that can
serve as microfactories, churning out previously
undiscovered and interesting chemicals. The hope
is that some, or even one, of those chemicals will
eventually lead to an important new treatment
to take on one of medicine’s many challenges—
including cancer.
“The marine environment is completely untapped,” Dr. MacMillan says. “There are
different evolutionary pressures on bacteria
in the marine environment that might give
rise to a great diversity in chemistry.”
Cancers are constantly developing
resistance to current chemotherapies. So the
discovery of natural products with different
mechanisms of action is vital to help restock
medicine’s arsenal. “If we take an unbiased
look at cancer and throw natural products at
cancer cells, it allows us to discover things
we wouldn’t have thought of before,” Dr.
MacMillan says. His work receives National
Cancer Institute R01 funding to support
development of a bacterial platform for
drug discovery.
Still, many steps lie between mud and
medicine. The researchers first work to
perfect the discovery process itself, devising
new ways to isolate novel bacteria from the
sediments and to understand the bacteria
and their products.
The MacMillan lab also collaborates
with biologists to develop techniques to
culture the bacteria, which can require
considerable coaxing to act naturally under
laboratory conditions. “It’s thought that
only 1 percent of bacteria are culturable in
the lab,” Dr. MacMillan says. “We’re trying to increase that percentage.” Once the
bacteria are collected and can be grown on
a large scale, the scientists ferment them—
and tiny chemical factories are born.
In many cases, researchers don’t know
why the organisms make the chemical compounds that they do. Still, the compounds’
value lies in the fact that they have been created and perfected by nature over billions of
years to interact with DNA and proteins—key
players in the development and proliferation
of cancer.
The library that the MacMillan lab has
compiled so far comprises about 4,500 fractions, together containing tens of thousands
of individual chemical compounds derived
from about 450 species of bacteria. With the
aid of the Cancer Center’s High-Throughput
Screening Shared Resource, the researchers
test these fractions for anti-cancer (or other
medicinal) capabilities. Such phenotypic
screens—simply testing whether a compound, when applied to cancer cells, can
disrupt their activity—are fundamental to
finding new drugs, Dr. MacMillan says.
When a “hit” is found—that is, when a
fraction kills cancer cells—scientists have to figure
out exactly which compound in the fraction was
active. They may purify the fraction, test it again,
purify it some more, and ultimately determine
exactly which chemical entity was responsible for
the biological activity detected in the screening.
At this stage, the chemists in Dr. MacMillan’s lab and biologists at UT Southwestern
team up to elucidate the workings of the active
compound. “UT Southwestern is very unique
in how collaborative research can be,” he says.
“I don’t have to try to do all these things on my
own and become a cancer biologist as well as
a chemist.”
Dr. MacMillan and his colleagues work
to discern the molecule’s structure, function,
and useful properties. The researchers also
try to manipulate that structure to improve
therapeutic potential. Details, such as whether
a molecule in three dimensions is “left-handed”
or “right-handed,” can be the difference between a medicine and a poison.
Research also focuses on figuring out
why, exactly, the active molecule affects
cancer cells. One new natural product,
Dr. MacMillan says, can spawn decades of
research by multiple investigators.
Reporter genes
Sunken Treasures
Natural product
fractions and kinase
C
17
Feature: GLIOMA
‘A UNIQUE GROUP’
PICTURE THIS
Broad research collaboration creates novel windows
to understanding tumor activity in the brain.
Brain cancers pose special challenges. Growing within the organ that governs nearly everything a body does, these
tumors can severely hamper a person’s ability to move, feel, think, or remember. Depending on where in the brain the
cancers are, accessing them even just to get a firm diagnosis can be risky. And details about their development—and
WHAT CAN DRIVE THEM TO BECOME ESPECIALLY VIRULENT AFTER MONTHS OR YEARS OF DORMANCYˆARE ELUSIVE s "UT A MASSIVE
multi-investigator initiative at Simmons Cancer Center is addressing those challenges. Tapping expertise from across
UT Southwestern, in areas including neurology, neuro-oncology, neurosurgery, radiology, pathology, cancer
biology, and physiology, researchers are devising novel ways to understand the biochemistry and behavior of cancer
CELLS IN THE BRAIN s (ELPING TO PROPEL THESE EFFORTS IS A THRIVING RESEARCH PROGRAM IN METABOLIC IMAGING BASED IN
UT Southwestern’s Advanced Imaging Research Center, where scientists are exploiting ever more powerful magnetic
resonance imaging technology and are constantly innovating to capture better data about cancers.
Research by Elizabeth Maher, M.D., Ph.D. (left),
and Changho Choi, Ph.D. (right), helped direct
treatment for brain tumor patient Thomas Smith.
18
The research is rooted
in a robust neuro-oncology
program at the Cancer Center.
Three core missions underpin
the program, says Elizabeth
Maher, M.D., Ph.D., Associate
Professor of Internal Medicine
and Neurology and Neurotherapeutics. First is multidisciplinary clinical care. Second
is a focus on clinical trials that
test new treatments and other
approaches that might benefit
people with brain cancer. Third,
“translational” research is
emphasized, bridging the gap
between scientific discovery
and patient care.
h7EHAVEAUNIQUEGROUPv
says Dr. Maher, a member of
the Cancer Center’s Development and Cancer Program.
“The translational program has
offered new and novel insights
into brain tumor metabolism,
and the imaging research has
identified new clinical biomarkers—biochemical traits of these
tumors that can aid their diagnosis, monitoring, and treatment.” One such biomarker,
known as 2-hydroxyglutarate,
or 2HG, has the potential to
help doctors detect brain
cancers at earlier stages.
The work focuses on gliomas, a group of primary brain
TUMORSTHATCOMMONLYAFmICT
young adults. Gliomas arise
from glial cells, which surround
and support the brain’s gray
matter, or “thinking” tissue.
Low-grade gliomas infiltrate
stealthily in the brain, creeping around the thinking cells
without destroying them, but
eventually putting pressure on
brain circuits and causing neurological symptoms that often
lead to the tumors’ discovery.
Doctors typically manage a
cancer that presents as a slowgrowing brain mass by treating
adverse symptoms (such as
seizures and headaches), and
closely following the tumor to
see whether it takes a more
aggressive form—which war-
rants combined treatment
with surgery, chemotherapy,
and radiation. Fast-growing
gliomas, called glioblastomas,
are the deadliest of tumors that
originate in the brain: Despite
aggressive therapies, survival
times average less than
15 months.
VISIONS OF THE FUTURE
UT Southwestern’s neurooncology investigators have an
ambitious set of goals: to learn
when and how cells in these tumors transition from dormant to
AGGRESSIVETOIMPROVEIMAGING
TECHNIQUESTOBETTERSEEWHICH
metabolic pathways are active
INGROWINGTUMORSTODETERmine whether such tumors are
RESPONDINGTOTREATMENTANDTO
identify new potential therapies.
The work could help reshape
brain cancer research. One
novel avenue of study—supported by a $1 million National
Institutes of Health Challenge
Grant from 2009 federal stimulus funding—focuses on metabolic activity in brain tumors
that are about to be surgically
removed. Patients are infused
with specially tagged sugar
molecules (carbon 13–labeled
glucose), beginning about two
hours before their operation.
Once the tumors are removed,
researchers from the Advanced
Imaging Research Center use
nuclear magnetic resonance
spectroscopy, a high-tech
method of chemical analysis,
to provide a “snapshot” of the
tumor cells’ metabolic processing of the glucose, a fuel that
cancers readily consume.
In a recent study of nine
patients with malignant
gliomas, and two with tumors
in the brain that had spread
there from other sites, researchers demonstrated that
THETECHNIQUECOULDPROVIDE
novel metabolic data about
the cancers—beyond what
scientists can learn from tumor
cells in lab dishes, or from
IMAGINGTHATONLYQUANTIlESA
tumor’s glucose consumption.
Specifically, the team led by Dr.
Maher found that tumor cells
metabolize glucose at a much
higher rate than the rest of
the brain, using the energy for
survival and as a resource for
building blocks that sustain the
ceaseless growth of new tumor
cells. This same fundamental
process supported the growth
of glioblastoma cells and also
lung and breast cancer cells
that had metastasized to the
brain, the team found.
h)TSAUNIQUELOOKATTHEDEtails of glucose metabolism of
brain tumors while they are still
in the body—how they allocate
glucose into multiple bioenergetic and biosynthetic pathways,” says Development and
Cancer Program member Ralph
De Berardinis, M.D., Ph.D.,
Assistant Professor of Pediatrics in the Children’s Medical
Center Research Institute at
UT Southwestern. He and Craig
Malloy, M.D., Medical Director of
the Advanced Imaging Research
Center, developed analytic
TECHNIQUESUSEDINTHERESEARCH
The findings, Dr. DeBerardinis
says, may provide clues to how
scientists can interfere with
particular mechanisms involved
in the energy production of the
tumors, in order to kill them.
BLAZING TRAILS
Meanwhile, in efforts spearheaded by Assistant Professor
of Neurology and Neurotherapeutics and Internal Medicine
Robert Bachoo, M.D., Ph.D.,
and Professor of Neurological
Surgery, Otolaryngology—Head
and Neck Surgery, and Radiation
Oncology Bruce Mickey, M.D.,
researchers are blazing trails in
the development of “orthotopic”
mouse models of glioblastoma.
“For the past 30 years,
standard brain tumor cell lines
that have been used to test
potential therapies have consistently failed to predict whether
a drug will benefit patients,”
says Dr. Bachoo, a member of
the Development and Cancer
Program. “To meet this unmet
19
need we have developed an
animal model in which a brain
tumor patient’s cancer cells
are taken at the time of surgery
from the operating room, and
within two to three hours are
injected into a mouse brain.”
Ninety percent of glioblastoma tumors can be successfully grown in the mouse brain,
which closely mimics the human
brain environment, Dr. Bachoo
says. Once the mouse develops
symptoms, usually in about three
months, tumor cells are isolated
and then serially implanted into
large numbers of new mice.
“We have successfully
performed this procedure for
over 40 glioblastoma patients,
and the same tumors have
been maintained in the mouse
brain for up to three years,” Dr.
Bachoo says.
Over six to nine months,
researchers can generate numerous such orthotopic models
of a patient’s tumor. That time
frame provides a chance to
strategically select and test new
drugs or drug combinations
in the mice, while the patient’s
cancer is still dormant from
standard treatments. Glioblastomas typically recur in about
MONTHSANDCANQUICKLYBE
fatal, Dr. Bachoo notes.
“Generating mouse tumor
models with exactly the same
cell types that make up the
patient’s tumor represents individualized therapy in the true
sense,” he says.
Orthotopic mouse models
are also allowing investigators to capture action shots of
abnormal metabolic pathways
in brain tumors. Such research
relies on the expertise of Dean
Sherry, Ph.D., Professor and
Director of the Advanced Imaging Research Center, and Dr.
Malloy, plus Center members
including Associate Professor
of Radiology Changho Choi,
Ph.D., and Assistant Professor
of Radiology Matthew Merritt,
20
Ph.D. Working with colleagues,
including Dr. Bachoo and James
Bankson, Ph.D., of the UT M.D.
Anderson Cancer Center, they
are investigating the use of “hyperpolarizing” carbon 13–labeled
tracers. This process makes the
tracers much easier to detect
with magnetic resonance imaging. The work, along with related
projects, is supported by more
than $2 million in funds from the
Cancer Prevention and Research
Institute of Texas (CPRIT).
UNRAVELING SECRETS
Another avenue of research is
unraveling the secrets of glioblastoma’s ability to infiltrate normal
brain tissue in a diffuse manner
and initiate new tumors—traits
that cause substantial impairment and make the disease
surgically incurable. Teaming up
with engineering faculty members from UT Arlington, and supported by a CPRIT grant of more
than $941,000, Dr. Bachoo has
developed a model, called an in
vitroMICROmUIDICCHANNELSYSTEM
that mimics spatial and structural
features of brain tissue.
That research has shed light
on how glioblastoma cells commit their treachery: They can
migrate through tight spaces—
even spaces smaller than their
own nucleus—and can exert
large lateral forces to propel
themselves through the brain.
The scientists are now working
to develop optical systems that
allow them to monitor glioblastoma cells implanted in the brains
of mice and to identify the key
steps that propel tumor cell migration as well as potential drug
targets to block migration. “If we
could simply block migration, we
could turn these invariably fatal
tumors into a chronic disease,”
says Dr. Bachoo.
THE PATIENT PICTURE
Technological and biological
advances at UT Southwestern
are also converging to provide
real-time glimpses of tumors
while they are still in patients’
brains. Like law officers learning
to peer into a criminal’s hideout
without breaking down the
doors, Cancer Center scientists
are developing ways to noninvasively see what masses in
the brain are doing—whether
they are malignant or benign
and, based on metabolic or
other chemical activity, how
active they might be.
One line of research is
focused on developing a
method to noninvasively detect
levels of the chemical glycine,
which have been found to be
elevated in fast-growing gliomas, compared with normal tissue and slow-growing tumors.
Because glycine is essential in
the synthesis of proteins and
other molecules crucial to cell
growth and proliferation, its
metabolism might help gauge
tumor activity, investigators
suspect. But there’s a trick:
With widely available imaging
technology, glycine—which occurs in brain tumors in relatively
low concentrations—can be
hard to distinguish from another
molecule, myo-inositol.
Using powerful MRI technolOGYHOWEVERANDATECHNIQUE
called point-resolved spectrosCOPYSEQUENCEOR02%33
researchers were able to detect
elevated tumor glycine levels
in eight of 12 glioblastoma
patients. The findings suggest
that glycine is increased only in
some gliomas.
Another noninvasive approach to assessing tumors,
using the metabolic biomarker
2HG, has yielded dramatic
results. In normal brain tissue,
2HG is scarce. But in gliomas,
2HG builds up due to mutations
in two genes, called IDH1 and
IDH2. Increasing levels of 2HG
signal that a tumor is growing.
With Dr. Choi optimizing an
imaging and analysis techNIQUECALLEDPROTONMAGNETIC
resonance spectroscopy, researchers were able to peer
into the brains of 30 patients
with gliomas. Levels of 2HG in
the patients’ tumors are 100
percent correlated with mutations in the culprit genes, the
scientists found, and are also
linked to levels of a form of
2HG found in the tumors once
they are removed.
The work appears to be
the first demonstration of a
noninvasive imaging biomarker
that is directly linked to a genetic
mutation in a cancer cell, Dr.
Maher says. IDH mutations occur in 70 percent of low-grade
gliomas and 10 percent of glioblastomas, and are associated
with better odds of survival.
Measuring 2HG is potentially
a powerful means of sizing up
the course of dormant gliomas
and identifying the point when
they become life-threatening
ANDREQUIREAGGRESSIVETREATMENT4HETECHNIQUEMIGHTALSO
reveal when chemotherapy is
working to kill the multiplying
tumor cells, Dr. Maher notes.
Such knowledge, she adds,
could transform at least one of
brain cancer’s challenges—the
struggle patients endure as
they live their lives under the
shadow of a tumor that will, at
some unknown time, become
deadly. Recognizing early signs
of tumor aggression might help
delay—or someday prevent—
that inevitability.
Robert Bachoo, M.D., Ph.D., Assistant Professor, Neurology and
Neurotherapeutics and Internal Medicine
Elizabeth Maher, M.D., Ph.D., Associate Professor, Internal Medicine and
Neurology and Neurotherapeutics
Bruce Mickey, M.D., Professor, Neurological Surgery, Otolaryngology-Head
and Neck Surgery, and Radiation Oncology
21
leadership
development and cancer
Probing the essential mechanics of normal and malignant cells, researchers
are uncovering possible ways to overcome treatment resistance and suppress
cancers’ growth and spread.
AT A GLANCE
goal
To bring together investigators in the
related fields of cancer biology, stem cell
biology, and developmental biology to
shed light on how aberrant developmental
processes contribute to the initiation and
progression of cancer.
approaches
Defining the interactions between malignant tumor cells and their local environment; revealing molecular mechanisms
that allow stem cells and cancer stem cells
to renew themselves and to develop into
more than one type of cell; and enhancing
cancer-focused interactions between
clinical investigators and basic scientists.
2012 funding
TOTAL: $31 million
National Cancer Institute: $3.2 million
Other National Institutes of Health:
$15.3 million
Cancer Prevention and Research
Institute of Texas: $9.1 million
peer-reviewed
publications
22
2009-2012: 333
Luis F. Parada, Ph.D., Professor and Chair,
Stephen X. Skapek, M.D., Professor, Pediatrics;
Developmental Biology
Director, Department of Pediatrics Division of
Hematology/Oncology
Dr. Parada is a leading international authority
on cancer biology, and particularly on sophisticated mouse models of cancer. Using these mouse
models, he has discovered important properties of
the brain tumor glioblastoma—for example, that
it derives from abnormal neural stem cells. His
laboratory has also made important advances
in plexiform neurofibroma, a nerve-associated
tumor that afflicts people with neurofibromatosis. He is a member of the National Academy
of Sciences, the Institute of Medicine, and the
American Academy of Arts and Sciences, and
holds the Southwestern Ball Distinguished
Chair in Nerve Regeneration Research and the
Diana K. and Richard C. Strauss Distinguished
Chair in Developmental Biology. He directs
the Kent Waldrep Center for Basic Research on
Nerve Growth and Regeneration.
Dr. Skapek, a renowned expert on malignant soft
tissue tumors, has expertise ranging from basic
studies to the design and conduct of clinical trials.
His research focuses on elucidating mechanisms
by which the tumor suppressor gene Arf triggers
blood vessel shrinkage in the developing eye and
in tumors, and the molecular basis and the control
of rhabdomyosarcoma, which arises from skeletal
muscle tissue. Dr. Skapek is Medical Director of
Children’s Medical Center’s Center for Cancer
and Blood Disorders and is a steering committee
member for the Children’s Oncology Group Soft
Tissue Sarcoma Committee. He holds the Children’s Cancer Fund Distinguished Professorship
in Pediatric Oncology Research.
A colored angiogram X-ray of the liver
showing a rounded tumor (upper center).
23
impact
Alternative Fuels
Studies of cancer cells’ metabolism shed
light on mechanisms of survival, treatment
resistance.
A growing tumor’s hunger seems to know no
bounds. But research at the Simmons Cancer
Center may someday reveal how to starve
malignant cells into oblivion.
Using techniques from molecular and
cell biology and biochemistry, Cancer Center
member Ralph DeBerardinis, M.D., Ph.D.,
and his colleagues are deciphering exactly
how signal transduction, a cascade of changes
triggered inside a cell, impacts cancer cells’
metabolism—the intake of nutrients and
their conversion into useful substances.
A
B
“Metabolism underlies basically every process
that occurs in the cell,” says Dr. DeBerardinis,
Assistant Professor of Pediatrics in the Children’s Medical Center Research Institute at
UT Southwestern.
“It takes a tremendous amount of energy
for cells, including cancer cells, to grow and
to replicate themselves. Ultimately one of the
major goals of cancer therapy is to suppress
that unabated cell growth, and aiming new
therapies at tumor metabolism might be one
way to do that.”
While metabolism has long been
interesting to cancer researchers, molecular
findings of recent decades have shifted the spotlight to cancer-causing genes, Dr. DeBerardinis
says. It turns out, though, that many of those
Compared with a typical tumor cell (left), a tumor cell with defective mitochondria (right), the energy
producers, is unable to produce the lipids it needs through the normal metabolism of glucose and glutamine.
Instead, to create the lipid building block acetyl-coA, this cell relies almost exclusively on the metabolism of
glutamine carbon (red pathway). This aberrant pathway represents a complete reversal of the normal Krebs,
or citric acid, cycle.
A glutamine molecule.
A
Typical cancer cell
Cancer cell with defective mitochondria
Glucose
Glucose
Lipids
Lipids
Pyruvate
Lactate
Acetyl-coA
Pyruvate
Acetyl-coA
Acetyl-coA
Citrate
Oxaloacetate Citrate
CAC
Isocitrate
α-kg
Oxaloacetate
Other
metabolites
α-kg
Oxaloacetate
Isocitrate
Other
IDH
NADP+ metabolites
CO2
Glutamine
B
24
Lactate
Glutamine
NADPH
so-called oncogenes regulate metabolism in
addition to their other activities. Inserting an
activated oncogene into a normal cell causes
the cell to develop some of the same metabolic features as a tumor cell, the investigators
have found. On the other hand, blocking
some of those metabolic activities in cancer
cells prevents them from forming a tumor.
“The idea that cancer cells may not only
prefer, but rely on, exclusive dietary sources is
a powerful one. It would mean that by removing that unique dietary requirement, cancer
cells could be starved without affecting noncancer cells,” says Luis Parada, Ph.D., Chair
of Developmental Biology and Co-Leader of
the Cancer Center’s Development and Cancer
Program. “Dr. DeBerardinis and his colleagues
are at the forefront of this compelling area
of investigation.”
While tumors often have a voracious
appetite for glucose, the DeBerardinis lab
is interested in alternative fuels—especially
the amino acid glutamine, and the enzymes
involved in its metabolism. He and his
colleagues have devised ways to study the
various moving parts of multiple metabolic
pathways simultaneously at work in cells,
painting a more complete portrait not just of
glutamine metabolism, but also of metabolic
variations used by different types of cancer
cells to sustain themselves and to circumvent
the effects of cancer treatment.
“We tend to think of cancer metabolism as a list of individual pathways operating
independently of each other. But in reality
the metabolism of a tumor, like the metabolism of the heart or liver, is the sum effect of
many pathways acting in concert, like the
gears of a watch turning together,” Dr. DeBerardinis says. While complex, metabolism is
nevertheless finite, he adds, “so there are only
so many different ways a cell can compensate.
We need to have better ways to understand
how these pathways cooperate together
to achieve cellular outcomes like survival,
growth, and proliferation.”
Still, these multiple gears make cancer
cells surprisingly flexible in the face of metabolic stress. For instance, working with cells
in culture from the brain cancer glioblastoma
multiforme, Dr. DeBerardinis and colleagues
have thrown molecular monkey wrenches
into the gear driving glucose metabolism.
The investigators have found that a cancercausing gene called c-Myc devises a workaround using the enzyme glutamate dehydrogenase, or GDH, that—driven by the cell’s
newfound inability to convert glucose into
lactic acid—sets an alternative glutaminesupplied gear into action, providing an ongoing source of fuel for the malignant cell.
“It’s almost like a roadblock and a detour.
Sometimes the detour is a little less efficient
than the highway, but it still gets the job done,”
says Dr. DeBerardinis, whose research is
funded by a $200,000 Cancer Prevention and
Research Institute of Texas high-risk grant, an
R01 from the National Cancer Institute, and a
Damon-Runyon Clinical Investigator Award.
Further work has uncovered the
various moving parts—enzymes and transporters—that sustain the glutamine pathway.
The work demonstrates how targeting
glutamine metabolism may help overcome
resistance to treatments that interfere with cancer cells’ glucose metabolism, Dr. DeBerardinis
says. He and members of the Cancer Center’s
neuro-oncology group are also devising techniques to capture information about metabolic
activity of human brain tumors implanted into
mice (with the aid of the Cancer Center’s Small
Animal Imaging core), and in tumors just after
they are resected from patients (page 18).
Lung cancer is another key focus of the
DeBerardinis lab, which has developed techniques to hunt for novel metabolic pathways
in large panels of tumor cell lines. Drawing
on UT Southwestern’s vast lung cancer expertise and sweeping drug discovery program
(page 52), DeBerardinis and colleagues are
utilizing a large collection of lung cancer cell
lines housed at UT Southwestern to search for
new links between cancer-causing genes and
specific metabolic pathways.
The researchers’ metabolic fingerprinting
technique uses stable isotopes (for example,
heavy carbon) to label nutrients going into a
cell and, with the aid of mass spectrometry,
discerns the composition of metabolites the
cells produce. “We’ll learn what the metabolic
diversity is across a given type of human cancer, and whether there are any really unique
metabolic pathways that could not have been
predicted,” Dr. DeBerardinis says. “Even with
conventional metabolic pathways we may be
able to find new connections to a particular
oncogene or to the efficacy of a particular
chemotherapeutic agent.”
Using isotope tracing techniques with
osteosarcoma and kidney cancer cells, the
scientists noted that an unusual mutation is
linked to a directional reversal of the ubiquitous metabolic pathway known as the Krebs,
or citric acid, cycle. These mutations appear
to force the cancer cells to depend on the
reverse cycle for growth.
“We’re really excited about this,” Dr.
DeBerardinis says. “You can hardly find a
metabolic pathway in the literature that is
more familiar to biochemists than the Krebs
cycle. The findings imply that even a very
well-known, familiar pathway can operate in
a new manner to support cancer cell growth.”
The researchers believe that there may
be certain proteins required for function of
the reversed pathway, and that these could
be suitable targets for new cancer drugs. “If
a subset of cancer cells relies on this pathway
for growth, but cells from the rest of the body
use the cycle in the normal direction, then
targeting the reversed pathway might be safe
and effective,” Dr. DeBerardinis says.
More broadly, he notes that UT Southwestern, with a cadre of experts in metabolism across departments, is poised to meet
other cancer-related challenges. Metabolic
disturbances in cancer don’t occur just at the
cellular level, but at the whole-body level,
too—for instance, cancer patients often suffer
from a devastation of fat and muscle tissue
known as cachexia. “We really have an amazing critical mass of investigators here who are
accustomed to thinking about metabolism,”
Dr. DeBerardinis says.
DEVELOPMENT AND CANCER
HIGH-IMPACT PUBLICATIONS
Chen J, Li Y, Yu TS, McKay RM, Burns DK,
Kernie SG, Parada LF. A restricted cell
population propagates glioblastoma growth after
chemotherapy. Nature 2012;488:522-526.
Cheng T, Sudderth J, Yang C, Mullen AR, Jin
ES, Mates JM, DeBerardinis RJ. Pyruvate
carboxylase is required for glutamine-independent
growth of tumor cells. Proc Natl Acad Sci USA
2011;108:8674-8679.
Choi C, Ganji SK, DeBerardinis RJ, Hatanpaa
KJ, Rakheja D, Kovacs Z, Yang XL, Mashimo
T, Raisanen JM, Marin-Valencia I, Pascual JM,
Madden CJ, Mickey BE, Malloy CR, Bachoo
RM, Maher EA. 2-hydroxyglutarate detection
by magnetic resonance spectroscopy in IDHmutated patients with gliomas. Nat Med 2012;
18:624-629.
Ding L, Saunders TL, Enikolopov G, Morrison
SJ. Endothelial and perivascular cells maintain
haematopoietic stem cells. Nature 2012;
481(7382):457-62.
Eliazer S, Shalaby NA, Buszczak M. Loss of
lysine-specific demethylase 1 nonautonomously
causes stem cell tumors in the Drosophila ovary.
Proc Natl Acad Sci USA 2011;108:7064-7069.
Hatley ME, Patrick DM, Garcia MR, Richardson
JA, Bassel-Duby R, van Rooij E, Olson
EN. Modulation of K-Ras-dependent lung
tumorigenesis by MicroRNA-21. Cancer Cell
2010;18:282-293.
Kumar R, Hunt CR, Gupta A, Nannepaga S,
Pandita RK, Shay JW, Bachoo R, Ludwig T, Burns
DK, Pandita TK. Purkinje cell-specific males absent
on the first (mMof) gene deletion results in an
ataxia-telangiectasia-like neurological phenotype
and backward walking in mice. Proc Natl Acad Sci
USA 2011;108:3636-3641.
Liu Y, Liu Q. ATM signals miRNA biogenesis
through KSRP. Mol Cell 2011;41:367-368.
Lu WJ, Chapo J, Roig I, Abrams JM. Meiotic
recombination provokes functional activation of
the p53 regulatory network. Science
2010;328:1278-1281.
Marin-Valencia I, Yang C, Mashimo T, Cho S,
Baek H, Yang XL, Rajagopalan KN, Maddie M,
Vemireddy V, Zhao Z, Cai L, Good L, Tu BP,
Hatanpaa KJ, Mickey BE, Mates JM, Pascual
JM, Maher EA, Malloy CR, Deberardinis RJ,
Bachoo RM. Analysis of tumor metabolism
reveals mitochondrial glucose oxidation in
genetically diverse human glioblastomas in the
mouse brain in vivo. Cell Metab 2012;15:827-837.
(Continued on page 27)
25
impact
Bits with Bite
Research reveals how tiny but influential
RNAs can be pivotal in cancer’s development.
Little bits of genetic material called microRNAs
appear to be big players in influencing how cells
in the body implement normal biological functions—and, when gone awry, in contributing to
the growth and spread of cancer.
MicroRNAs—or miRNAs, for short—
have just about two dozen of the genetic building blocks called nucleotides. That compares
with the few thousand that make up a typical
messenger RNA molecule, which carries a gene’s
template for producing proteins essential to a
cell’s functioning. By targeting messenger RNA,
microRNAs can regulate the amount of it that’s
available for making proteins.
“MicroRNAs have a lot of influence in
cells—each one can regulate many, perhaps hundreds, of messenger RNAs,” says Josh Mendell,
M.D., Ph.D., a Simmons Cancer Center member
whose work is elucidating microRNAs’ role in
cancer. His research team has found that correcting a microRNA aberration in tumor cells
holds promise in fighting liver cancer.
Research in many tumor types over the
last decade has shown that cancer cells produce
abnormal amounts of miRNAs. Some miRNAs
are present in excessive amounts and promote
tumor formation, while others act to suppress
tumor growth and exist at low levels in cancer
cells. MicroRNAs can also be involved in metastasis, says Dr. Mendell, a Professor of Molecular
Biology at UT Southwestern. “Every stage of the
multistep progression through which a normal
cell becomes a cancer cell can be influenced
by microRNAs.”
Complicating the analysis of microRNA
expression in cancer is the fact that different
types of cells have different microRNA expression patterns. “Because of this,” Dr. Mendell
says, “apparently abnormal microRNA expression in tumors could be a reflection of the
different cell types in a tumor compared with
the corresponding normal tissue. Therefore
functional experiments using cellular and
animal models of cancer are essential to determine whether a given microRNA actually promotes or inhibits cancer and would represent
a promising therapeutic target.”
A
The abundance of microRNA-26 (miR-26) is reduced in mouse liver tumors (depicted in figure) and has been shown to be similarly reduced in human liver cancer.
Researchers have engineered a virus known as AAV to produce miR-26 with the aim of boosting levels of the microRNA in the liver.
B
Insertion of a gene responsible for production of green fluorescent protein allows researchers to track how thoroughly AAV infects targeted tissue. Top images:
GFP is produced equally well by AAV that is also engineered to produce miR-26. Bottom images: When delivered to a mouse liver (left), AAV is present globally.
C
A liver from an untreated mouse (left) is riddled with cancer while one from a mouse whose liver cancer was treated (right) appears far healthier.
AAV control
B
NORMAL LIVER
A
TUMOR
B
miR-26a
C
26
AAV miR-26a
With that in mind, Dr. Mendell and
his colleagues set out to identify microRNAs
that participate in key pathways known to be
important in driving tumor formation. One such
pathway the Mendell laboratory has studied
extensively is controlled by a cancer-causing gene
called Myc, which is often hyperactive in cancer
cells. Dr. Mendell’s research group discovered
that the Myc oncogene can directly control the
expression of many microRNA genes, turning
some on and others off. Moreover, some of these
microRNAs that Myc controls are themselves
able to promote or inhibit tumor growth.
The next step was to determine whether
Myc’s impact on miRNAs was important to
the gene’s ability to promote cancer formation.
First, in cell lines, and then in a mouse model
of cancer, the researchers took tumor cells with
hyperactive Myc and restored the activity of
microRNAs that Myc normally suppresses. “In
several cases we found that if Myc could no longer turn these microRNAs off, tumor formation
was blocked,” Dr. Mendell says. “Even though the
cancer cells had activated Myc, one of the most
potent oncogenes, the cells completely lost their
ability to form tumors.”
Dr. Mendell and his colleagues also
noticed that Myc suppresses a microRNA called
miR-26, which functions to prevent tumor development and growth. So the researchers decided
to explore whether they could deliver miR-26
effectively to tumor cells in a mouse model, and
to see if the approach could yield a novel therapeutic strategy.
The liver, with its central function as a
filter for the body, proved to be an optimal target.
Dr. Mendell’s lab engineered a benign virus,
adeno-associated virus, or AAV—which easily
infects the liver and is being used in experimental
gene therapy trials for a variety of diseases—to
produce miR-26 and boost levels of the microRNA
in a mouse model of cancer. In the model, the Myc
oncogene triggers the formation of liver tumors
resembling hepatocellular carcinoma.
“After giving a single injection of this
modified virus, we were able to deliver miR-26
to nearly every cell in the liver without causing
any measureable toxic effects,” Dr. Mendell says.
“The microRNA was able to strongly suppress the
formation of very aggressive tumors in this mouse
model—after the mice received the microRNA
they had far fewer tumors, and the tumors that
remained were much smaller than control-treated
mice. The effect was potent.”
It was also highly selective. “When we
looked carefully at tumors that had received miR26 therapy, we found the microRNA activated
programmed cell death in those cancers, but the
normal part of the liver was completely spared
from that effect,” Dr. Mendell says. “We don’t
yet understand the mechanism underlying this
observation, but it’s very promising from a therapeutic standpoint.” Because miR-26 is already
abundant in normal cells, supplying more by
AAV delivery may have had minimal additional
effects, he says. But the tumor cells, which had
very low levels of miR-26, were highly sensitive
to the restored expression of the microRNA.
Besides liver cancer, the Mendell lab has
been studying the roles of many other microRNAs
in a number of different tumor types, including
colon and pancreatic cancer and lymphoma.
MicroRNAs seem to contribute to all tumor types,
although which specific microRNAs are participating can vary according to the cancer site.
As for miR-26, a great deal of study
remains to capture the details regarding its role
in cancer—for instance, the specifics of how it
can so effectively quell tumor growth. “We have
only scratched the surface of understanding
which of its messenger RNA targets are important,” Dr. Mendell says. Also, his lab is developing new cell and mouse models to investigate
miR-26’s role in normal biology, to determine
whether any harmful effects might result from
using the microRNA therapeutically.
One key challenge will be delivering
microRNA therapies to tumors at sites other than
the liver. “Much work is still needed to devise
ways to efficiently deliver miRNAs throughout
the body,” Dr. Mendell says.
UT Southwestern and the Cancer Prevention and Research Institute of Texas (CPRIT)
have provided the investigators a unique chance
to pursue such challenges, says Dr. Mendell, who
has received a $4.5 million Recruitment of Rising
Stars Award from CPRIT and who came to Dallas
from Johns Hopkins University in Baltimore.
“This was a tremendous opportunity to really
improve our science,” he says.
Luis Parada, Ph.D., Co-Leader of Simmons’
Development and Cancer Program, notes that
the field of microRNAs is so new “that it is likely
that we are only tapping the tip of the iceberg.” Dr.
Mendell’s research, he says, “will not only instruct
cancer biology but will also, through local interactions, have untold impact on general research here
at UT Southwestern.”
DEVELOPMENT AND CANCER
HIGH-IMPACT PUBLICATIONS
(Continued from page 25)
Mullen AR, Wheaton WW, Jin ES, Chen PH,
Sullivan LB, Cheng T, Yang Y, Linehan WM,
Chandel NS, DeBerardinis RJ. Reductive
carboxylation supports growth in tumour cells with
defective mitochondria. Nature 2012; 481:385-388.
Neumann JC, Chandler GL, Damoulis VA,
Fustino NJ, Lillard K, Looijenga L, Margraf L,
Rakheja D, Amatruda JF. Mutation in the type
IB bone morphogenetic protein receptor Alk6b
impairs germ-cell differentiation and causes
germ-cell tumors in zebrafish. Proc Natl Acad Sci
USA 2011;108:13153-13158.
Park J, Sarode VR, Euhus D, Kittler R, Scherer
PE. Neuregulin 1-HER axis as a key mediator of
hyperglycemic memory effects in breast cancer.
Proc Natl Acad Sci USA 2012;109:21058-21063.
Terada LS, Nwariaku FE. Escaping Anoikis
through ROS: ANGPTL4 controls integrin signaling
through Nox1. Cancer Cell 2011;19:297-299.
Xu K, Sacharidou A, Fu S, Chong DC, Skaug B,
Chen ZJ, Davis GE, Cleaver O. Blood vessel
tubulogenesis requires Rasip1 regulation of
GTPase signaling. Dev Cell 2011;20:526-539.
Xu Y, Nedungadi TP, Zhu L, Sobhani N, Irani
BG, Davis KE, Zhang X, Zou F, Gent LM, Hahner
LD, Khan SA, Elias CF, Elmquist JK, Clegg DJ.
Distinct hypothalamic neurons mediate estrogenic
effects on energy homeostasis and reproduction.
Cell Metab 2011;14:453-465.
Ye X, Huang N, Liu Y, Paroo Z, Huerta C, Li P,
Chen S, Liu Q, Zhang H. Structure of C3PO and
mechanism of human RISC activation. Nat Struct
Mol Biol 2011;18:650-657.
Zheng J, Umikawa M, Cui C, Li J, Chen X,
Zhang C, Huynh H, Kang X, Silvany R, Wan X,
Ye J, Canto AP, Chen SH, Wang HY, Ward ES,
Zhang CC. Inhibitory receptors bind ANGPTLs
and support blood stem cells and leukaemia
development. Nature 2012;485:656-660.
Zheng J, Umikawa M, Zhang S, Huynh H,
Silvany R, Chen BP, Chen L, Zhang CC. Ex vivo
expanded hematopoietic stem cells overcome
the MHC barrier in allogeneic transplantation. Cell
Stem Cell 2011;9:119-130.
Zhou J, Shrikhande G, Xu J, McKay RM, Burns DK,
Johnson JE, Parada LF. Tsc1 mutant neural
stem/progenitor cells exhibit migration deficits and
give rise to subependymal lesions in the lateral
ventricle. Genes Dev 2011;25:1595-1600.
Zhou Q, Gallagher R, Ufret-Vincenty R, Li X,
Olson EN, Wang S. Regulation of angiogenesis
and choroidal neovascularization by members of
microRNA-23~27~24 clusters. Proc Natl Acad Sci
USA 2011;108:8287-8292.
Boldface denotes Cancer Center members in
the Development and Cancer program; underline
denotes members affiliated with another scientific
program within the Cancer Center.
27
Feature: BREAST CANCER
CASTING A WIDER NET
IT’S PERSONAL
Breast cancer care and research
focuses on the circumstances of each individual.
While the fight against breast cancer may be a race to find a cure, it’s also a steadfast march of progress in the areas of risk
ASSESSMENTPREVENTIONDETECTIONANDTREATMENTs4HEFOOTFALLSOFSUCHPROGRESSECHOEVERYDAYINTHELABORATORIESAND
clinics of UT Southwestern and the Simmons Cancer Center’s Center for Breast Care. There, researchers and clinicians
AREBLAZINGANEWTRAILINASSESSINGINDIVIDUALCANCERRISK4HEYREADVANCINGTECHNOLOGYTOANSWERCRUCIALQUESTIONSABOUT
WHATUNDERLIESTUMORDEVELOPMENTANDARElNDINGBETTERWAYSTODETECTANDTREATBREASTMALIGNANCIESs4HERESULTFOR
patients in the Dallas-Fort Worth area and well beyond, is a continuum of comprehensive care that’s at work long before a
suspicious lump is detected. That care starts with individual risk assessment.
A new, state-of-the-art system being
deployed over the next two years will enable
patients in select Texas counties to connect
with UT Southwestern genetic counselors
via a fast, secure, online video connection.
Pictured: Genetic Counselor Pia Summerour,
M.S., C.G.C., tests the technology.
28
)NTHEPASTAFmUENTORWELL
insured women have been the
main beneficiaries of testing
for genetic mutations linked to
breast (and ovarian) cancer.
But with the support of almost
$1.6 million in funding from
the Cancer Prevention and
Research Institute of Texas
(CPRIT), the Cancer Center has
established a population-based
cancer genetics screening
program that targets uninsured,
underinsured, minority, and
rural populations—people who
typically have little chance to
learn about the hereditary risk
of cancer, and what they can
do in terms of prevention and
early detection.
The program, led by Cancer
Center member and Professor of
Surgical Oncology David Euhus,
M.D., doesn’t just test for genetic
mutations in women who have
breast cancer or a clear family
history of the disease. It also
casts a wider net, seeking out
high-risk patients by adminisTERINGABRIEFQUESTIONNAIRETO
every woman undergoing mammography at any of three North
Texas hospitals—as well as
most women screened through
several hospital-based mobile
mammography units—covering
a total of seven counties. Sites
include the safety-net hospital
systems of John Peter Smith
(JPS) Hospital in Fort Worth
as well as Parkland Memorial
Hospital in Dallas, where the
program got started.
“UT Southwestern has really
been a leader in getting into the
community,” Clinical Cancer Genetics Manager Linda
Robinson, M.S., C.G.C., says
of the program. “We have lots
of satellite sites we go into once
a month, or once a week, that
can bring this care to patients.”
"ASEDONRESULTSOFTHEQUEStionnaire, program counselors
then work with at-risk patients,
scrutinizing family histories, discussing how particular genetic
vulnerabilities to cancer can be
inherited across generations,
and how diet, lifestyle, and
OTHERFACTORSALSOINmUENCEA
person’s odds of getting the
disease. In some cases, genetic
testing, which is performed using DNA from a blood or saliva
sample, will be recommended.
Once results are in, patients
who test positive for a genetic
predisposition to cancer are
assigned a patient navigator—an expert who will steer
them through the complexities
of follow-up screening and
whatever other individualized
care is needed.
“We have a checklist to make
sure they’re getting all the care
they need to prevent cancer,”
Ms. Robinson says. “We’re very
proactive, because these are the
highest-risk patients.”
BEST PRACTICE MODEL
Meanwhile, outreach to those
patients’ family members, who
might share the same genetic
vulnerabilities to cancer, can
entail a variety of tasks, such as
writing a letter in Spanish describing any relevant mutation
or providing a DVD that clearly
and simply explains the genetic
findings and their implications.
As part of the same grant,
all colon cancer patients at
program sites who are under
age 70, and uterine cancer
patients under 50, are screened
for Lynch syndrome, a hereditary condition in which patients
and their family members have
an increased risk for these and
other cancers, including tumors
of the stomach, ovaries, urinary
tract, breast, and brain.
In the first nine months, the
program identified 26 individuals with the syndrome—and
more than 100 of their firstdegree relatives with 50-50
odds of having the condition.
Without aggressive screening
and other interventions, people
with Lynch syndrome face, for
example, a colon cancer risk of
80 percent, Ms. Robinson says.
“But now that we can watch
them carefully, we can increase
the chances of diagnosing cancer at an early, curable stage.”
The outreach program is
considered a best practice
model by the American College of Surgeons’ Commission
on Cancer, says Dr. Euhus,
Co-Director of the Mary L.
Brown Breast Cancer Genetics and Risk Assessment
Program. Also, based on work
at Parkland and JPS, Cancer
Center Genetic Counselor Sara
Pirzadeh-Miller, M.S., C.G.C.,
has published “how-to” information on starting a genetics clinic
for the medically underserved.
“We have hospitals all over
the country calling us, saying,
‘How do you do genetic testing
where there’s no money?’” Ms.
Robinson says. Komen affiliates—as well as Myriad Genetics, the laboratory company
that does the testing—have
helped pay for the testing.
EFFICIENT AND PORTABLE
Another innovation, used at
all 16 of the Genetics Program’s
clinical sites, is CancerGene
Connect, an Internet-based genetics counseling environment
that stores data and generates
patient reports and explanatory
graphics. CancerGene Connect—developed and honed
by Dr. Euhus, Cancer Center
programmer analyst Tirun Lin,
and the genetic counseling
staff—is based on a program
called CancerGene, which was
created by Dr. Euhus and is
29
used worldwide. CancerGene
mathematically determines patients’ odds of carrying various
genes that heighten cancer risk.
One advantage of the online
resource is efficiency. Before
counseling appointments,
patients can log in and complete their family health history,
allowing them to consult with
relatives in advance, and saving
time and paperwork at their
counseling session.
Portability is also a plus.
“My clinic is my laptop,” Ms.
Robinson says. “It’s a model
that could change the way
cancer genetic counseling is
done around the world.”
ADVANCING THE FIELD
Cancer Center scientists
and clinicians have helped set
the standard for personalized
breast care in other ways, too.
For instance, research co-led
by Professor of Surgical Oncology Marilyn Leitch, M.D., is
changing surgical approaches
in patients whose breast cancer
has spread to just one or two
key lymph nodes in the armpit.
Until recently, cancer in those
“sentinel” lymph nodes has
been considered an indicator
that surgeons should remove
even more lymph nodes to prevent further metastasis. But the
research found that patients undergoing lumpectomy to excise
their tumor, along with wholebreast radiation treatment,
have similar survival times and
recurrence rates regardless of
whether those additional lymph
nodes are removed.
Limiting lymph node removal
can allow for speedier recoveries,
Dr. Euhus notes, and it might
let patients avoid arm problems
such as lymphedema, numbness, and a decrease in range
of motion.
“We’ve dropped axillary
dissection [of lymph nodes]
in those patients,” he says.
“We hate the morbidity that
it causes.”
Meanwhile, the Center for
Breast Care has also contributed to research showing that
digital mammography is superior to traditional, film-screen
mammography, leading to
adoption of the digital technology throughout the U.S., says
Phil Evans, M.D., Professor of
Radiology and Director of the
Center for Breast Care. And
UT Southwestern researchers
helped test the nation’s first
approved mammography
device that provides a 3-D view
of the breast.
The Center has also been
involved in determining which
imaging technologies, including
ultrasound and magnetic resonance imaging (MRI), are most
appropriate and cost-effective
for women at differing levels
David Euhus, M.D., Professor of Surgical Oncology and Medical Director of the Cancer Genetics Program
30
of breast cancer risk. “We’ve
made significant efforts to try to
personalize imaging care,” Dr.
Evans says.
BIGGER AND BETTER VISION
At the same time, UT Southwestern researchers are propelLINGCANCERIMAGINGTECHNIQUES
far past current limitations.
While technologies including CT
scanning, ultrasound, and MRI
are better than ever, and can
provide useful information on a
tumor’s volume or location, “that
only takes us so far,” says Craig
Malloy, M.D., Medical Director
of UT Southwestern’s Advanced
Imaging Research Center.
“There’s a great deal of interESTINTRYINGTOACQUIREOTHER
information about tumors, such
as the type of tissue or conditions of the tissue where tumors
arise,” he says.
To capture such information
noninvasively, UT Southwestern
researchers led by Dr. Malloy are
collaborating with Texas A&M
University on a $1.17 million
CPRIT grant to transform highfield MRI and spectroscopy.
High-field MRI uses a very
powerful magnet. While community radiology practices
typically use fields between 1
and 3 tesla (a measurement
of magnetic field strength), the
new effort is aimed at crafting
MRI technology that provides
the clearest pictures—and optimizes comfort for breast cancer
patients—at 7 tesla.
That’s where Texas A&M
electrical and biomedical engineers Mary McDougall, Ph.D.,
and Steven Wright, Ph.D.,
come in. They’re designing better coils—in essence, antennas
that transmit radio waves and
detect waves from nuclei in the
body’s cells during the application of a magnetic field. “Better
COILSEQUALBETTERSIGNALSIN
ANDOUTWHICHEQUALSABETTER
picture,” Dr. Malloy explains.
The researchers have already
shown that 7 tesla MRI can
provide some details about the
fat composition of breast tissue,
a capability that might eventually shed light on how diet
impacts breast cancer risk.
“There’s evidence that the ratio of omega-6 to omega-3 fatty
acids in mammary fat is higher
in women who get breast
cancer,” says Dr. Euhus, whose
research interests include the
role of breast composition in
cancer risk. “Better MRI would
be able to measure that.”
UT Southwestern’s Advanced
Imaging Research Center, under
the direction of Cancer Center
member A. Dean Sherry, Ph.D.,
is the ideal setting to help develop and test such technology.
UT Southwestern, the Department of Defense, and the
National Institutes of Health
have invested millions of dollars
EQUIPPINGTHEIMAGINGCENTER
Dr. Malloy notes.
University administrators,
he adds, have encouraged
researchers on campus to
connect with peers who can
help overcome specific technological hurdles. “As a conseQUENCEWEHAVESOMEVERY
high-end engineering that can
help us move the field forward.”
THE IDEAL SETTING
Using nonradioactive, carbon
isotope tracers, investigators
also hope to capture crisper
images of glucose metabolism,
a cellular process that kicks into
high gear in tumors. “Higherfield MRI can detect these
tracers more efficiently than at
lower fields,” Dr. Malloy says.
The scientists also want to
use the technology to detect
choline, a molecule that’s
involved in the turnover of cell
membranes and which occurs
in high concentrations in many
breast tumors. Suspecting
those concentrations are relatEDTOHOWQUICKLYCANCERCELLS
proliferate, researchers plan to
investigate whether choline can
serve as a marker that cancer
is present or that a tumor is
responding to treatment.
Genetic Counselors Linda Robinson, M.S., C.G.C. (left), and Sara Pirzadeh-Miller, M.S., C.G.C.,
attended the National Ovarian Cancer Walk to educate patients and their families about the link
between ovarian cancer and breast cancer.
31
leadership
cancer cell networks
Shining a spotlight on some crucial molecules implicated in cancer, investigators
are illuminating pathways that could potentially yield more effective treatments
for patients.
AT A GLANCE
goal
To promote research that will contribute
to an understanding of the mechanisms
at work in aberrant cell regulatory
networks that support cancer initiation
and growth.
approaches
To define the fundamental regulatory
states that generate and maintain needed
restraints on cell growth, proliferation, and
survival; to determine how aberrations
in that regulatory behavior contribute to
the genesis of cancer; and to foster collaborations with translational and clinical
scientists to test the therapeutic benefits
of manipulating cell regulation.
James Brugarolas, M.D., Ph.D., Assistant
Professor, Internal Medicine, Division of Hematology/Oncology and Developmental Biology
Dr. Brugarolas, a Virginia Murchison Linthicum
Scholar in Medical Research, leads a research
program on renal cell carcinoma that spans
from the molecular genetics of kidney cancer to
clinical trials. His research established a foundation for targeting mTORC1 in renal cancer, and he
is the recipient of multiple awards, including a V
Scholar Award from the V Foundation for Cancer
Research and a Research Scholar Award from the
American Cancer Society.
Melanie Cobb, Ph.D., Professor, Pharmacology
Dr. Cobb is a leader in efforts to understand the
molecular biology of signal transduction, the
relaying of chemical signals from a cell’s exterior to alter function inside the cell. She holds
the Jane and Bill Browning Jr. Chair in Medical Science. She was elected to the National
Academy of Sciences in 2006 in recognition of
pioneering work on a class of enzymes known
as MAP kinases.
2012 funding
TOTAL: $36.5 million
National Cancer Institute: $2.8 million
Other National Institutes of Health:
$16.3 million
Cancer Prevention and Research
Institute of Texas: $10.5 million
peer-reviewed
publications
32
2009-2012: 359
Trichrome staining of malignant tissue in
a mouse model of pancreatic ductal adenocarcinoma shows dense fibrous connective
tissue (blue staining) throughout the tumor.
The connective tissue serves to enhance
tumor cell survival and can be a barrier to
drug delivery.
33
impact
In Pursuit of Better Therapies
Elucidation of an enzyme called TBK1 holds
promise in fighting pancreatic, other cancers.
For patients, cancer can be a race against
time. For scientists seeking effective treatments, it’s also a race against biology—one
with many potential opponents.
For researchers at the Simmons Cancer
Center, those opponents can be a host of
molecules that perform a multitude of
functions in normal cells. But even a single
misstep by one of these molecules can set a
cell on a course toward cancer.
A protein called Ras is notorious in
such missteps. Ras functions in cells as a
signaling intermediate: Normally, external
chemical messages received on the cell
surface trigger a series of subsequent internal
reactions, amid which Ras can be activated.
In its oncogenic, or cancer-promoting, form,
Ras is activated, and stays activated, without
any external signal. It’s as if a relay runner,
who normally would be set into motion by
the passing of a baton, instead begins his
part of the race without any handoff. The
result: Cells can reproduce rapidly and avert
signals that tell them to die off.
Stopping oncogenic Ras in its tracks
holds enormous promise for cancer therapy,
says Associate Professor of Surgery Rolf
Brekken, Ph.D., a member of the Cancer
A
Hematoxylin- and eosin-stained tumor tissue from the mouse model of pancreatic cancer, magnified approximately 200 times. The images show the histology of control-treated (left) and Compound II-treated (right) tumors.
Darker purple areas represent normal pancreatic acinar tissue that is apparent after treatment with Compound II.
B
Expression of amylase (green), which marks normal acinar tissue and corresponds to the darker purple areas
in the top panel.
C
Expression of phosphorylated GSK-3ß (dark brown), a protein downstream of active TBK1. Inhibition of
TBK1 by Compound II reduced the level of phosphorylated GSK-3ß, as shown in the tumor tissue from
Compound II-treated animals. The mice were about 7 weeks old, and those receiving Compound II had
been treated for 17 days.
Control
Hematoxylin and eosin
A
Amylase
B
pGSK-3ß
C
34
Cmpd II
Center’s Development and Cancer Program.
“Ras is a beautiful drug target, except that no
one has been able to hit it effectively,” he says.
However, discoveries made at
UT Southwestern show that when Ras runs
rogue, another part of the cancer-causing
relay can be halted by interfering with a
subsequent “runner.” That runner is TANKbinding kinase-1, or TBK1, an enzyme that is
found in many types of cells and is involved
in immune response to viruses.
Inhibiting TBK1, it turns out, can blunt
the effects of rogue Ras, says Dr. Brekken,
whose laboratory studies pancreatic cancer.
“TBK1 may be a way to attack Rasdriven tumors, and pancreatic cancer is a
major Ras-driven tumor. Ninety percent of
pancreatic patients have a Ras mutation,”
he says. “If we knock out the TBK1 gene or
inhibit it … that really could become a major
weapon in the anti-cancer arsenal.”
Cancer Center Associate Director for
Basic Science Michael White, Ph.D., notes
that although TBK1 lies downstream from
Ras, other pathways can engage TBK1 too.
TBK1 is sometimes a necessary tool, but
not the only one, that Ras uses to transform
healthy cells into cancerous ones, he says.
However, TBK1 becomes an attractive target
under conditions where it is indispensable
for cancer cell survival.
Besides pancreatic cancer, non–small
cell lung tumors—and perhaps other cancer
types—might also be vulnerable to this novel
means of Ras attack, although researchers
say further study is needed. Tests on cells in
culture suggest that a substantial portion of
lung cancer cell lines might depend on TBK1
for survival.
Dr. White, a member of the Center’s
Cancer Cell Networks Program, and his
colleagues made the TBK1 discovery while
working to trace exactly how Ras, when
it runs amok, contributes to cancer. The
researchers found a signaling pathway where
Ras activates another protein, called Ral,
which in turn engages the exocyst complex,
a cluster of proteins that normally helps
relay signals to TBK1 upon cellular invasion
by disease-causing agents (i.e., pathogens).
“Oncogenes like Ras can hijack this signaling
pathway,” Dr. White says, “and that becomes
important for tumor cells to be able to
survive the stress of dysregulated growth
and proliferation.”
TBK1, it turned out, was often active in
the cancerous cells that the researchers studied. When its function was blocked in cancer
cells, they died, yet when it was blocked in
healthy cells, they survived. But, Dr. White
notes, “We still have some work to do to figure out what characteristics of a tumor mark
it as TBK1-sensitive.”
Other research at UT Southwestern has
shown that Ras and TBK1 weren’t the only
star runners in this cancer relay. Students
in Dr. White’s lab, trying to figure out just
how TBK1 promoted cancer cell survival,
have discovered that it could independently
engage another well-known culprit in cancer,
the protein AKT, which Dr. White describes
as “the mother of all survival kinases.”
Researchers had previously known of only
one, indirect way to activate AKT—involving another enzyme, called PI3 kinase. The
new finding allows scientists to use AKT as a
gauge of whether any compounds meant to
disable TBK1 are actually working.
By looking at those downstream effects,
researchers are developing a potential way
to discern which patients might be most
responsive to compounds targeting TBK1.
“Patients with tumors that have active AKT
might be good candidates for a TBK1 inhibitor,” Dr. Brekken says.
The TBK1 discoveries have sparked the
interest of the biotechnology firm Amgen.
Based on the UT Southwestern work and
findings elsewhere, Amgen screened more
than 250,000 chemical compounds to learn
which ones could best inhibit TBK1, a process that led to the discovery of a promising
molecule nicknamed Compound II (and
known formally as 6-aminopyrazolopyrimidine). Early tests of the compound suggest
that it, or substances like it, might be able to
subdue TBK1 selectively, with minimal toxic
effects, Dr. Brekken says.
In research using mice genetically
engineered to develop pancreatic cancer,
UT Southwestern researchers have found
that Compound II can provide additional
therapeutic benefit when administered with
a standard chemotherapy drug, gemcitabine.
The combined therapy suppresses tumor
growth by about 50 percent, compared with
roughly half that for gemcitabine alone,
Dr. Brekken says. The therapy has a comparable impact on tumor metastases.
“I’m hoping when the next compound
comes around or when we figure out how
to deliver this better, we’ll have even more
efficacy,” Dr. Brekken says. Currently the
investigators use a tiny pump to elute the
drug over a period of several weeks into the
abdomens of the mice.
Pancreatic cancer is particularly deadly,
with a five-year survival rate of less than 5 percent, Dr. Brekken says. Much of the problem
traces to the fact that the cancer is usually
detected late, when surgery—the best chance
of cure—is not possible. Pancreatic tumors
also are highly resistant to current therapies,
such as chemotherapy, that attack the cancer
throughout the body, while agents that target
specific biological processes related to the
cancer have been disappointing so far.
“We need therapies that are going to
enhance the efficacy of standard chemotherapy as well as hit these mechanisms that drive
pancreatic tumor progression,” Dr. Brekken
says. “That’s why something like an inhibitor
of TBK1 is quite exciting.”
CANCER CELL NETWORKS
HIGH-IMPACT PUBLICATIONS
Asaithamby A, Hu B, Chen DJ. Unrepaired
clustered DNA lesions induce chromosome
breakage in human cells. Proc Natl Acad Sci USA
2011;108:8293-8298.
Bodemann BO, Orvedahl A, Cheng T, Ram RR,
Ou YH, Formstecher E, Maiti M, Hazlett CC,
Wauson EM, Balakireva M, Camonis JH, Yeaman
C, Levine B, White MA. RalB and the exocyst
mediate the cellular starvation response by direct
activation of autophagosome assembly. Cell 2011;
144:253-267.
Duan L, Cobb MH. Calcineurin increases
glucose activation of ERK1/2 by reversing
negative feedback. Proc Natl Acad Sci USA
2010;107:22314-22319.
He C, Bassik MC, Moresi V, Sun K, Wei Y, Zou
Z, An Z, Loh J, Fisher J, Sun Q, Korsmeyer S,
Packer M, May HI, Hill JA, Virgin HW, Gilpin C,
Xiao G, Bassel-Duby R, Scherer PE, Levine B.
Exercise-induced BCL2-regulated autophagy is
required for muscle glucose homeostasis. Nature
2012;481(7382):511-515.
Hou F, Sun L, Zheng H, Skaug B, Jiang QX, Chen
ZJ. MAVS forms functional prion-like aggregates
to activate and propagate antiviral innate immune
response. Cell 2011;146:448-461.
Hung RJ, Yazdani U, Yoon J, Wu H, Yang T, Gupta
N, Huang Z, van Berkel WJ, Terman JR. Mical
links semaphorins to F-actin disassembly. Nature
2010;463:823-827.
Jacob LS, Wu X, Dodge ME, Fan CW, Kulak O,
Chen B, Tang W, Wang B, Amatruda JF, Lum
L. Genome-wide RNAi screen reveals diseaseassociated genes that are common to Hedgehog
and Wnt signaling. Sci Signal 2011;4:ra4.
Jeong Y, Xie Y, Xiao G, Behrens C, Girard L,
Wistuba II, Minna JD, Mangelsdorf DJ.
Nuclear receptor expression defines a set of
prognostic biomarkers for lung cancer. PLoS Med
2010;7:e1000378.
Kinch L, Grishin NV, Brugarolas J. Succination
of Keap1 and activation of Nrf2-dependent
antioxidant pathways in FH-deficient papillary
renal cell carcinoma type 2. Cancer Cell
2011;20:418-20.
Klein AM, Dioum EM, Cobb MH. Exposing
contingency plans for kinase networks. Cell
2010;143:867-869.
Lee AY, Chen W, Stippec S, Self J, Yang F,
Ding X, Chen S, Juang YC, Cobb MH. Protein
kinase WNK3 regulates the neuronal splicing
factor Fox-1. Proc Natl Acad Sci USA U S A
2012;109:16841-16846.
Rolf Brekken, Ph.D., Associate Professor,
Surgery and Pharmacology
Lee HC, Li L, Gu W, Xue Z, Crosthwaite SK,
Pertsemlidis A, Lewis ZA, Freitag M, Selker EU,
Mello CC, Liu Y. Diverse pathways generate
microRNA-like RNAs and Dicer-independent small
interfering RNAs in fungi. Mol Cell 2010;38:803-814.
(Continued on page 37)
35
impact
Possible Dream
Investigators find previously unknown
vulnerabilities in key cancer pathways.
A
Genetic (RNAi) screens in cultured cells reveal
disease-associated genes that give rise to deviant
signaling in the Hedgehog pathway (vertical axis and
lines) and Wnt pathway (horizontal axis and lines).
At right is the molecular structure of chemicals that
specifically target each of these pathways identified
by screening a large chemical library maintained at
UT Southwestern. Results of the genetic and chemical
screens allow researchers to target specific genetic
malfunctions with appropriate chemicals.
A
36
What once seemed an unbeatable foe might
someday yield under the weight of discoveries by Simmons Cancer Center investigator
Lawrence Lum, Ph.D., and his colleagues.
Dr. Lum, an Associate Professor
of Cell Biology at UT Southwestern, has
focused his work on two developmentally
important cell-cell communication systems
that are frequently exploited in cancers.
The cellular responses controlled by the
Hedgehog and Wnt (pronounced “wint”)
molecules are key players during embryonic
development in coordinating collective cell
fate outcomes, marshaling groups of cells
to form, say, a heart or a liver. Research in
Dr. Lum’s laboratory, in collaboration with
the High-Throughput Screening Resource,
has shed light on the function of genes that
drive these pathways at every step—and
on aberrations that steer healthy cells to
become cancerous ones.
The Wnt pathway, for instance, “really
has its fingers in just about everything during development,” says Dr. Lum, including
essential functions such as programmed cell
death, cell migration, differentiation of cells
into varied types of tissue, and more. Nineteen Wnt molecules and at least 10 receptors
make up a complex signaling system that
allows multiple cells, by secreting proteins,
to coordinate their activity—much as a
group of people might use mobile phones
to text one another and organize their actions. “Such communication is essential in a
multicellular organism with specific tissues
like the heart and lungs,” Dr. Lum says. “If
you knock out Wnt signaling, you don’t have
these functions occurring.”
In adults, a major function of Wnt
proteins is maintaining the integrity of adult
stem cells, a type of cell that can be molded
into the specialized cells needed to replenish specific tissues in the body. Genetic
evidence suggests that the processes that
maintain normal stem cells can be corrupted to maintain cancer-initiating cells,
thereby seeding malignant growth.
Research by the Lum laboratory, using
cultured mouse cells and a screening technique
called ribonucleic acid interference (RNAi), has
revealed two novel vulnerabilities in the Wnt
pathway involving the liver kinase B1 gene,
or LKB1, which is mutated in about four in
10 non–small cell lung cancers and ordinarily
may apply a brake on runaway Wnt signaling.
Furthermore, by screening a chemical library
of some 200,000 compounds in the same type
of cells, the team identified two classes of
chemical compounds that hold promise for
counteracting these LKB1 glitches.
Screening chemical compounds and
performing genome-scale RNAi on the same
assay for inhibiting Wnt signaling is a novel
approach that is much more powerful than
screening either RNAi or compounds alone,
says Professor of Biochemistry Michael Roth,
Ph.D., Interim Dean of the UT Southwestern
Graduate School of Biomedical Sciences and
a collaborator in the Wnt research. One of the
challenges for treating cancer is that many of
the mutations that seem to be associated with or
cause cancer are in proteins that are not themselves good drug targets. Screening with RNAi
links proteins that are mutated in cancer with a
druggable signaling pathway, such as Wnt, and
screening compounds identifies chemicals that
might become leads for new drugs for controlling the Wnt pathway, Dr. Roth says.
This groundbreaking work may represent
an important step in developing medicines tailored to treat cancers that have LKB1 mutations.
In addition, because the action of the chemical
compounds could be reversed, the findings suggest that diseased cells could be targeted without
permanently interfering with the function of
healthy cells, Dr. Lum says.
More recently, the Lum laboratory
has discovered other classes of compounds
that can achieve the same specificity. One is
called IWPs, or inhibitors of Wnt production. IWPs target an enzyme called Porcupine, an essential player in the production
of Wnt proteins. “If you shut this enzyme
down you have wiped out most if not all
Wnt signaling,” Dr. Lum says. Another class,
IWRs, or inhibitors of Wnt response, target
an enzyme called tankyrase. In a collaboration that includes Chemistry and Cancer
Program member Noelle Williams, Ph.D.,
Associate Professor of Biochemistry, the
researchers are working to optimize both
types of compounds for medicinal delivery
inside the body and testing them in rodent
models of lung and colon cancer and leukemia.
Use of a zebrafish model developed by Assistant
Professor of Pediatrics, Internal Medicine, and
Molecular Biology James Amatruda, M.D.,
Ph.D., a member of the Development and
Cancer Program, has meanwhile proved instrumental in drug development and beta testing for
various compounds.
Glitches in Wnt signaling have also
been linked to other malignancies, including
breast and renal cancers. Moreover, about 90
percent of patients with colon cancer—the
third most frequently diagnosed cancer in
the United States, and third leading cause
of cancer death in men and women—have
mutations in the adenomatous polyposis
coli gene, or APC, a well-established Wnt
suppressor. When working improperly, APC
unleashes a torrent of Wnt signaling that
otherwise would be suppressed in adults.
This suggests that dampening that signaling would be effective in fighting colon
cancer. “That’s the grand hypothesis that
needs to be rigorously tested,” Dr. Lum says.
The hunt for new chemicals that inhibit Wnt signaling is intense, he adds. “Given
the association of deviant Wnt signaling in a
broad range of cancer types, such molecules
may have general value as an anti-cancer
agent that extends beyond colorectal cancer
cases,” he says. Dr. Lum has received a $1.3
million grant from the Cancer Prevention
and Research Institute of Texas to support
the work with Wnt signaling.
Like the Wnt pathways, Hedgehog
(Hh)-mediated signaling is crucial to
embryonic development and is involved
in maintaining adult stem cells. It, too, is
frequently exploited in cancer.
Research spearheaded by Dr. Lum has
identified a new collection of potent, targeted, and easy-to-synthesize inhibitors of Hh
response, or IHRs. He and Associate Professor of Biochemistry Chuo Chen, Ph.D., have
found that one such molecule, IHR-1, can
be modified to become a double-barreled
weapon of sorts—with part designed to
target the Hedgehog pathway, and part open
for another means of attack—including, perhaps, disruption of the Wnt pathway. Such
a Hedgehog-Wnt weapon might be useful
against the brain cancer medulloblastoma,
which frequently arises from misactivation
of either one of these signaling pathways.
“Given its versatility, IHR-1 allows us to
play with these chemicals as if they are Lego
pieces, to build the best formula for attacking various types of cancer,” Dr. Lum notes.
Overall, the Wnt and Hedgehog research
has provided a foundation for an energetic
back-and-forth exchange between scientists,
Dr. Lum says. “It’s quite a dynamic partnership
involving multiple scientific disciplines, but
centered on the same anti-cancer goals.”
CANCER CELL NETWORKS
HIGH-IMPACT PUBLICATIONS
(Continued from page 35)
Mata MA, Satterly N, Versteeg GA, Frantz D,
Wei S, Williams N, Schmolke M, Peña-Llopis S,
Brugarolas J, Forst CV, White MA, GarciaSastre A, Roth MG, Fontoura BM. Chemical
inhibition of RNA viruses reveals REDD1 as a host
defense factor. Nat Chem Biol 2011;7:712-719.
Orvedahl A, Sumpter R Jr, Xiao G, Ng A, Zou
Z, Tang Y, Narimatsu M, Gilpin C, Sun Q, Roth
M, Forst CV, Wrana JL, Zhang YE, Luby-Phelps
K, Xavier RJ, Xie Y, Levine B. Image-based
genome-wide siRNA screen identifies selective
autophagy factors. Nature 2011;480(7375):113-7.
Ou YH, Torres M, Ram R, Formstecher E, Roland
C, Cheng T, Brekken R, Wurz R, Tasker A,
Polverino T, Tan SL, White MA. TBK1 directly
engages Akt/PKB survival signaling to support
oncogenic transformation. Mol Cell 2011;41:458-470.
Peña-Llopis S, Vega-Rubin-de-Celis S, Schwartz
JC, Wolff NC, Tran TA, Zou L, Xie XJ, Corey
DR, Brugarolas J. Regulation of TFEB and
V-ATPases by mTORC1. EMBO J 2011;30:3242-3258.
Potthoff MJ, Boney-Montoya J, Choi M, He T,
Sunny NE, Satapati S, Suino-Powell K, Xu HE,
Gerard RD, Finck BN, Burgess SC, Mangelsdorf
DJ, Kliewer SA. FGF15/19 regulates hepatic
glucose metabolism by inhibiting the CREB-PGC1alpha pathway. Cell Metab 2011;13:729-738.
Tu SW, Bugde A, Luby-Phelps K, Cobb MH.
WNK1 is required for mitosis and abscission. Proc
Natl Acad Sci USA 2011;108:1385-1390.
Wang RC, Wei Y, An Z, Zou Z, Xiao G, Bhagat G,
White M, Reichelt J, Levine B. Akt-mediated
regulation of autophagy and tumorigenesis
through Beclin 1 phosphorylation. Science
2012;338:956-959.
Yue X, Schwartz JC, Chu V, Younger ST, Gagnon
KT, Elbashir S, Janowski BA, Corey DR.
Transcriptional regulation by small RNAs at
sequences downstream from 3’ gene termini.
Nat Chem Biol 2010;6:621-629.
Yu B, Martins IR, Li P, Amarasinghe GK, Umetani
J, Fernandez-Zapico ME, Billadeau DD, Machius
M, Tomchick DR, Rosen MK. Structural
and energetic mechanisms of cooperative
autoinhibition and activation of Vav1. Cell
2010;140:246-256.
Zeng W, Sun l, Jiang X, Chen X, Hou F, Adhikari
A, Xu M, Chen ZJ. Reconstitution of the RIG-I
pathway reveals a signaling role of unanchored
polyubiquitin chains in innate immunity. Cell
2010;141:315-330.
Lawrence Lum, Ph.D., Associate Professor,
Cell Biology
Boldface denotes Cancer Center members in
the Cancer Cell Networks Program; underline
denotes members affiliated with another scientific
program within the Cancer Center.
37
spotlight
Constructing the Future
The new Clements University Hospital will
enhance cutting-edge care, research on campus.
Building on seven decades of clinical, teaching, and research excellence, UT Southwestern Medical Center is constructing a new,
$800 million hospital on a 32-acre site
on campus.
Groundbreaking for the 12-story,
460-bed William P. Clements Jr. University
Hospital was in March 2011; the facility is
expected to open in late 2014.
The new, 1.3 million-square-foot hospital will replace St. Paul University Hospital, a 271-bed, half-century-old facility that
began as a community hospital.
It also will complement the 149-bed Zale
Lipshy University Hospital, which opened
in 1989 and is at full capacity, as well as the
30,000-square-foot Simmons Cancer Center
Clinics, which are located in state-of-the-art
facilities on the University’s North Campus.
The new Clements University Hospital
represents a crucial step on the University’s
climb to the highest echelon of U.S. academic medical centers. Hundreds of faculty
physicians, nurses, technicians, support
staff, and patients took part in planning the
new facility, which is designed around the
needs of patients and their loved ones, as
well as to support the University’s research
mission. The new structure features space
to accommodate clinical and translational
research; an electronic health records system, with in-room monitors to allow review
of records and imaging; and the latest in
robotics and other patient care technology. Each floor will include “rounding
rooms” where health care teams can confer
privately; family and staff conference rooms
and teaching spaces; and on-call rooms and
facilities for physicians.
The entire 11th floor will be dedicated to hematology/oncology care, with a
focus on patient safety and comfort as well
as family support. The space will include a
32-bed unit for stem cell transplantation, as
well as specially filtered air throughout the
floor to protect patients against infection.
Family resource and education areas are
also included in the units.
The new hospital is being financed
through bond sales, clinical revenues, and
private philanthropy, without the use of
state or other public funds.
The University’s two other major
teaching hospitals in the Southwestern
Medical District are Parkland Memorial
Hospital, which is also constructing a new
facility (see sidebar), and Children’s Medical
Center of Dallas. UT Southwestern faculty
and residents provide care to more than
100,000 hospitalized patients and oversee
nearly 2 million outpatient visits each year.
BUILDING PROGRESS
Beginning in 2014, UT Southwestern
faculty will be practicing in another stateof-the-art facility: a new, 862-bed Parkland
Memorial Hospital.
The $1.3 billion project—the largest hospital
construction project in the United States—
replaces the county’s six-decade-old safety
net facility. Parkland is UT Southwestern’s
primary teaching hospital, with university
faculty responsible for most of the patient
care at the facility.
The new Parkland Hospital under construction.
The new Parkland will include 1.7 million
square feet for its acute-care hospital, plus
380,000 square feet in outpatient clinics.
The hospital currently admits about 55,000
patients, and provides more than a half-billion
dollars in uncompensated care annually.
William P. Clements Jr. University Hospital is scheduled to open in late 2014 (artist rendering).
38
39
leadership
experimental therapeutics of cancer
Mapping molecular vulnerabilities of cancer cells, multidisciplinar y teams are
devising new methods to assess patients’ tumors and to select and deliver
potentially lifesaving therapies.
AT A GLANCE
goal
To identify and validate novel targets,
pathways, and therapies for selective tumor
targeting; to establish biomarkers that can
predict tumor response; and to test the
efficacy of resulting potential medicines in
clinical trials.
approaches
David A. Boothman, Ph.D., Professor, Pharmacology and Radiation Oncology
Dr. Boothman, Associate Director for Translational Research within the Simmons Comprehensive
Cancer Center, is a renowned expert on cellular stress responses. His research focuses on DNA
repair pathways and delineating links between RNA transcription termination and nonhomologous
DNA double-strand break end joining. He is also developing novel NQO1 bioactivating drugs for
the treatment of solid cancers, including non–small cell lung, pancreatic, prostate, breast, and head
and neck cancers. He holds the Robert B. and Virginia Payne Professorship in Oncology.
Applying basic knowledge regarding
mechanisms underlying cancer, especially
in the areas of DNA damage and repair, cell
stress responses, and the tumor microenvironment; and providing a platform for
basic researchers, clinical scientists, and,
where appropriate, industry participants to
develop and conduct early clinical trials.
2012 funding
TOTAL: $33 million
National Cancer Institute: $9.5 million
Other National Institutes of Health:
$6.4 million
Cancer Prevention and Research
Institute of Texas: $8.1 million
peer-reviewed
publications
40
2009-2012: 508
A polarized light micrograph of crystals
of estradiol, a form of estrogen.
41
impact
Experimental Therapeutics of Cancer
Program Leader and Professor of Radiation Oncology and Pharmacology David A.
Boothman, Ph.D., has devoted two decades
to unraveling the many chemical steps that
make beta-lapachone lethal in malignant
cells. He and his colleagues are developing practical testing that will show which
cancer patients are likely to benefit from the
treatment. Meanwhile, a longtime collaborator—Cancer Center member and Professor
of Pharmacology Jinming Gao, Ph.D.—is
crafting a cutting-edge delivery vehicle to
ensure the medicine hits its target.
Early on, Dr. Boothman discovered that
beta-lapachone could synergize with radiation, with the two treatments together causing
enough DNA damage to be deadly to tumors,
while leaving normal cells unaffected. But
that’s only one part of a two-fold attack.
Beta-lapachone also perverts a detoxification process performed by NQO1, an
enzyme whose production is cranked into
overdrive in cancer cells. A sort of loop cycle
arises, in which levels of beta-lapachone
remain undiminished despite the enzyme’s
efforts to clean it out. The interaction generates
a flood of reactive oxygen species—free radicals that irreparably damage the cancer cells.
Long and Productive Path
Research into anti-cancer agent
beta-lapachone may be nearing fruition.
Effective cancer treatments don’t just grow on
trees. Promising substances require years of
research to understand their mechanism of
action, whom they will help most, and how to
ensure their effective delivery in patients.
Simmons Cancer Center investigators have made huge strides in bringing one
such potential therapy, a substance extracted
from the South American lapacho tree, from
bark to bedside. The substance, called betalapachone, could have an impact on many
of the most deadly cancers, including lung,
pancreatic, prostate, and breast.
A
B
Mice bearing lung cancers were treated with betalapachone mixed in HPßCD, a compound that aids
solubility (bottom), or with HPßCD alone (top). After
14 days, tumor volumes (dark purple) were reduced
90 percent in the mice receiving beta-lapachone.
Polymeric micelle nanoparticles home in onto solid
tumors for the delivery of beta-lapachone or imaging
nanocrystals for image-guided therapy of cancer
(artist rendering).
Untreated
A
B
Beta-lapachone
“The actual mechanism of death is this back
reaction,” Dr. Boothman explains.
And the cancer cells die an unusual
death, his research has shown. Rather than
perishing by apoptosis (an orderly, genetically programmed self-destruction) or by
necrosis (a bursting of the cell, initiated by
injury), beta-lapachone causes the cells to be
destroyed by “programmed necrosis.”
“It’s sort of a cross between apoptosis
and conventional necrosis,” says Dr. Boothman.
Beta-lapachone is the only potential
treatment ever identified to cause programmed necrosis specifically in cancer cells
that overproduce NQO1, Dr. Boothman adds.
“The advantage is that there is no drug resistance known through this death pathway, and
it doesn’t cause a huge inflammatory reaction,
which can lead to initiation of cancer and
other problems.”
The thwarted detoxification enzyme,
NQO1, is an exciting target for cancer
treatment, says Cancer Center member and
Assistant Professor of Internal Medicine
David Gerber, M.D., who is heading a Phase
I clinical trial of one form of beta-lapachone
in cancer patients.
“A lot of the cancer therapies being
developed work in, say, a subset of kidney
cancers, or a subset of lung cancers, or one type
of leukemia,” Dr. Gerber notes. “But what betalapachone does biologically is something that
could be applicable to a lot of cancer types.”
High NQO1 levels are found in more
than 80 percent of pancreatic cancers, 70
percent of non–small cell lung cancers and
prostate cancers, and 60 percent of breast cancers. Yet healthy cells are comparatively void
of the enzyme, meaning normal tissue would
probably be shielded from ill effects
of treatment.
Dr. Gerber’s trial is testing an injectable
form of beta-lapachone called ARQ 761, developed by the biotechnology company ArQule,
in patients with advanced solid tumors that are
untreatable or treatment-resistant. Although
the central goal is to systematically determine
the medicine’s highest safe dose, the study could
yield important data about how the ArQule
formulation acts in the body and on tumors.
Dr. Boothman’s lab is working with
Dr. Gerber’s team to test tissue from patients’
tumor biopsies for levels of NQO1 and
another enzyme, catalase, which breaks down
toxic hydrogen peroxide into water and
oxygen. The investigators believe the ratio of
NQO1-to-catalase in tumor tissue, compared
with that in normal tissue from the same organ, will predict how effective beta-lapachone
treatment will be.
Meanwhile, Dr. Gao is leading the effort
to develop a nanotechnology platform—a
vehicle on the scale of just billionths of a
meter—to effectively deliver beta-lapachone to
tumors. But the substance poses several challenges. For one thing, by itself beta-lapachone
isn’t readily soluble. And cancer cells need
to be exposed to it for at least two hours to
induce programmed necrosis, Dr. Gao says.
In work supported by nearly $1 million
from the Cancer Prevention and Research
Institute of Texas, Dr. Gao’s lab is addressing
those challenges. He and his colleagues are
creating tiny carriers known as polymeric
micelles, which keep the beta-lapachone stable
and in fighting form as it is delivered directly
to tumor tissue.
Polymeric micelles are a unique type
of nanoparticle, Dr. Gao says. In water
they self-assemble into a core-shell structure with its cores repelled from water—in
this case, the cores are a tangle of polymer
strands impregnated with beta-lapachone—
and a stabilizing outer shell that is drawn to
and soluble in water. The result is a vehicle
that gives beta-lapachone a half-life of 28
hours, allowing it to circulate long enough
to be effective.
Also, by design the micelles are small
enough to leak out from blood vessels in
tumors and accumulate, something they don’t
do in healthy tissue. “This is the unique aspect
of cancer nanotech,” Dr. Gao says. “We can
actually change the pharmacokinetics—how a
medicine circulates, and how it’s distributed.”
So far the micelles have been tested
mainly in animal models of non–small cell
lung cancer. In more than a dozen treated
mice, tumors disappeared and showed no
signs of returning after almost 300 days, Dr.
Boothman says.
The researchers, working with the
biotech startup StemPAR Sciences, believe that
within three years the beta-lapachone micelles
can be optimized for delivery. But of course,
the micelles that would be needed to begin
clinical trials won’t just grow on trees, either.
Instead, plans call for them to be
produced in a state-of-the-art, federally
certified current Good Manufacturing
Practice (cGMP) facility being developed on
the UT Southwestern campus in collaboration with the University of Texas at Dallas.
“This could be a very unique facility,” Dr.
Boothman says of the cGMP Nanoparticle
and Cell Processing Facility, which is expected
to be in operation in 2013. The laboratory
will have sterile manufacturing environments
and standard operating procedures to ensure
consistent output of products, including the
beta-lapachone-laden micelles.
The saga of beta-lapachone illustrates
the decades of work needed to discover,
develop, and produce the next generation
of cancer therapies. “Just having a drug that
works in cell culture is not enough,” Dr. Gao
says. “You have to translate it in the context of
the tumor-bearing animals—an intact physiological system—to evaluate the safety and
antitumor efficacy of the therapy.”
EXPERIMENTAL THERAPEUTICS
OF CANCER
HIGH-IMPACT PUBLICATIONS
Boike TP, Lotan Y, Cho LC, Brindle J, DeRose
P, Xie XJ, Yan J, Foster R, Pistenmaa D, Perkins
A, Cooley S, Timmerman R. Phase I doseescalation study of stereotactic body radiation
therapy for low- and intermediate-risk prostate
cancer. J Clin Oncol 2011;29:2020-2026.
Chang KH, Li R, Papari-Zareei M, Watumull L,
Zhao YD, Auchus RJ, Sharifi N. Dihydrotestosterone synthesis bypasses testosterone to drive
castration-resistant prostate cancer. Proc Natl
Acad Sci USA 2011;108:13728-13733.
Gerber DE, Stopeck AT, Wong L, Rosen LS,
Thorpe PE, Shan JS, Ibrahim NK. Phase I Safety
andPharmacokinetic Study of Bavituximab, a Chimeric Phosphatidylserine-Targeting Monoclonal
Antibody, in Patients with Advanced Solid Tumors.
Clin Cancer Res 2011;17:6888-6896.
Knudsen ES, Pajak TF,Qeenan M, McClendon AK,
Armon BD, Schwartz GF, Witkiewicz AK. Retinoblastoma and phosphate and tensin homolog tumor
suppressors: impact on ductal carcinoma in situ
progression. J Natl Cancer Inst 2012;104:1825-1836.
Li LS, Bey EA, Dong Y, Meng J, Patra B, Yan J,
Xie XJ, Brekken RA, Barnett CC, Bornmann WG,
Gao J, Boothman DA. Modulating endogenous
NQO1 levels identifies key regulatory mechanisms
of action of ß-lapachone for pancreatic cancer
therapy. Clin Cancer Res 2011;17:275-285.
Liu L, Mason RP. Imaging beta-galactosidase
activity in human tumor xenografts and transgenic
mice using a chemiluminescent substrate. PLoS
One 2010;5:e12024.
Naina HV, Levitt D, Vusirikala M, Anderson
LD, Jr., Scaglioni PP, Kirk A, Collins RH Jr.
Successful treatment of relapsed and refractory
extramedullary acute promyelocytic leukemia with
tamibarotene. J Clin Oncol 2011;29:e534-e536.
Rule W, Timmerman R, Tong L, Abdulrahman
R, Meyer J, Boike T, Schwarz RE, Weatherall P,
Chinsoo CL. Phase I dose-escalation study of stereotactic body radiotherapy in patients with hepatic
metastases. Ann Surg Oncol 2011. 18(4):1081-7.
Zhao D, Chang CH, Kim JG, Liu H, Mason RP.
In vivo near-infrared spectroscopy and magnetic
resonance imaging monitoring of tumor response
to combretastatin A-4-phosphate correlated with
therapeutic outcome. Int J Radiat Oncol Biol Phys
2011;80:574-581.
Zhou K, Liu H, Zhang S, Huang X, Wang Y, Huang
G, Sumer BD, Gao J. Multicolored pH-tunable
and activatable fluorescence nanoplatform
responsive to physiologic pH stimuli. J Am Chem
Soc 2012;134:7803-7811.
Boldface denotes Cancer Center members in the
Experimental Therapeutics of Cancer Program;
underline denotes members affiliated with another
42
scientific program within the Cancer Center.
43
impact
NHRs are transcription factors, meaning they
bind to DNA and determine whether the
instructions the DNA contains are enacted.
Different tumors—even when they are
the same kind of cancer—can have different
sets of NHR instruments on stage. Breast
cancers, for instance, might be classified as
estrogen-receptor-positive, meaning there’s
an abundance of these receptors, like a violin
section quite literally on steroids, that engage
in the presence of the female hormone
estrogen. By preventing the hormone from
binding to the receptors, the drug tamoxifen
can help quiet this cancer-promoting din.
Such nuclear receptor profiling in breast
and other cancers, though, is limited—like
listening only for the violin and percussion
A Concerted Approach
Massive project focuses on collective role of
nuclear receptors in lung and breast cancer.
Even the most awful of symphonies is
the product of more than one instrument.
Which instruments play when helps
determine exactly how it sounds.
Similarly, how terrible a cancer is—or
even whether it develops to begin with—can
be a product of many different molecular
instruments. Consider nuclear hormone
receptors (NHRs). Like an auditorium full
of musical instruments waiting for musicians to play them, these proteins sit inside
cancer and other cells, ready for hormones to
activate (or, alternately, mute) them.
Based upon a previously reported genetic signature, messenger RNA expression analysis of the 48 nuclear
receptors in a large panel of lung tumor specimens maintains predictive power for patient outcomes. The green
line represents patients whose NHR signature predicted better outcomes, while the red line represents patients
whose prognostic signature indicated worse outcomes (new analysis by Yang Xie; based on data from Jeong
et al. PLoS Medicine 2010).
B
The genetic knockdown, one-by-one, of each of the 48 nuclear hormone receptors and 72 co-regulators shows
a broad spectrum of responses among 54 individual lung cancer cell lines. Disabling genes for some NHRs or
co-regulators results in general toxicity (right section), while the loss of other genes causes increased growth
(left section). However, some gene knockouts cause differential responses, with toxicity in some cell lines and
growth in others.
20%
40%
60%
80%
N = 151
(Testing FFPE)
P = 0.007
0%
Percentage of patients surviving
A
100%
A
0
2
4
6
8
10
Survival time in years
48 NHRs and 72 co-regulator knockdown targets
Percentage of cell lines
B
Generally cause growth
44
Differential response
Generally toxic
section, rather than the combined sound of
all the instruments.
But NHR expert David Mangelsdorf,
Ph.D., UT Southwestern’s Chair of Pharmacology and member of the Cancer Center’s
Cancer Cell Networks Program, focuses on
the entire orchestra of nuclear receptors—48
in all, along with about 120 relevant genes and
some 100 helpers, or “coregulators.” Different
patterns of collective activity among NHRs
relate to a cancer’s genesis and growth, Dr.
Mangelsdorf has found. Such patterns can
reveal which subtype of non–small cell lung
cancer a patient has, or suggest how long a
patient is likely to survive. In breast cancer,
a more complete picture of NHRs promises,
among other things, to shed light on why
estrogen-receptor-positive tumors don’t
always respond to drugs like tamoxifen.
Medicine’s anti-cancer arsenal is
rife with costly drugs that don’t work well
enough, or don’t work in very many people,
Dr. Mangelsdorf notes. “The problem is
some people respond and some people
don’t,” he says. “The crucial question is,
why?”— and how can physicians ensure
that patients only receive medicines that
are likely to be effective.
More than $2.2 million in funding
from the Cancer Prevention and Research
Institute of Texas (CPRIT) is allowing UT
Southwestern investigators to test a comprehensive strategy using nuclear hormone
receptors in cancer treatment, says Internal
Medicine and Pharmacology Professor John
Minna, M.D. The project leverages a core
strength of the Simmons Cancer Center as
one of the top institutions in the nation for
lung cancer research and treatment. Other
Cancer Center members collaborating on
the research include Professor of Molecular
Biology and Pharmacology Steven Kliewer,
Ph.D., and Assistant Professor of Pharmacology Ralf Kittler, Ph.D., in the Eugene
McDermott Center for Human Growth
and Development.
A breast cancer arm of the project is
headed by Suzanne Fuqua, Ph.D., and Bert
O’Malley, M.D., at Baylor College of Medicine
in Houston; also collaborating in the work
is Ignacio Wistuba, M.D., at the UT MD
Anderson Cancer Center. The research’s aim
is to sample a patient’s tumor; generate a comprehensive profile, or “signature,” of nuclear
receptor–related activity; and select the most
effective treatments based on the findings.
“Our whole goal within the next two
years is to be able to move this into clinical
trials,” says Dr. Minna, Co-Leader of the
Cancer Center’s Lung Cancer Program.
The project—which also receives
support from the National Institutes of
Health, the Howard Hughes Medical
Institute and the Welch Foundation—is
massive: Researchers are characterizing the
activity of the four dozen NHRs, and their
accompanists, in 500 lung and 500 breast
tumor samples collected from patients
over the past decade. For each tumor
sample, researchers have an extensive set
of clinical notations about the patient’s
cancer, prognosis, treatment and response,
as well as other details that will help shed
light on which treatments worked best for
which tumors.
“It’s as robust a clinical picture as any
patient would have,” Dr. Minna says.
Preclinical work has shown that about
10 percent of lung and of breast tumors have
an abundance of NHRs that are cued into
action by the hormone vitamin D. “The question is, should you antagonize the vitamin D
receptor or agonize it—stimulate it or block
it?” Dr. Minna says. Using mice with human breast or lung tumors implanted under
their skin, and mice genetically engineered
to develop one of those cancers, researchers profiled tumors for their expression of
the vitamin D receptor and then selectively
tested hormonal treatments. “It turns out you
should stimulate the receptor—then growth
of the cancers that express the vitamin D
receptor is inhibited, and they will die.”
Deciphering NHR expression patterns is also likely to improve doctors’ ability
to predict how aggressive a cancer is, Dr.
Mangelsdorf says, noting that the goal of any
such cancer biomarker is to diagnose and
characterize a tumor early, to improve treatment at that crucial juncture. “As a biomarker
for prognosis, we want to move this into the
clinic as fast as possible. We already believe
it’s going to work,” he says.
NHR signatures might even distinguish
whether a patient suspected of having lung
cancer actually does—or is about to. For example, a former smoker might suspect cancer
is present, but testing is inconclusive, and in
any case wouldn’t identify a cancer that is
newly developing, Dr. Mangelsdorf says. “We
have seen that the nuclear hormone receptor
signature can actually predict whether a person is going to get cancer or not,” he says. “If
you have a signature, you can start treating.”
Compared with other biomarkers of
tumors that might guide therapy, NHRs
offer several advantages. For starters, scientists have decades of research explaining
how nuclear receptors work. Also, medicines that act on them are already in use
and have an established safety record. And
by targeting specific characteristics of tumor
cells, these hormonal treatments are likely
to be less toxic than traditional chemotherapy, which uses a scattershot approach.
Combining such treatments could generate
a synergistic effect that allows for lower doses
of hard-to-tolerate chemotherapies, Dr.
Mangelsdorf adds.
The researchers have dubbed their
approach “theragnostics”—an umbrella
term covering NHRs’ potential to aid cancer
diagnosis, increase prognostic accuracy, and
improve therapeutic strategies. “We want to be
able to tell you what type of cancer you have,
how long you’re going to live, how aggressive it’s going to be, and how to treat you,” Dr.
Mangelsdorf says. “That’s what a biomarker is
supposed to do.”
45
Feature: SABR
SABR one day might be able
to take the place of surgery for
certain indications, says lung
cancer researcher and Simmons Cancer Center Deputy
Director Joan Schiller, M.D. “By
USINGTECHNIQUESTHATFOCUS
the radiation on the tumor with
pinpoint accuracy, one can
deliver much higher doses
of radiation than one would
usually be able to, and without
injuring surrounding tissues
and organs,” she says. “More
radiation means more killing of
cancer cells.”
TACTICIANS AND CLINICIANS
Te a m o f e x p e r t s d e v i s e s n e w s t r a t e g i e s t o d e l i v e r
c u t t i n g - e d g e s t e r e o t a c t i c a b l a t i v e r a d i o t h e r a p y ( “ S A B R ” ).
Approaching a problem like cancer from all sides can yield major treatment advances. That’s the idea, literally, behind steREOTACTICRADIATIONTHERAPYINWHICHHIGHLYFOCUSEDBEAMSOFRADIATIONARElREDFROMNUMEROUSANGLESATATUMORTARGETs
Now researchers and clinicians at Simmons Cancer Center are taking even that multidirectional approach in entirely new directions. Cancer Center experts have helped to move stereotactic radiotherapy, initially used only in the brain, into the body.
The scientists have already achieved success against cancers in patients who otherwise would be difficult to treat effectively.
Now, Simmons researchers are testing stereotactic ablative radiotherapy, or SABR, head-to-head against well-established
TREATMENTSs#OMPAREDWITHCONVENTIONALRADIATIONTHERAPYAKEYADVANTAGEOF3!"2ALSOKNOWNASSTEREOTACTICBODY
radiation therapy, or SBRT) is that numerous, individually less-potent beams of radiation travel through different areas of
EXPANDING IMPACT
HEALTHYTISSUECAUSINGMINIMALHARMTHEREASTHEYCONVERGEONATUMORCONFORMINGTOITSSHAPEANDCOLLECTIVELYINmICTING
dramatic damage. SABR is administered on an outpatient basis in five or fewer strong treatments—instead of the many
WEAKERONESTHATAREDELIVEREDWITHCONVENTIONALRADIATIONOVERTHECOURSEOFWEEKSORMONTHSs&OR3!"2PRECISIONIS
vital at every step. A targeted tumor is first carefully imaged and studied. A team with expertise in radiology, surgery, oncology, and physics develops a detailed treatment plan, including how many sessions of SABR will be needed, how the patient
will be positioned, and the radiation doses and angles of approach that a cutting-edge instrument like the CyberKnife will
USE$URINGTHETREATMENTASQUADOFEXPERTSˆPOSITIONEDINFRONTOFABANKOFCOMPUTERANDVIDEOSCREENSˆMONITORS
scrutinizes, and verifies every action and decision.
Associate Professor of Radiation Oncology
Lucien Nedzi, M.D. (right), and Stella Stevenson,
BSRT(T), assist a patient at Annette Simmons
Stereotactic Center at Zale Lipshy
University Hospital.
46
Stereotactic radiation was
first used in the brain more
than four decades ago, simply
because that organ, which sits
relatively still, was easiest to
image and target, says Robert
Timmerman, M.D., Professor
of Radiation Oncology and a
leader in the development of
SABR. “In the body there’s
so much deformation and
movement, you would have
missed,” he says. But a series
of innovations beginning in
the 1990s—many pioneered
at UT Southwestern—have
made possible the necessary
precision for a stereotactic
approach in the body.
SABR research at the University focused initially on lung
tumors, and the short-course,
high-dose therapy has worked
surprisingly well, Dr. Timmerman says. “Tumors appeared
to be very well controlled,
much better than with conventional radiation—and the
toxicity was much less than
with conventional radiation.”
A striking success has
been with early-stage lung
cancer patients who are too
frail to undergo surgery. In
Phase II testing of SABR in
this population, Simmons
Cancer Center researchers
found primary tumor control
rates—meaning elimination
of the initial tumor—of 98
percent, compared with between 30 and 40 percent reported for usual treatments.
Three-year survival was 60
percent, compared with 30
percent for the standard of
care. Of the patients who
did not survive, many died of
other causes, such as emphysema or cardiovascular
disease rather than cancer,
Dr. Timmerman notes.
“That was a big deal, to
double the survival of patients
who had very poor odds,”
he says. The research was
highlighted in a special
cancer-themed issue of The
Journal of the American
Medical Association in March
2010, and was listed by the
American Society of Clinical
Oncology as one of the key
accomplishments in cancer
therapy for the year.
“It would have been
unheard of 10 years ago to
think that surgery would have
been challenged by another
therapy,” Dr. Timmerman says.
Phase III trials in this
patient population are under
way. The goal is to enroll 400
patients. Kemp Kernstine,
M.D., Ph.D., Chair of Thoracic Surgery, and Michael
DiMaio, M.D., Professor of
Thoracic Surgery, are leading
the trial at UT Southwestern, which offers operable
patients with co-existing
MEDICALPROBLEMSUNIQUE
options between SABR and
minimally invasive surgery.
With more than $2.3 million
in funding from the Cancer
Prevention and Research
Institute of Texas (CPRIT),
Simmons scientists are
also developing a high-tech
treatment approach that is a
hybrid of SABR and conventional radiation, aimed at
patients with more advanced
lung cancers—in stages 2
and 3. The goal is not just
to reduce tumor size, but to
improve survival.
Like SABR, this treatment provides more potent
doses of radiation in fewer
sessions—15 instead of
33—but not as few as with
SABR. The study incorporates the latest image
GUIDANCETECHNIQUESASWELL
as motion tracking technology to account for normal
and irregular respiration and
other movement, and highly
conformal dosimetry, which
ensures the dose distribution
matches the tumor’s shape.
Patients throughout Texas
stand to benefit. A program
has been established at St.
Paul University Hospital to
train health care providers
from research sites across the
state to deliver the therapy.
“We’re sort of giving away our
secrets, but we want them to
be mainstreamed. This has
always been our goal,” Dr.
Timmerman says.
Robert Timmerman, M.D.,
Professor, Radiation Oncology
A separate, $4.1 million
grant from CPRIT is tapping
the Cancer Center’s expertise in the biological effects
of radiation—aiming to make
tumor cells more vulnerable
by impeding their ability to
repair genetic damage caused
by radiotherapy. “We hope to
manipulate the radiation sensitivity of the lung tumor cells so
that a similar efficacy can be
reached with a lower dose per
fraction or lower total dose. By
doing this, we could reduce
normal tissue damage,”
47
Hak Choy, M.D., Chair,
Department of Radiation Oncology
says Professor of Radiation
Oncology David Chen, Ph.D.
Collaborators include Professor of Pharmacology Phil
Thorpe, Ph.D., and Professor
of Radiology Ralph Mason,
Ph.D., both members of the
Experimental Therapeutics of
Cancer program.
The investigators are examining whether tumors that
resist radiation because they
are highly hypoxic, or able to
withstand oxygen deprivaTIONCANBEVANQUISHEDBY
SABR’s escalated radiation
doses, Dr. Chen says. The
research will also explore
whether a therapy called
bavituximab, which thwarts
development of blood vessels that nourish a tumor,
can synergize with SABR
and increase the cancer’s
vulnerability to treatment.
Another part of the project
incorporates sophisticated
technology to test stereotactic radiation in small-animal
models of lung cancer.
A BROADER ASSAULT
SABR is also under development to fight tumors that
arise in the liver from cancers
originating at other sites,
commonly the colon or breast.
These liver metastases greatly
threaten a patient’s survival,
and while surgery to remove
them often helps, Simmons
scientists hope SABR will provide another treatment option.
Phase I research—a
collaboration that included
Assistant Professor of Radiation Oncology Jeffrey Meyer,
M.D., and Roderich Schwarz,
M.D., Ph.D., and involved
more than 100 patients—has
shown that high-dose SABR
has a 90 percent probability
of eliminating liver metastases using a five-treatment
regimen. That research was
published in April 2011 in
Annals of Surgical Oncology.
Current work aims to refine
this localized therapy so it
can be given in a single treatment, something that will
be easier to integrate with
other approaches that attack
the cancer systemically, or
throughout the body, such
as chemotherapy.
Meanwhile, a slate of new
research projects is using SABR
to take on metastases in lung,
breast, kidney, prostate, and
gynecological cancers. This
broad assault taps the expertise of collaborators who focus
on these specific cancers,
including Assistant Professor of
Internal Medicine David Gerber,
-$0ROFESSOROF)NTERNAL
-EDICINE"ARBARA(ALEY-$
Assistant Professor of Internal
Medicine James Brugarolas,
M.D., Ph.D., Co-Leader of
Dan Garwood, M.D., Associate Professor of Radiation Oncology, consults with a patient in the W.A. Monty and Tex Moncrief Radiation Oncology Building.
48
the Cancer Cell Networks
PROGRAM0ROFESSOROF5ROLOGY
9AIR,OTAN-$AND!SSOCIate Professor of Obstetrics
and Gynecology Jayanthi Lea,
-$PLUSIMMUNOLOGIST%LLEN
Vitetta, Ph.D., Professor in
the Cancer Immunobiology
Center. Early results show that
the protocol for metastatic
lung cancer, for instance, has
yielded a median progressionfree survival of 20 months—
meaning that half the patients
survived at least that long
without their tumors growing.
That compares with a figure
of just two or three months
using conventional treatments. “This is very exciting
work,” Dr. Timmerman says.
CREATING NEW OPTIONS
Simmons researchers are
also developing SABR as an
adjuvant treatment for earlystage breast tumors. A new
Phase I trial that has been accruing patients rapidly (30 so
far at UT Southwestern), and
which will be conducted in
partnership with Stanford
University and Fox Chase
Cancer Center, aims to
determine the optimal dosing
strategy. According to Dan
Garwood, M.D., Associate
Professor of Radiation Oncology, this trial is the first of its
kind in this population.
After breast-conserving
surgery, radiation traditionally has been given five days
a week for 6.5 weeks. But
researchers have learned
that the key aspect of such
treatment is the radiation that
is delivered right to the tissue
where the tumor was growing, says Professor of Surgical
Oncology David Euhus, M.D.,
the Cancer Center’s Associate
Director for Clinical Research.
“Dr. Garwood is now using the
CyberKnife for that very accurate targeting,” he says, adding
that this approach is less
disfiguring and more convenient than other very targeted
TECHNIQUESh3ELECTEDBREAST
cancer patients here can go
on the CyberKnife trial and
get their radiation once a day
for five days.”
Overall, strides made in
improving SABR and expanding its use have relied not just
on surgical and radiotherapy
expertise, but broad partnerships across UT Southwestern, says Dr. Timmerman.
Precision, teamwork, and
the use of carefully designed
approaches are all essential
elements to success. With
those, “you can pull off these
potentially dangerous treatments and make them safe,”
he says. “It’s really a collaborative effort.”
Perfexion Gamma Knife at Annette Simmons Stereotactic Center at Zale Lipshy University Hospital is currently
the only one of its kind in North Texas.
49
leadership
lung cancer
Targeting the second-leading cause of death in the U.S., the new Lung Cancer
Program is shedding light on the molecular intricacies of tumors and developing
new strategies to treat patients.
AT A GLANCE
goal
To identify lung cancer biomarkers that
can aid screening and early diagnosis; to
identify, develop, and test new targeted
therapies based on molecular characterization of individual tumors; and to study
mechanisms of drug resistance.
approaches
To use risk biomarkers and other data
to develop personalized strategies for
lung cancer screening and prevention;
and to use tumor molecular biomarkers
and drugs-in-development associated
with those biomarkers to set the stage
for early-phase clinical trials as well as
highly personalized lung cancer therapies in the clinic.
2012 funding
TOTAL: $9.7 million
National Cancer Institute: $2.8 million
Cancer Prevention and Research
Institute of Texas: $2.1 million
peer-reviewed
publications
John D. Minna, M.D., Professor, Internal Medicine
Joan Schiller, M.D., Professor, Internal Medicine,
and Pharmacology
and Chief, Hematology/Oncology
Dr. Minna is well-known for his study of the
molecular processes that contribute to the genesis of lung cancer and for his research translating basic laboratory findings into clinical
applications. He is principal investigator for the
National Cancer Institute’s Specialized Project
of Research Excellence (SPORE) in lung cancer,
leading the joint UT Southwestern and M.D.
Anderson Cancer Center SPORE for more than
a decade. Dr. Minna is Director of the Nancy B.
and Jake L. Hamon Center for Therapeutic Oncology Research, and Director of the W.A. “Tex”
and Deborah Moncrief Jr. Center for Cancer
Genetics. He holds the Sarah M. and Charles E.
Seay Distinguished Chair in Cancer Research
and the Max L. Thomas Distinguished Chair in
Molecular Pulmonary Oncology.
Dr. Schiller is internationally recognized for
her work related to the diagnosis and treatment
of lung cancer. Her research interests include
small-cell and non–small cell lung cancer,
experimental therapeutics, drug development,
and clinical trials. She is associate editor for
the Journal of Clinical Oncology, former board
member of the International Association for
the Study of Lung Cancer (IASLC), and founder
and president of the National Lung Cancer
Partnership. She holds the Andrea L. Simmons
Distinguished Chair in Cancer Research.
Colored X-ray of the chest of a patient
with small-cell lung cancer.
2012: 51
50
51
impact
Waging an All-Out War
In launching the new Lung Cancer Program,
investigators draw ambitious battle lines.
Military strategists point to a handful of principles
as essential to victory: Know your enemy; identify
vulnerabilities; choose your weapons well.
Simmons Cancer Center investigators—
veterans of the research war on lung cancer—are
applying the same fundamentals as they launch a
new scientific program aimed at conquering the
nation’s deadliest malignancy.
The new program’s attack plan relies on extensive reconnaissance: to find biological markers
that will aid early detection of lung cancer, and to
identify specific genetic vulnerabilities in each
A
B
Professor of Biochemistry Michael Roth, Ph.D.,
a member of the Chemistry and Cancer Program,
is collaborating with colleagues to wage a war on
lung cancer.
Bruce Posner, Ph.D., Associate Professor of
Biochemstry, oversees the High-Throughput
Screening Resource.
A
52
tumor that will serve as Achilles’ heels for carefully selected therapeutic arrows. Armed with such
information, program members will test new,
targeted weapons and ultimately provide patients
in the clinic with the latest, highly personalized
treatments available.
While the Lung Cancer Program is the first
scientific program at Simmons to target a specific
cancer, it builds on a multitude of forces already
on the march. Crucial among those are the Cancer
Center’s strength in conducting Phase I, II and
III clinical trials, both investigator-initiated and
through national cooperative groups; a breadth
and depth in basic, translational, and clinical
science; and a host of scientific collaborations that
tap UT Southwestern expertise in chemistry, development, epidemiology, cell biology, molecular
medicine, and more.
The new program’s team includes widely
renowned lung cancer investigators, medical
oncologists, surgeons, radiation oncologists, and
basic scientists. “Lung cancer research has always
been such a major strength here,” says Cancer
Center Deputy Director Joan Schiller, M.D.,
Chief of Hematology/Oncology and Co-Leader
of the new program. “As we’ve gotten stronger
and stronger, we realized it could become its own
stand-alone program.” As such, it joins just a few
other lung cancer programs at National Cancer
Institute–designated centers across the U.S.
Growth in the realm of clinical medicine
is another key asset for the program. Longtime
smokers who are patients at the Cancer Center
can benefit from the newest type of imaging,
spiral CT scans, for early lung cancer detection. Robotic, minimally invasive surgery
for lung tumors can greatly reduce pain and
shorten post-operative hospital stays to just a
day or two. And the Cancer Center’s radiation
oncology expertise is allowing many patients’
tumors to be treated with the latest technology
to administer more powerful radiation doses,
even as side effects are lessened.
The Research Front
Underpinning the new scientific program
is UT Southwestern’s longtime lung cancer
Specialized Program of Research Excellence
(SPORE), a translational-research–focused
initiative supported by the NCI. SPORE designation requires state-of-the-art research in a wide
spectrum of lung cancer topics, pioneering efforts
in how research is conducted, and collaborations
across institutions. (UT Southwestern’s program,
first funded in 1996, is a collaboration with the
UT MD Anderson Cancer Center in Houston.)
Also, as a member of the Lung Cancer
Mutation Consortium, Simmons Cancer Center and the new lung program are helping to
lead the charge nationally to personalize lung
cancer treatment.
The consortium, a high-profile alliance
of 16 top academic cancer centers and hospitals
across the U.S., is working to match lung cancer
patients to therapies based on characterization
of genetic mutations in each individuals’ tumors.
The key goals, Dr. Schiller says, are to learn all the
types of mutations that occur (and how frequent
they are) in non–small cell lung cancer, and to
determine through clinical trials whether patients
given drugs to target those mutations will fare
better than they would with standard treatments.
The consortium effort at UT Southwestern relies on the work of Professor of Pathology
Prasad Koduru, Ph.D., and Associate Professor
of Pathology Dwight Oliver, M.D., who have
been developing a molecular pathology lab that
will accommodate analyses for more and more
mutations. So far the lab is set up to analyze a
panel of 15 genes in non–small cell lung cancer.
Mutations in two of the genes on the panel can
be targeted by medicines that are now commercially available, while clinical studies are under
way at UT Southwestern or other sites to test
drugs targeting mutations in several of the
other genes.
Meanwhile, a host of other trials, attacking
lung cancer on a variety of fronts, are ongoing at
within the new scientific program. Prominent
among them is Phase III testing of stereotactic ablative radiotherapy (SABR, also known as SBRT),
a radiation technique pioneered at UT Southwestern, in patients who have early-stage lung
tumors but are too frail to undergo surgery. Phase
II results indicated the cutting-edge radiotherapy
doubled patients’ odds of surviving three years,
compared with standard treatment. Lung Cancer
Program investigators are also working to develop
a hybrid form of SABR and conventional radiation treatment for patients with more advanced
lung cancers (story on Page 46).
Another clinical trial at UT Southwestern
is targeting a common mutation in non–small
cell lung cancer. The trial, led by Experimental
Therapeutics of Cancer Program member and
Assistant Professor of Internal Medicine David
Gerber, M.D., is testing a type of drug called a
focal adhesion kinase, or FAK, inhibitor. Known
as VS-6063, the drug is an oral medicine targeting
a cancer-promoting mutation in a gene called
KRAS. KRAS mutations occur in up to 30 percent
of lung adenocarcinomas, a subtype of non–small
cell lung cancer, and are associated with poor
patient prognosis, insensitivity to post-surgery
chemotherapy, and resistance to a major class of
lung cancer therapies known as EGFR inhibitors.
Research led by Assistant Professor of Internal
Medicine Pier Paolo Scaglioni, M.D., a member of the Cancer Cell Networks program, in a
mouse model of lung cancer has shown that FAK
inhibitors can effectively treat tumors with KRAS
mutations and prolong survival, yet aren’t effective
in tumors without the mutation.
Battle Royal
Amid UT Southwestern’s war on lung
cancer, the mother of all molecular battles—a
five-year, $13.7 million effort—is raging. The
project aims to identify the various genetic forms
in which non–small cell lung cancer occurs;
what vulnerabilities exist in each of those forms;
how best to attack them, through the development of new medicines; and which patients will
benefit most.
“Each of these lung cancers will have
certain weaknesses that they won’t share with
normal cells and they won’t share with most other
cancers,” says one of the key collaborators on the
project, Professor of Biochemistry Michael Roth,
Ph.D., a member of the Chemistry and Cancer
Scientific Program. “If we can find those, then the
medicines we use should not only work better on
the cancer, but do less harm to the patient.”
The project builds on more than 30 years
of research by Professor of Internal Medicine and
Pharmacology John Minna, M.D., that has been
dedicated to distinguishing differences in lung cancers’ molecular characteristics. Any of a number of
genetic mutations, or deviations in the composition
of DNA molecules, can be crucial in driving normal cells to become cancerous.“What we’re looking
for are actionable mutations—mutations that, when
we find them, would direct what the therapy would
be,” says Dr. Minna, Co-Leader of the new Lung
Cancer Program.
This massive lung cancer drug discovery
project—funded by a series of grants from CPRIT
(Cancer Prevention and Research Institute of
Texas) and led by Chemistry and Cancer Program
Co-Leader Steven McKnight, Ph.D., Chair of Biochemistry—engages multiple forces from Simmons
Cancer Center as well as from the UT M.D. Anderson Cancer Center, UT Austin, Baylor College of
Medicine, and Columbia University. Foundational
studies to test the researchers’ approach were supported by research funds from the NCI.
At UT Southwestern, Dr. Minna is spearheading efforts to scout out previously unknown
molecular flags, or biomarkers, that signal potential
vulnerabilities specific to each of the various
non–small cell lung cancers. Associate Professor of Biochemistry Bruce Posner, Ph.D., oversees the High-Throughput Screening Resource that
is informing researchers about those vulnerabilities
as well as about biological and chemical weapons
that can exploit them.
LUNG CANCER
HIGH-IMPACT PUBLICATIONS
Cancer Target Discovery and Development Network,
Schreiber SL, Shamji AF, Clemons PA, Hon C,
Koehler AN, Munoz B, Palmer M, Stern AM, Wagner
BK, Powers S, Lowe SW, Guo X, Krasnitz A, Sawey
ET, Sordella R, Stein L, Trotman LC, Califano A,
Dalla-Favera R, Ferrando A, Iavarone A, Pasqualucci
L, Silva J, Stockwell BR, Hahn WC, Chin L, DePinho
RA, Boehm JS, Gopal S, Huang A, Root DE, Weir
BA, Gerhard DS, Zenklusen JC, Roth MG, White
MA, Minna JD, MacMillan JB, Posner BA.
Towards patient-based cancer therapeutics. Nat
Biotechnol 2010;28:904-906.
Gazdar AF, Girard L, Lockwood WW, Lam WL,
Minna JD. Lung cancer cell lines as tools for
biomedical discovery and research. J Natl Cancer
Inst 2010;102:1310-1321.
Gerber DE, Minna JD. ALK inhibition for nonsmall-cell lung cancer: from discovery to therapy
in record time. Cancer Cell 2010;18:548-551.
Hoang T, Dahlberg SE, Schiller JH, Mehta
MP, Fitzgerald TJ, Belinsky SA, Johnson DH.
Randomized phase III study of thoracic radiation
in combination with paclitaxel and carboplatin with
or without thalidomide in patients with stage III
non-small-cell lung cancer: the ECOG 3598 study.
J Clin Oncol 2012;30:616-622.
Jeong Y, Xie Y, Lee W, Bookout AL, Girard L,
Raso G, Behrens C, Wistuba II, Gadzar AF,
Minna JD, Mangelsdorf DJ. Research resource:
Diagnostic and therapeutic potential of nuclear
receptor expression in lung cancer. Mol Endocrinol
2012;26:1443-1454.
Sequist LV, von Pawel J, Garney EG, Akeley WL,
Brugger W, Ferrari D, Chen Y, Costa DB, Gerber
DE, Orlov S, Ramlau R, Arthur S, Gorbachewsky
I, Schwartz B, Schiller JH. Randomized phase
II study of erlotinib plus tivantinib versus erlotinib
plus placebo in previously treated non-small-cell
lung cancer. J Clin Oncol 2011;29:3307-3315.
Shay JW, Reddel RR, Wright WE. Cancer.
Cancer and telomeres--an ALTernative to telomerase.
B
Science 2012;336:1388-1390.
Timmerman R, Paulus R, Galvin J, Michalski J,
Straube W, Bradley J, Fairis A, Bezjak A, Videtic G,
Johnstone D, Fowler J, Gore E, Choy H. Stereotactic body radiation therapy for inoperable early
stage lung cancer. JAMA 2010;303:1070-1076.
Xie Y, Minna JD. A lung cancer molecular
prognostic test ready for prime time. Lancet
2012;379:785-787.
(Continued on page 55)
53
impact
Professor of Cell Biology Michael White, Ph.D.,
the Cancer Center’s Associate Director for Basic
Science, is overseeing intelligence about the cells’
molecular variations in order to predict where
and how potential “smart bomb” medicines are
likely to work. Professor of Biochemistry Joseph
Ready, Ph.D., and Associate Professor of Biochemistry Noelle Williams, Ph.D., are leading
efforts, respectively, to perfect the most promising of those medicinal weapons and to test them
against cancer in animals.
“One thing is certain that will come out
of this project,” says Dr. Roth, Interim Dean of
UT Southwestern’s Graduate School of Biomedical
Sciences, “we’re going to learn lots of new things
about cancer.”
A
A selection of the large team of clinicians
and researchers focused on lung cancer.
B
Sharon Woodruff, ANP-C, is the patient coordinator
for lung cancer.
Getting to Know the Enemies
Central to the drug discovery project is
a set of 108 lung cancer cell lines collected and
maintained by Dr. Minna and Adi Gazdar, M.D.,
Professor of Pathology in UT Southwestern’s
Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research. Each line, derived
from a different patient’s cancer, is accompanied
by a tumor sample plus information on how the
person was treated and the outcome. As part of
the university’s lung cancer SPORE, researchers
had already analyzed those, along with normal,
cell lines to create profiles capturing every gene’s
expression, or level of activity, in the cells.
As lung tissue develops from normal to
cancerous, hundreds of mutations in genetic
coding can arise, notes Dr. White, a member of
the Cancer Cell Networks Program. Moreover,
these mutations can differ widely from tumor to
tumor. But only a few of them matter. “The rest
are just noise,” he says.
Homing in on about 100 genes considered significant, the researchers have looked
for mutations that the different malignant cell
lines had in common. This allowed development
of a preliminary framework of cell line “families” showing which lines appeared related and
which were very different, based on their gene
mutation and expression patterns. Within the
families, mutations in cancer-related genes, or
oncogenes, were similarly frequent.
Additional, far-reaching testing is beginning to clarify the family groupings. “At the end
of the day we can put these lines into families
where the members of each are all sensitive to
the same compounds and targets but insensitive
to others,” Dr. White says. That allows researchers to look for a specific molecular trait, or biomarker, that can define membership for the cell
lines in one family but no other—and ultimately
can steer doctors to effective treatments.
Identifying Vulnerabilities
Massive resources—which, due to the
march of technology, are now less expensive,
faster and more accurate than even just a few
years ago—are being deployed to test the cancer
cell lines for specific weaknesses. Based on the
preliminary groupings, the researchers tested a
few cell lines representing each family against two
libraries of small interfering RNAs—molecules
that each sabotage a single gene—in a process
known as high-throughput screening. The results
highlight which among the thousands of human
A
genes are essential gear for the different cell lines
to survive.
If non–small cell lung cancer is a highly
variegated disease—or, as Dr. White puts it,
comes in many “flavors”—then disabling one
gene at a time, to see which can kill the cancerous cells, would reveal that the different cell lines
have very few vulnerable genes in common.
“And that’s exactly what happened,” he says.
“That’s a gut-wrenching observation,
that the majority of genes we [knocked out]
had absolutely no effect on the majority of cell
lines we tested them in. The cell lines were
very idiosyncratic.”
In another type of high-throughput
screen, about 200,000 synthetic compounds,
along with 20,000 natural products from the
laboratory of Chemistry and Cancer Program
member John MacMillan, Ph.D., Assistant
Professor of Biochemistry, were also tested,
one by one, against each of the representative cancer cell lines to see which compounds
could kill members of one family grouping,
but were less toxic against the other cell lines
and normal cells.
From the screening, researchers have
identified about 300 drug-like compounds that
can kill specific lung cancer cell lines, as well as
a like number of genes that, when knocked out,
will cause the cells’ demise.
“Presumably the nature of these genes is
telling us something about the mechanism of
action of these compounds,” Dr. White says.
Compounds that selectively kill members of
the same cell line family are probably targeting
a specific set of genetic mutations—although
the picture would be complicated if more than
one mechanism of action is responsible for the
cells’ death.
To help ensure the correct mechanism
of action is attributed to specific compounds,
the team has identified a set of just eight
marker genes whose expression can readily be
measured before and after a gene is disabled or
a chemical compound is used to treat the cells.
If those marker genes yield the same results
in both types of tests, researchers have good
reason to believe the chemical is affecting the
suspected target. “That’s turning out to be very
efficient to measure the mechanism of action of
the compounds we’re isolating in these screens,”
says Dr. White.
The CPRIT funding is enabling more
extensive analysis to pinpoint cancer cell biomarkers, definitively sort many more cell lines
into families, determine which genes promote
cancer growth and survival in each grouping,
and to learn which chemical compounds are
most promising for killing the members of each
family. Like converging divisions of an army on
the move, other research will simultaneously
seek to develop those promising chemicals into
practical pharmacologic weapons that are more
potent, tolerable, and accessible to the body; to
begin testing them against cancers in animals;
and to learn how to identify patients in the
clinic whose tumors might be quelled by one of
these emerging therapies.
“Linking the mutation state to the disease
is the key for being able to rapidly, practically,
and cheaply identify what class of disease a
tumor belongs to, and what medicine will work,”
Dr. Roth says.
Such comprehensive, innovative research
promises to distinguish the Cancer Center’s new
Lung Cancer Program as a pace-setter among its
peers. Says Dr. Schiller: “This is on the leading
edge of how cancer research is done.”
LUNG CANCER
HIGH-IMPACT PUBLICATIONS
(Continued from page 53)
Xie Y, Xiao G, Coombes KR, Behrens C, Solis
LM, Raso G, Girard L, Erckson HS, Roth J,
Heymach JF, Moran C, Danenberg K, Minna JD,
Wistuba II. Robust gene expression signature
from formalin-fixed paraffin-embedded samples
predictsprognosis of non-small-cell lung cancer
patients. Clin Cancer Res 2011;17:5705-5714.
Boldface denotes Cancer Center members in
the Lung Cancer Program; underline denotes
members affiliated with another scientific program
within the Cancer Center.
B
LUNG CANCER TEAM
From left to right:
SHARON WOODRUFF, ANP-C,
Patient Coordinator
DAVID GERBER, M.D.,
Assistant Professor, Internal Medicine
KEMP KERNSTINE, M.D., PH.D.,
Professor and Chair, Thoracic
Surgery
MICHAEL DIMAIO, M.D.,
Professor, Cardiovascular and
Thoracic Surgery
JONATHAN DOWELL, M.D.,
Associate Professor, Internal Medicine
RANDALL HUGHES, M.D.,
Associate Professor, Internal Medicine
54
MUHANNED ABU-HIJLEH, M.D.,
Associate Professor, Internal Medicine
JOAN SCHILLER, M.D.,
Professor and Chief, Internal
Medicine/Hematology-Oncology
ADI GAZDAR, M.D.,
Professor, Pathology
HAK CHOY, M.D.,
Professor and Chair,
Radiation Oncology
JOHN MINNA, M.D.,
Professor, Internal Medicine
and Pharmacology
PUNEETH IYENGAR, M.D., PH.D.,
Assistant Professor, Radiation Oncology
ROBERT TIMMERMAN, M.D.,
Professor, Radiation Oncology
and Neurological Surgery
JYOTI BALANI, M.D.,
Assistant Professor, Pathology
THOMAS CHIU, M.D.,
Assistant Professor,
Internal Medicine
GENE EWING, M.D.,
Professor, Pathology
CECELIA BREWINGTON, M.D.,
Professor, Radiology
55
Feature: HEPATOCELLULAR CANCER
The vast majority of HCC patients have underlying cirrhosis,
a severe scarring of the liver.
Cirrhosis can result from chronic
hepatitis C or B infection, alcoholism, or advanced nonalcoholic
fatty liver disease, says Assistant
Professor of Surgery Adam
Yopp, M.D., also a member of
the Population Science Program. Between 2 percent and 8
percent of patients with cirrhosis
develop HCC each year, Dr.
Yopp says. “If you live 20 years
with cirrhosis, you have about
a 40 percent risk of developing
hepatocellular carcinoma.”
In a chronic hepatitis C infecTIONINmAMMATIONMAYSILENTLY
simmer for decades before
liver function falters enough for
doctors to notice the virus or
the scarring it has caused. An
estimated 3.2 million Americans have chronic hepatitis C.
“Once you have these hepatitis
cases that have progressed to
cause significant liver scarring
or fibrosis, those patients are at
the highest risk of developing
liver cancer,” says Professor of
Internal Medicine Jorge Marrero,
M.D., M.S.
Risk factors for hepatitis C
have subsided in recent years,
signaling that eventually the
epidemic will wane. But a new
epidemic that poses a huge risk
to the liver—obesity—is fast on
the rise. Like heavy alcohol use,
obesity has been strongly linked
CRITICAL MASSES
Diagnosis and treatment challenges, combined with local
demographics, make liver cancer a priority for progress.
Compared with more common cancers like breast or prostate, liver cancer doesn’t get a lot of press. And the possibility of
ITARISINGINVULNERABLEPATIENTSDOESNTGETENOUGHATTENTIONFROMMANYDOCTORSs3IMMONS#OMPREHENSIVE#ANCER#ENTER
scientists are working to change that. They are unraveling the reasons that high-risk patients often aren’t monitored for
cancer development and are devising ways to prompt physicians to keep a closer eye when predisposing liver conditions
AREPRESENTs3IMMONSRESEARCHERSALSOAREINVESTIGATINGNEWPOTENTIALBIOLOGICALMARKERSTHATMIGHTSIGNALTHEPRESENCEOF
liver cancer earlier than current surveillance tests, which alone provide only modest results. Work is under way to determine
whether a standard chemotherapy drug performs better when another medicine, developed at UT Southwestern, is added
to the treatment of advanced liver cancer. And clinicians from a range of disciplines have teamed up to create a one-stop
CLINICWHEREPATIENTSCANRECEIVETHEMOSTSUITABLETREATMENTSFORTHEIRMALIGNANCYˆANDRECEIVETHEMMOREQUICKLYTHANTHEY
WOULDINATYPICALONCOLOGYSETTINGs!LLTHESEEFFORTSFOCUSONHEPATOCELLULARCARCINOMA(##THEMOSTCOMMONFORMOF
liver cancer in adults. HCC is both unlikely to be detected early and—because it usually arises amid severe liver disease—is
COMPLEXTOTREATs)NRECENTYEARS.ORTH4EXASHASBECOMEANEPICENTERFOR(##BECAUSETWONATIONALEPIDEMICSHAVE
collided with local demographic trends. HCC incidence is growing the fastest among all cancers in Texas, and Dallas County
accounts for about one-tenth of the cases in the state, notes Assistant Professor of Internal Medicine Amit Singal, M.D., a
member of the Cancer Center’s Population Science and Cancer Control Program.
Every Friday at the Hepatocellular Carcinoma
Conference, a multidisciplinary group of physicians, nurses, social workers, and more confer to
discuss patients’ cases and plan for their needs
the following week. Pictured from left: Jackie
Shaw, R.N., B.S.N., Muhammad Shaalan Beg,
M.D., Adam Yopp, M.D., and Amit Singal, M.D.
56
to fatty liver disease (also known
as hepatic steatosis), a condition
that can lead to cirrhosis.
Studies indicate that 60 percent to 95 percent of patients
with nonalcoholic fatty liver
disease are obese. Related
conditions such as diabetes,
metabolic syndrome, and high
cholesterol also appear to be
factors in fatty liver.
Moreover, Texas, along with
many other Southern states, is at
the heart of the obesity epidemic.
“That’s where the focus is going
to be in 15 years,” says Dr. Yopp.
Magnifying the problem locally
is the fact that Hispanics overall
have twice the rate of chronic
liver disease as non-Hispanic
whites and are 1.7 times as likely
to die from liver cancer. In Dallas
County, Hispanics account for
about 39 percent of the population, compared with less than 17
percent nationwide.
The Cancer Center is confronting all these challenges
head-on, Dr. Yopp says. “Over
the last six months we’ve
published close to 15 papers
on what we’re seeing here, and
that’s important because in the
U.S. there’s not a lot of investigators doing clinical research
on HCC.”
INCREASING VIGILANCE
Across the disease continuum, from fatty liver to cirrhosis
and then to HCC, detection is
INADEQUATE&OR(##$R3INgal is developing new strategies to ensure physicians order
needed surveillance for patients
at high risk. His research is testing whether electronic medical
records can be deployed to find
ANDmAGPATIENTSWHOHAVESIGNS
of cirrhosis in order to improve
HCC surveillance, early detection
rates, and, ultimately, survival.
“Patients whose cancers are
found early are eligible for curative treatment [i.e., surgery or liver
transplantation] and can have
five-year survival rates near 75
percent,” Dr. Singal says. “Patients who are found at advanced
stages have a median survival of
less than one year. “
Optimal surveillance currently
involves a strategy combining abdominal ultrasound and
blood testing for a protein
called alpha-fetoprotein, or AFP.
“By performing both of these
tests every six months, you can
find a majority of cancers at an
early-stage,” roughly 70 percent, Dr. Singal says. “But only
a minority of high-risk patients
are getting surveillance.”
Drs. Singal, Yopp, and
Marrero, along with other UT
Southwestern investigators,
recently analyzed exactly where
surveillance for HCC falls short.
Only 20 percent of patients in the
study had undergone surveillance within two years before
HCC diagnosis. For those who
did not, 20 percent were not
known to have liver disease, and
19 percent were not known to
HAVECIRRHOSISPERCENTLACKED
physician orders for surveillance
despite the fact they were known
TOHAVECIRRHOSISANDPERCENT
failed to follow through on surveillance recommendations.
“Studies show patients accept
surveillance testing and they’re
highly compliant with surveillance recommendations by
doctors,” Dr. Singal says. “This
Hepatologist Amit Singal, M.D., examines liver cancer patient Stuart Hunt.
57
a population picture
At the Hepatocellular Carcinoma Conference, clockwise from left:
Adam Yopp, M.D., Amit Singal, M.D., Jorge Marrero, M.D., and Muhammad
Shaalan Beg, M.D.
is a physician issue in terms of
not recognizing cirrhosis and not
ordering surveillance tests as
they should.”
BETTER BIOMARKERS
Delays in diagnosing HCC—
and the fact that advanced cancers or underlying liver damage
prevent current therapies from
benefiting many patients—highlight the urgency of developing
better approaches to detection
and treatment. At the Cancer
Center’s new HCC clinic, blood
samples are collected and
archived from every patient, in a
search for biomarkers indicating which patients with cirrhosis
or hepatitis are likely to develop
liver cancer. Tumor samples are
likewise archived to learn which
biochemical traits of the cancers
are vulnerable to specific medicines. “We think the biomarker
possibilities will be very big,” says
Dr. Yopp.
Testing for AFP, the current blood
MARKERFOR(##IShACOINmIPv
he says. “Only about 50 percent
of people with this type of cancer
produce this kind of biomarker.”
Dr. Marrero is leading a
National Cancer Institute (NCI)funded study following patients
at eight sites throughout the
United States who have chronic
liver disease to see whether two
potential biomarkers—known as
$#0ANDOSTEOPONTINˆCANmAG
development of HCC earlier than
standard detection methods.
58
“What we’re trying to do is
combine this new blood test for
these two biomarkers with AFP
and learn whether it complements
ultrasound,” he says. Plans call
for expanding the study, begun
in mid-2011, to a site in China,
increasing the sample size from
a couple of thousand people to
around 8,000.
In other work at Simmons,
investigators are hoping an
immune-boosting medicine
called bavituximab—developed
at UT Southwestern by Professor of Pharmacology Philip
Thorpe, Ph.D., a member of the
Experimental Therapeutics of
Cancer Program—will enhance
the effects of a drug commonly
used for HCC, sorafenib. The
combination, which has shown
promise against non–small cell
lung cancer, is undergoing Phase
II research against advanced
HCC. While it’s too soon to have
firm results, very early evidence
regarding the survival time of the
first few patients is tantalizing,
says Dr. Yopp. “We think there’s
something there.”
NEW STANDARDS OF CARE
Meanwhile, the Cancer
Center’s new HCC clinic, much
like a similar Parkland clinic
launched before it, promises
to markedly improve patient
care. The multidisciplinary clinic
at Simmons—relatively rare
among liver cancer programs—
allows patients to see whatever
practitioners they need in one
visit, whether it is a transplant
hepatologist, surgical or medical oncologist, interventional
radiologist, or other provider.
“Sometimes you need a
combination of treatments to
get the best survival,” notes Dr.
Singal, adding that HCC patients’
other liver complications also
REQUIREMANAGING7ITHOUTSUCH
a clinic, patients shuttle from one
provider to another and might
not see the needed specialists.
“There’s not only underutilization
of surveillance, but of effective
treatments as well. In our clinic,
we give patients the most effective therapies, and we provide
THEMQUICKERv
Establishing the similar clinic at
Parkland highlighted the impact
a multidisciplinary approach can
make in HCC, Dr. Yopp recalls.
“What we noticed was, almost
immediately, within the first year
that clinic opened, our survival
times had doubled.”
Beyond patient care, Dr. Marrero says, the Cancer Center is
home to many basic and translational scientists who can apply
all types of research innovations
to HCC. “The people who study
genetics or cancer biology are
getting involved and may help us
develop better tools to identify
who’s going to develop cancer,
or can tell us the behavior of the
cancer and possibly how best to
treat it. You have that for breast
and other tumors, but that’s
sorely lacking in the world of liver
cancer,” he says.
“Having an NCI-designated
cancer center is going to help us
combat this disease.”
PNPLA3:
A PUTATIVE LIPASE
Allele Frequency
I148M
50
49%
40
30
%
23%
20
17%
10
0
African European Hispanic
American American
Prevalence of
Hepatic
Steatosis in DHS
50
45%
40
30
33%
%
20
24%
10
0
African European Hispanic
American American
Hispanics are more likely than European
Americans, and African-Americans are less
likely, to carry a genetic allele linked to fatty
liver disease (top). That pattern is reflected
in actual rates of fatty liver disease, as measured by the Dallas Heart Study (bottom).
Research at UT Southwestern over the past
decade is elucidating interethnic differences
in incidence of fatty liver disease, a condition
that can lay the groundwork for liver cancer.
While fatty liver, or hepatic steatosis,
is reversible, a portion of cases progress to
more severe disease, with some leading to
cirrhosis and a subset developing into hepatocellular carcinoma (HCC).
As part of the Dallas Heart Study, a
population-based study of Dallas County
adults, researchers including Helen Hobbs,
M.D., Professor in the Eugene McDermott
Center for Human Growth and Development, measured liver fat in about 2,300 participants. Results published in 2005 indicated
one-third had hepatic steatosis—typically
along with obesity and insulin resistance.
African-Americans had lower rates
of fatty liver (24 percent) than European
Americans (33 percent), and Hispanics
had higher rates (45 percent)—a finding
that couldn’t be explained by body weight
or presence of insulin resistance. That
suggested a genetic influence.
Conducting a genome-wide association
study, researchers indeed found a genetic
link: a one-sequence variation in the gene
coding the enzyme PNPLA3, described in
2008. The variation, or allele, was less common in African-Americans and more common in Hispanics, compared with European
Americans.
“This allele accounts for about 70 percent of the interethnic differences in hepatic
steatosis,” Dr. Hobbs says.
“If you’re thin and you have this allele,
it’s unlikely you’ll have fatty liver,” Dr. Hobbs
adds. “But if you’re obese and have this allele,
you’re at much higher risk.”
The allele is associated with every
step in the progression of nonalcoholic
fatty liver, including steatohepatitis, cirrhosis, and HCC. “But we do not know
whether it contributes directly to the
development of steatohepatitis, cirrhosis,
and hepatocellular carcinoma or indirectly
by promoting the deposition of fat in liver
cells,” Dr. Hobbs says.
This genetic variation in PNPLA3 is
also associated with alcoholic liver disease.
Approximately 15 percent of alcoholics
develop cirrhosis. Individuals who have
two copies of this PNPLA3 variant have up
to a fourfold increased risk of developing
alcohol-related cirrhosis.
The PNPLA3 discovery may represent the identification of a first step in HCC
development and could help pinpoint those
with fatty liver who are at greater risk of
developing significant liver disease, notes
Professor of Internal Medicine Jay Horton,
M.D., who investigates factors that lead
to steatosis. “The focus moving forward is
figuring how the polymorphism alters one’s
progression. How does it work?” Answering
that, researchers might develop therapeutics
to influence the gene’s activity and head off
more serious conditions.
Dr. Hobbs and Professor of Internal
Medicine Jonathan Cohen, Ph.D., have
created a mouse model that overexpresses
the allele and has developed fatty liver. They
described the mouse model in 2012 in the
Journal of Clinical Investigation. Next, they
will determine whether the condition
progresses in the model to cirrhosis, then
to cancer. “We are trying a number of
perturbations to see if PNPLA3 promotes
progression,” Dr. Cohen says.
Jonathan Cohen, Ph.D.
Professor, Internal Medicine
C. Vincent Prothro Distinguished Chair in
Human Nutrition Research
Helen Hobbs, M.D.
Professor, Eugene McDermott Center for Human
Growth & Development
(OWARD(UGHES-EDICAL)NSTITUTE)NVESTIGATOR
;=$ALLAS(EART"ALL#HAIRIN#ARDIOLOGY2ESEARCH
Philip O’Bryan Montgomery Jr., M.D., Distinguished
#HAIRIN$EVELOPMENTAL"IOLOGY%UGENE-C$ERMOTT
Distinguished Chair for the Study of Human Growth
and Development
Jay Horton, M.D.
Professor, Internal Medicine
The Dr. Robert C. and Veronica Atkins Chair in
Obesity & Diabetes Research
59
leadership
population science and cancer control
Converting knowledge into know-how, clinician-scientists are focusing on
optimal ways to promote recommended screening and to deliver better cancer
and sur vivorship care.
AT A GLANCE
goal
To understand and impact factors
associated with cancer risk in clinical,
safety net, and community settings
among diverse populations.
approaches
To conduct innovative research to generate
new discoveries in cancer prevention,
early detection, and survivorship, with
special focus on cancer health disparities
and cancer genetics.
2012 funding
TOTAL: $3.5 million
National Cancer Institute: $1.1 million
Cancer Prevention and Research
Institute of Texas: $2.2 million
Celette Sugg Skinner, Ph.D., Professor, Clinical Sciences, and Director, Behavioral
and Communication Sciences
For two decades Dr. Skinner has been principal or co-investigator on randomized trials promoting
cancer screening and risk assessment, mostly among low-income and minority populations. She
specializes in algorithmically driven systems that mass-produce interventions for patients and providers
that are tailored to personal characteristics and needs. Her research has been continually funded by
the National Cancer Institute (NCI) since 1994. Dr. Skinner led the first tailored intervention trial for
cancer screening in 1994, led an NCI working group evaluating “first-generation” tailored interventions
in 1999, and continues participating in NCI-wide working groups on the state of the science. From 2001
to 2007, she chaired Cancer Genetics Network’s Behavioral Sciences National Working Group, which
conducted and published results from eight randomized clinical trials assessing minority participation
in genetics research. Dr. Skinner is a member of the National Institutes of Health’s Community-Level
Health Promotion study section and leads UT Southwestern’s Community-Engaged Research Function
through the Clinical Translational Sciences Initiative.
peer-reviewed
publications
2009-2012 : 100
The Population Science and Cancer Control
Program conducts research to improve cancer
prevention, early detection, and survivorship
across diverse populations.
60
61
impact
Preventive Outreach
PROSPR project aims to improve colorectal
screening behaviors in general population.
A
Ethan Halm, M.D., is Co-Leader of the
Parkland-UT Southwestern PROSPR Center.
B
Jasmin Tiro, Ph.D., leads a PROSPR project
examining factors that contribute to cancer
screening follow-through.
C
62
Samir Gupta, M.D., initiated a PROSPR project
focused on screening for colon cancer in
Tarrant County.
There’s no doubt that widespread colorectal
cancer screening saves lives. But there are a lot of
questions about how best to achieve it, especially
in uninsured or minority populations.
Simmons Cancer Center is poised to
start answering those questions. Aided by
a highly competitive, five-year, $6.3 million
National Cancer Institute (NCI) grant secured
last fall, the Cancer Center—in partnership
with Parkland Health and Hospital System,
the Texas Cancer Registry, and the UT School
of Public Health in Dallas—is establishing the
Parkland-UT Southwestern PROSPR Center.
Leading the new center is Celette Sugg Skinner,
Ph.D., Associate Director of Population Science
and Cancer Control, and Ethan Halm, M.D., a
Cancer Center member and Chief of General
Internal Medicine at UT Southwestern.
PROSPR, which stands for Population-based Research Optimizing Screening through Personalized Regimens, will
expand and refine pilot projects already
under way at UT Southwestern. The goal is
to better understand colorectal screening
behaviors and obstacles, particularly in a
“safety-net” population, which lacks health
care resources and relies on facilities such as
Parkland, Dallas County’s public hospital,
to provide health care. Fewer than four
in 10 uninsured patients receive recommended colon cancer screenings, research
has shown.
Three PROSPR centers focusing on
colon cancer screening are funded across
the country, and a handful of other sites
have been selected to study breast or cervical cancer screening.
“PROSPR is a major initiative that’s a
long time in the making,” says Dr. Skinner, who
leads the Cancer Center’s Population Science
and Cancer Control Program. While the NCI
has funded centers to study whether people
with specific types of cancer get the care they
need, no such centers have existed until now to
study the screening process—something that
Dr. Skinner notes is likely to have even a stronger impact in preventing cancer deaths.
At the new Dallas center, three projects
are on tap. One uses state-of-the-art risk assessment tools, including a bilingual, touch-screen
computer application in primary care and
colonoscopy clinics, to collect information about
patients’ colon cancer testing and risk factors
and to personalize screening recommendations.
Previous research has focused on
whether people get any screening, Dr. Skinner
says. “We are now at the point where we need
to look at resource use, and screening/surveillance guidelines, to make sure more people are
getting the exact screening the evidence-based
guidelines say they need—not less than they
need, or more,” she says. Such under-screening,
for example, could involve stool tests instead of
colonoscopy for patients with a strong family
history of colon cancer, while over-screening
could include yearly stool tests conducted after
a normal colonoscopy.
“We don’t know the extent to which
under- and over-screening occurs, or in
what situations it’s most likely,” Dr. Skinner
says, adding that the PROSPR projects will
help investigators understand exactly when
appropriate screening doesn’t occur. “This is
important in all settings, but especially so in
resource-limited safety nets.”
Another PROSPR project, led by
Assistant Professor of Clinical Sciences Jasmin
Tiro, Ph.D., is examining which factors in clinics and health systems contribute to screening
follow-through and which can best encourage
disadvantaged patients to pursue recommended
screenings. A key goal is to develop model interventions that other organizations can adopt.
Data from 2005 show that colorectal
cancer screening rates were near 50 percent
for people with insurance coverage, but only
about 15 percent for those without coverage. Meanwhile, almost half of whites age 50
or older had received some form of timely
cancer screening, compared with just 40
percent of African-Americans and less than
one-third of Latinos.
“The fundamental question is, how do
you do population-based colon cancer screening in groups that are at high risk for not getting
screened and thus for getting colon cancer?”
says Samir Gupta, M.D., who led another
PROSPR project, which builds on an existing
study involving Tarrant County’s safety-net
system, the John Peter Smith Health Network.
As researchers expand the JPS project
to Parkland patients, they hope to answer two
questions. First, can screening rates be increased
by identifying unscreened patients and reaching
out to them systemically? Second, what type
of screening is best to tackle the challenge in a
large, uninsured population?
At Parkland, researchers at the ParklandUT Southwestern PROSPR Center will assign
4,000 patients to receive, once a year for up to
three years, either a mailed invitation for a free
colonoscopy or an invitation for a free fecal immunochemical test, which detects blood in the
stool—a sign that cancer might be present. The
test kit also is included in that mailing.
Both forms of screening are recommended standards of care. But while many physicians
advocate colonoscopy for everyone, “we don’t
know if we can achieve high rates of colonoscopy participation in uninsured patients,” Dr.
Gupta says. “At Parkland we have over 10,000
patients who are unscreened.”
Even though the fecal test might be less
sensitive for colon cancer than a colonoscopy
every 10 years—and, unlike colonoscopy,
doesn’t eliminate precancerous polyps—it costs
only about $23, rather than several hundred
dollars or more. And the target patient population might find the fecal test more acceptable.
“If more people do this test, then there’s a
chance you actually help more people, even if it’s
not as sensitive,” Dr. Gupta says. On the other
hand, if only 10 percent of patients every year
decide to get a colonoscopy, but the total accumulates over a decade, that might ultimately
be as effective as the fecal test, which should be
performed annually.
UT Southwestern’s partnership with
Parkland brings a rare blend of assets to the
various PROSPR projects, Dr. Gupta notes.
Besides the comprehensive inpatient and
outpatient care Parkland provides and its
cutting-edge electronic medical records,
PROSPR will tap Parkland’s Center for Clinical Innovation, headed by Cancer Center
member and Assistant Professor of Internal
Medicine Ruben Amarasingham, M.D. The
Center uses IT, statistical, mathematic, and
epidemiological approaches to mine the electronic records and improve patient outcomes.
“The center is our partner in figuring out
how to use the Parkland medical record to track
who has been screened, who hasn’t, and where
people are falling off in the screening process,”
Dr. Gupta says. “We’re going to leverage the
knowledge that people have at Parkland, the
knowledge we have at UT Southwestern, and
the commitment we have to care for these
high-risk patients.”
POPULATION SCIENCE AND
CANCER CONTROL
HIGH-IMPACT PUBLICATIONS
Anhang Price R, Koshiol J, Kobrin S, Tiro JA.
Knowledge and intention to participate in cervical
cancer screening after the HPV vaccine. Vaccine
2011;29(25):4238-43.
Chando S, Tiro JA, Harris TR, Kobrin S, Breen N.
Effects of Socioeconomic Status and Health Care
Access on Low Levels of Human Papillomavirus
Vaccination Among Spanish-Speaking Hispanics in
California. Am J Public Health 2013;103(2):270-2.
Gupta S, Shah J, Balasubramanian BA.
Strategies for reducing colorectal cancer among
blacks. Arch Intern Med 2012;172(2):182-184.
Hamann HA, Howell LA, McDonald JL. “You did
this to yourself”: Causal attributions and attitudes
toward lung cancer patients. J Appl Soc Psychol
[in press].
Shuval K, Leonard T, Murdoch J, Caughy MO,
Kohl HW, Skinner CS. Sedentary behaviors
and obesity in a low-income, ethnic minority
population. J Phys Act Health 2013;10:136.
Singal AG, Yopp A, Skinner CS, Packer M,
Lee WM, Tiro JA. Utilization of hepatocellular
carcinoma surveillance among American patients.
A
J Gen Intern Med 2012;27(2):861-867.
Tiro JA, Pruitt SL, Bruce CM, Persaud D, Lau
M, Vernon SW, Morrow J, Skinner CS. Multilevel
correlates for human papillomavirus vaccination
of adolescent girls attending safety net clinics.
Vaccine 2012;30:2368-2375.
Boldface denotes Cancer Center members in the
Population Science and Cancer Control Program.
B
C
63
impact
Survivor Support
Institute seeks answers on how best to help
people cope with cancer’s fallout.
Comprehensive support for cancer survivors
is no longer just for people who are treated
at major academic hospitals. For Fort Worth
residents, the UT Southwestern Moncrief
Cancer Institute is delivering the latest in
prevention and survivorship services to a
broader swath of the community.
“Oncology services, especially during the transition from active treatment to
recovery, are fragmented and disjointed,”
says Keith Argenbright, M.D., the institute’s
Medical Director and Associate Professor
A
Cancer survivor Cindy Kraus (left) and fellow teacher Cynthia Woodson from Argyle, Texas, at the
2011 Komen North Texas Race for the Cure in Denton.
B
Moncrief Cancer Institute employees Katherine Stephens (left), Community Outreach Coordinator,
and Lori Drew, Executive Director, serve pink pancakes for breast cancer awareness at a community
outreach event.
A
64
B
of Clinical Sciences at UT Southwestern.
“The direct result is that cancer survivors are
anxious, confused, feel lost in the system,
and are at heightened fear of recurrence.
These types of survivorship programs will
help address these issues.”
With community partners as the
program’s pillars—and with the aid of more
than $800,000 in funding from the Cancer
Prevention and Research Institute of Texas
(CPRIT)—Moncrief has developed a sweeping
adult survivorship clinic that builds on existing
services, including a smoking cessation
program, psychiatric counseling, cancer
support groups, medical bill advocacy, and
transportation assistance.
Also incorporated into the clinic, called
the Fort Worth Program for Community
Survivorship (ProComS), are Moncrief ’s
nutritional services to decrease the risk of
cancer as well as aid patients in treatment, and
genetic screening and counseling for patients
with cancer and for those who are at high risk
for the disease.
But wait. There’s more.
ProComS participants—adults who
have been diagnosed with any kind of
cancer—can also benefit from a new exercise
program complete with a fitness instructor
who specializes in oncology care. And with
assistance from the staff of oncology-certified registered nurses, participants can document and understand the cancer treatment
they have received, and the future care they
will need. Plans also call for the addition of
physicians who can more closely monitor patients for long-term and late-developing side
effects caused by chemotherapy, radiotherapy, surgery, or by other aspects of someone’s
cancer or its treatment.
The survivorship program provides aid
and support to cancer patients and survivors
at any time, although it focuses on the period
when people are transitioning from active
treatment to life after treatment. The degree
of follow-up varies according to an individual’s needs, Dr. Argenbright says, adding that
while the program is relatively new, patients
so far have praised it.
As a community-based program of
UT Southwestern’s Simmons Cancer Center,
Moncrief can both utilize the latest in
scientific research on prevention, detection,
and survivorship, and effectively reach out to
local populations—especially those that have
limited access to health care and, therefore,
are most in need of its services.
Four steps are key to that outreach:
identifying survivors, then recruiting, enrolling, and engaging them. Also crucial to the
program is its network of local oncology providers, who serve on the program’s advisory
board and help lead the initiative. Moncrief
has worked closely with those providers,
including Fort Worth’s health care safety net,
JPS Health Network, to build collaboration
and trust. “This is a program that is designed
and directed by our community partners for
the benefit of our community,” Dr. Argenbright says. “This degree of community-wide
resource sharing is very, very unusual, yet
extremely beneficial to our patients.”
Coordinating community resources is
important to aid much of the population with a
history of cancer. While big academic medical
centers can concentrate resources, “most people
who are treated for cancer aren’t treated in an
academic medical center,” notes Heidi Hamann,
Ph.D., Assistant Professor of Psychiatry and
Clinical Sciences and coinvestigator on the
CPRIT grant. “One of the things we found in
preparing the grant is that there may be different resources out there, but they’re so disjointed
that it’s hard for patients to find them.”
The survivorship clinic will help
researchers learn what types of services
interest cancer survivors most, especially in a
community setting, she says. “We will have a
better sense of what a community survivorship program can look like, what sorts of
needs people in the community tend to have,
and how the different types of programs can
address those needs.”
ProComS was developed with an eye
toward recommendations from a 2006 Institute of Medicine report on cancer survivorship, titled “From Cancer Patient to Cancer
Survivor: Lost in Transition.”
One goal at Moncrief is to demonstrate
whether the comprehensive approach to survivorship recommended by that report actually
works, Dr. Argenbright says. Ultimately such
knowledge can benefit not only the estimated
4,500 Tarrant County patients expected to
be diagnosed cancer survivors in the coming
year, but approximately 12 million survivors
throughout the United States and millions
more worldwide.
Dr. Hamann is looking for evidence
indicating whether the survivorship clinic
will improve patients’ quality of life, alleviate depression and anxiety or other manifestations of distress, and impact behaviors
related to diet and exercise. Investigators
are interested in how, for instance, patients’
sleep quality might change over time as they
are integrated into the clinic. These factors are assessed when people first enroll
in ProComS—whether they have freshly
completed treatment or finished it years
ago—and are again measured three, six, and
12 months later. “If we can see across a lot of
people that particular services are related to,
say, decreases in depressive symptoms,” Dr.
Hamann says, “then we can learn how those
services may be helping people.”
Patients’ well-being varies greatly upon
entering the survivorship program, she adds.
“Some are doing very well emotionally; some
of them are struggling,” she says. “People
report that their family or friends say, ‘Well,
you’re done with treatment. Aren’t you happy
and ready to move on?’” For reasons including ongoing side effects of treatment and fear
of recurrence, that might not be the case.
Overall, the survivorship clinic will
help fill a dire need in cancer care locally, Dr.
Argenbright notes. “Survivorship is chronically
underfunded,” he says. “Behavioral and transitional services for the most part aren’t paid for
by insurance companies. Oftentimes patients
don’t understand or appreciate the need for
them and therefore don’t pay for them either.
As a health care delivery system, this is an issue
we’re going to need to wrestle with.”
Keith Argenbright, M.D., Medical Director,
Moncrief Cancer Institute
65
spotlight
profile
Moncrief Cancer Institute
Science plus resources equals results.
Although cancer is a common scourge, preventing and detecting it involves unique challenges
for individuals—a fact central to the mission of
Moncrief Cancer Institute.
Founded in 1958 as a radiation center that
treated patients regardless of ability to pay, Moncrief—an arm of UT Southwestern’s Simmons
Cancer Center—no longer provides such care.
The Fort Worth-based institute, while retaining
its focus on the medically underserved, instead
promotes cancer prevention, survivorship support, and community-oriented research.
With an expanding suite of services—
and a new, 60,000-square-foot building that
opened in 2012—Moncrief ’s impact on the
health of North Texans is burgeoning.
“We take those cancer strategies that
have been tested, and we look to see what
works and what doesn’t in different communities,” says the institute’s Medical Director, Keith
Argenbright, M.D. For instance, can patients
afford the type of screening or treatment they
need? Do they live close enough? What other
circumstances encourage—or discourage—
patients from seeking cancer-related care?
One vital initiative is the Breast Screening
and Patient Navigation, or BSPAN, program,
which tackles financial and geographical barriers
that prevent women from receiving mammograms and timely diagnostic services. Moncrief
doesn’t currently provide those services, but
facilitates screening and payment and helps
women whose mammograms show an abnormality get the follow-up services they need. The
program receives support from local affiliates
of Susan G. Komen for the Cure, and has won
a two-year grant of nearly $1 million from the
Cancer Prevention and Research Institute of
Texas (CPRIT). Moncrief also receives funds
from the Texas Department of State Health
Services in a contract to provide breast cancer
screening and follow-up services.
A new, 60,000-square-foot facility houses Moncrief’s
recently created Community Survivorship Clinic
along with a wellness center, meditation garden, and
100-seat auditorium for educational seminars.
BSPAN officially began in June 2010,
serving five rural counties surrounding Tarrant.
These counties—Denton, Wise, Parker, Hood,
and Johnson—together comprise almost 4,000
square miles, with slightly more than 1 million
people and one of the highest incidences of
breast cancer in Texas. Because Moncrief has
imaging and surgical partners in each county,
most women can receive diagnostic and treatment referrals close to home.
But referral is just one step. For patients
with few resources, numerous obstacles can be
present, such as the lack of health insurance,
transportation, or child care. “We facilitate. We
call, make the appointment, call the patient
back, and, if necessary, arrange transportation,
via cab vouchers, gas cards, or community
partnerships with local church vans or other
civic associations,” Dr. Argenbright says. “We
hold our patients’ hands every step of the way,
which is key in this population.”
In the first year of operation, BSPAN and
a related program in Tarrant County delivered
more than 2,300 mammograms, navigated to
a clinical resolution 663 abnormalities, and
diagnosed 68 breast cancers—80 percent at an
early-stage.
With the support of almost $2.7 million
in additional funding from CPRIT, Moncrief
expanded BSPAN’s service radius into 12 additional counties to the north, west, and south
of Tarrant in 2012. BSPAN’s service model also
is expanding into Dallas County, through a
partnership with the University of North Texas
Health Science Center that targets public housing residents with outreach through Parkland
and Methodist Health System.
Yet that’s only part of the health care gap
that Moncrief fills. The institute is coordinating
a colon cancer screening program in collaboration with the JPS Health Network in addition
to providing cancer education, promoting
community prevention awareness, and offering
behavioral and nutritional services, and genetic
screening and counseling.
“We want to provide our communities
with the science, the resources, and the programs
to reduce the threat and impact of cancer,”
Dr. Argenbright says.
Clay
Montague
W. Phil Evans, M.D.
A dedicated servant at the
American Cancer Society.
As Director of UT Southwestern’s Center for
Breast Care, Phil Evans, M.D., devotes his
working days to the battle against breast cancer.
As an American Cancer Society volunteer for
the past quarter-century and a national board
member since 2002, he spends his spare time
advocating publicly for cancer prevention, early
detection, and a host of other issues for the
benefit of cancer patients.
Yet for Dr. Evans, a kidney cancer survivor since 1996, fighting cancer is not just a
professional cause, but a personal one.
It’s those multiple perspectives—as
well as a deep compassion for patients and a
fierce determination to prevent cancer and
cancer deaths—that Dr. Evans brought to the
cause as he served as the American Cancer
Society’s national president for 2011-12.
Dr. Evans called that a tremendous
honor. “I’m humbled by the fact I was even
considered,” says Dr. Evans, a member of the
Simmons Cancer Center and a Professor of
Radiology at UT Southwestern. “I have a great
passion for the American Cancer Society.”
In its nearly 100 years of existence, the
organization has delivered messages promoting treatment, early detection, and prevention to every corner of the United States
and many areas of the world, Dr. Evans says.
“We’re looking forward in the 21st century to
making sure that effort continues—to try to
eliminate cancer by the end of this century.”
Key priorities, he says, are prevention
and early detection efforts for the nation’s
most common cancers: tobacco control to
prevent lung and other related cancers, and
boosting screening to find breast cancer
early and to prevent and detect colon cancer.
“That’s where we can get the most impact for
the resources we have.”
Promoting research is also vital to
the mission of the society, which has been
instrumental in keeping the National Cancer
Institute’s budget intact in recent years, he
says. The society itself funds a research program
totaling about $130 million annually.
When it comes to clinical care, longtime colleague Marilyn Leitch, M.D., Medical
Director of the Center for Breast Care, credits Dr. Evans with making radiology more
integral to patient care, instead of separate
from it, “and working for the convenience of
the patient rather than the convenience of
the system.”
“The patients love him because he is
such a kind person and is clearly interested
in their overall care, not just the X-rays done
that day,” says Dr. Leitch, a Cancer Center
member and Professor of Surgical Oncology.
Dr. Evans, she adds, brings a personal touch
to the cancer society, too.
“It’s not just about the statistics; it’s what
the statistics mean—what it means to have a
successful breast screening program, for
instance,” she says. “It’s not just the numbers—
you have saved people’s lives and made a difference for those individuals.”
Cooke
Tarrant County
BSPAN I
Jack
Young
Wise
Denton
BSPAN II
Palo Pinto
Parker
Hood
Tarrant
Dallas
Johnson
Erath
Somervell
Hill
Comanche
Bosque
Hamilton
The BSPAN program tackles barriers to breast cancer screening
and diagnosis in the counties surrounding Tarrant County.
66
Phil Evans, M.D., is Director of the UT Southwestern Center for Breast Care and was President of the American Cancer Society for 2011-12.
67
at a glance
PROGRAM
TOTAL
INTRAPROGRAMMATIC*
Chemistry
Development
32
60
4
6
12.5%
10%
9
23
28.1%
38.3%
2012
Cell Networks
Experimental
Therapeutics
Lung
88
16
18.2%
29
33%
2011
113
51
13
20
11.5%
39.2%
36
14
31.9%
27.5%
2010
571
399
2008
361
2007
199
2006
22.4%
3.8%
7.3%
4.1%
4.2% 5.7%
5.7%
Total Patients = 5,053
68
361
186
137
286
4. Thyroid and Endocrine
5. Kidney
5. Hodgkin’s Lymphoma
9. Lip, Mouth and Pharynx
190
157
177
253
2. Lymphoid Leukemia
4. Gynecologic
10. Non-Hodgkin’s Lymphoma
2012
1. Brain and Nervous System
21.2%
3. Sarcoma
8. Thyroid
2011
TOP DISEASE SITES
6. Myeloid and Monocytic Leukemia
3.3%
7. Non-Hodgkin’s Lymphoma
7. Colon
3.7%
2010
3. Lung
6. Melanoma
9.5%
76
2009
NEWLY REGISTERED CANCER PATIENTS, 2011
Children’s Medical Center
1. Breast
12.6%
2008
421
436
2007
61
188
28
138
113
81
24
2006
2. Prostate
30.5%
Total
945
640
600
0
13.1%
Institutional
1000
826
800
200
TOP DISEASE SITES
National Group
800
1000
400
NEWLY REGISTERED CANCER PATIENTS, 2011
UTSW University Hospitals, and Parkland Health
and Hospital System
600
ACCRUAL TO CLINICAL ONCOLOGY TRIALS, 2006-12
By Trial Type
Industrial
External Peer Review
TOTAL
$ 28,155,896
$ 44,336,880
$ 36,615,603
$ 11,126,801
$ 17,929,925
$ 138,165,105
400
538
83
129
110
55
211
588
200
356
National Cancer Institute
Other National Institutes of Health
Cancer Prevention and Research Institute of Texas
Other Federal Agencies (Department of Defense, NASA, etc.)
Other Funding Organizations
TOTAL
356
157
FUNDING FOR EXTRAMURAL RESEARCH PROJECTS
As of December 31, 2012
PROJECTS
538
177
0
FUNDING AGENCY
640
241
663
34%
663
316
66
433
230
224
22.8%
826
63
71
*Two or more Cancer Center members within a Scientific Program
**Two or more Cancer Center members across Scientific Programs
Totals are unduplicated
523
303
60
194
26.3%
AS % OF
CENTER TOTAL
945
374
283
5
63.2%
970
201
12
AS % OF
CENTER TOTAL
TOTAL
667
2009
19
Total
303
91
Population
Science and
Cancer Control
INTERPROGRAMMATIC**
65
PROGRAM
AS % OF
PROGRAM
TOTAL
ACCRUAL TO CLINICAL ONCOLOGY TRIALS, 2006-12
By Trial Type
Non-Interventional
Interventional
AS % OF
PROGRAM
TOTAL
970
PEER-REVIEWED PUBLICATIONS AND MEASURES OF COLLABORATION, 2012
237
PATHS TO PROGRESS
Funding from a wide range of
sources fuels a host of scientific
investigations, including collaborative, transdisciplinary
efforts with the potential to
broadly impact the state of
cancer knowledge and care.
The work helps thousands of
patients every year at Simmons
Cancer Center clinics, including
a growing number of people
receiving the latest in cancer
care through clinical trials.
85
at a glance
4.5%
8. All Others
21.2%
4.9%
11. All Others
9.8%
12.7%
Total Patients = 245
69
members
Simmons Cancer Center
development and cancer program
*denotes new members since 2010
chemistry and cancer program
Richard Bruick, Ph.D.
Associate Professor, Biochemistry
Chuo Chen, Ph.D.
Associate Professor, Biochemistry
Southwestern Medical Foundation Scholar
in Biomedical Research
Jef De Brabander, Ph.D.
Professor, Biochemistry
Julie and Louis Beecherl, Jr. Chair in Medical Science
J.R. Falck, Ph.D.
Professor, Biochemistry
The Robert A. Welch Distinguished Chair
in Chemistry
Kevin Gardner, Ph.D.
Professor, Biochemistry
W.W. Caruth, Jr. Scholar in Biomedical
2ESEARCH6IRGINIA,AZENBY/(ARA#HAIR
in Biochemistry
*John MacMillan, Ph.D.
Assistant Professor, Biochemistry
Chilton/Bell Scholar in Biochemistry
Steven McKnight, Ph.D.
Professor and Chairman, Biochemistry
Distinguished Chair in Basic Biomedical Research
The Sam G. Winstead and F. Andrew Bell Distinguished
Chair in Biochemistry
*Hamid Mirzaei, Ph.D.
Professor, Biochemistry
*Deepak Nijhawan, M.D., Ph.D.
Assistant Professor, Internal Medicine
Joseph Ready, Ph.D.
Professor, Biochemistry
Southwestern Medical Foundation Scholar
in Biomedical Research
Michael Roth, Ph.D.
Professor, Biochemistry
Diane and Hal Brierley Distinguished Chair in
Biomedical Research
*Uttam Tambar, Ph.D.
Assistant Professor, Biochemistry
W.W. Caruth, Jr. Scholar in
Biomedical Research
*Kenneth Westover, M.D., Ph.D.
Assistant Professor, Radiation Oncology
Noelle Williams, Ph.D.
Associate Professor, Biochemistry
Xiao-Song Xie, Ph.D.
Professor, McDermott Center for Human Growth
and Development
*Yonghao Yu, Ph.D.
Assistant Professor, Biochemistry
Virginia Murchison Linthicum Scholar in
Medical Research
John Abrams, Ph.D.
Professor, Cell Biology
James Amatruda, M.D., Ph.D.
Assistant Professor, Pediatrics
Nearburg Family Professorship in Pediatric Oncology
2ESEARCH(ORCHOW&AMILY3CHOLARIN0EDIATRICS
Robert Bachoo, M.D., Ph.D.
Assistant Professor, Neurology
Miller Family Professorship in Neuro-Oncology
*James Bibb, Ph.D.
Associate Professor, Psychiatry
Michael Buszczak, Ph.D.
Assistant Professor, Molecular Biology
E.E. and Greer Garson Fogelson Scholar
in Medical Research
Thomas Carroll, Ph.D.
Associate Professor,
Internal Medicine–Nephrology
Diego Castrillon, M.D., Ph.D.
Associate Professor, Pathology
John H. Childers, M.D. Professorship in Pathology
Ondine Cleaver, Ph.D.
Associate Professor, Molecular Biology
Deborah Clegg, Ph.D.
Associate Professor,
Internal Medicine–Diabetes
Ralph DeBerardinis, M.D., Ph.D.
Assistant Professor, Pediatrics
Sowell Family Scholar in Medical Research
Rene Galindo, M.D., Ph.D.
Assistant Professor, Pathology
Amyn Habib, M.D.
Assistant Professor, Neurology
Paul Harker-Murray, M.D., Ph.D.
Assistant Professor, Pediatrics
Jenny Hsieh, Ph.D.
Associate Professor, Molecular Biology
Jin Jiang, Ph.D.
Professor, Developmental Biology
Eugene McDermott Scholar in Medical Research
*Jane Johnson, Ph.D.
Professor, Neuroscience
Laura Klesse, M.D., Ph.D.
Assistant Professor, Pediatrics
Dedman Family Scholar in Clinical Care
*Andrew Koh, M.D.
Assistant Professor, Pediatrics
Makoto Kuro-o, M.D., Ph.D.
Professor, Pathology
Kern and Marnie Wildenthal President’s Research Council
0ROFESSORSHIPIN-EDICAL3CIENCE3OUTHWESTERN-EDICAL
&OUNDATION3CHOLARIN"IOMEDICAL2ESEARCH4HE&REDERIC
C. Bartter Professorship in Vitamin D Research
Lu Q. Le, M.D., Ph.D.
Assistant Professor, Dermatology
Qinghua Liu, Ph.D.
Associate Professor, Biochemistry
W.A. “Tex” Moncrief Jr. Scholar in Medical Research
70
Q. Richard Lu, Ph.D.
Associate Professor,
Developmental Biology
Southwestern Medical Foundation Scholar
in Medical Research
Ray MacDonald, Ph.D.
Professor, Molecular Biology
Elizabeth Maher, M.D., Ph.D.
Associate Professor, Internal Medicine
Hematology/Oncology
Theodore H. Strauss Professorship in Neuro-Oncology
*Joshua Mendell, M.D., Ph.D.
Professor, Molecular Biology
*Sean Morrison, Ph.D.
Professor, Pediatrics
Mary McDermott Cook Chair in Pediatric Genetics
Howard Hughes Medical Institute Investigator
Fiemu Nwariaku, M.D.
Professor, Surgery
Malcolm O. Perry, M.D., Professorship in Surgery
*Kathryn O’Donnell, Ph.D.
Assistant Professor, Molecular Biology
Eric Olson, Ph.D.
Professor and Chairman,
Molecular Biology
Annie and Willie Nelson Professorship in Stem Cell
2ESEARCH0OGUE$ISTINGUISHED#HAIRIN2ESEARCH
ON#ARDIAC"IRTH$EFECTS4HE2OBERT!7ELCH
Distinguished Chair in Science
Luis Parada, Ph.D.
Professor and Chairman, Developmental Biology
Southwestern Ball Distinguished Chair in
Nerve Regeneration Research
Diana K. and Richard C. Strauss Distinguished Chair in
Developmental Biology
Philipp Scherer, Ph.D.
Professor, Internal Medicine–Diabetes
Gifford O. Touchstone Jr. and Randolph G. Touchstone
Distinguished Chair in Diabetes Research
Stephen X. Skapek, M.D.
Professor, Pediatrics
Director, Division of Pediatric Hematology/Oncology
Children’s Cancer Fund Distinguished Professorship in
Pediatric Oncology Research
Philip Shaul, M.D.
Professor, Pediatrics
Associates First Capital Corporation
Distinguished Chair in Pediatrics
*Yihong Wan, Ph.D.
Assistant Professor, Pharmacology
Virginia Murchison Linthicum Scholar in Medical Research
cancer cell networks program
*Neal Alto, Ph.D.
Assistant Professor, Microbiology
Rita C. and William P. Clements, Jr. Scholar
in Medical Research
Steven Altschuler, Ph.D.
Associate Professor, Pharmacology
*Bruce Beutler, M.D.
Professor and Director, Center for the
Genetics of Host Defense
2EGENTAL0ROFESSOR2AYMONDAND%LLEN7ILLIE
Distinguished Chair in Cancer Research, in Honor
of Laverne and Raymond Willie, Sr.
James Brugarolas, M.D., Ph.D.
Assistant Professor, Internal Medicine
& Developmental Biology
Virginia Murchison Linthicum Endowed Scholar
in Medical Research
*Ezra Burstein, M.D.
Associate Professor, Internal Medicine
Digestive/Liver Diseases
*Min Chen, Ph.D.
Assistant Professor, Clinical Sciences
Zhijian (James) Chen, Ph.D.
Professor, Molecular Biology
George L. MacGregor Distinguished Chair
in Biomedical Science
Howard Hughes Medical Institute Investigator
Cheng-Ming Chiang, Ph.D.
Professor, Simmons Cancer Center
*Yuh Min Chook, Ph.D.
Associate Professor, Pharmacology
Eugene McDermott Scholar in Medical Research
Melanie Cobb, Ph.D.
Professor, Pharmacology
Jane and Bill Browning, Jr. Chair in Medical Science
David Corey, Ph.D.
Professor, Pharmacology
George DeMartino, Ph.D.
Professor, Physiology
Robert W. Lackey Professorship in Physiology
Beatriz Fontoura, Ph.D.
Professor, Cell Biology
*Elizabeth Goldsmith, Ph.D.
Professor, Biophysics
Patti Bell Brown Professorship in Biochemistry
Lily Huang, Ph.D.
Assistant Professor, Cell Biology
*Thomas Wilkie, Ph.D.
Associate Professor, Pharmacology
Bethany Janowski, Ph.D.
Assistant Professor, Pharmacology
*Agnieszka Witkiewicz, M.D.
Associate Professor, Pathology
UT Translational STARS Award
*Qiu-Xing Jiang, Ph.D.
Assistant Professor, Cell Biology
Alec (Chengcheng) Zhang, Ph.D.
Assistant Professor, Physiology
Michael L. Rosenberg Scholar in Medical Research
*Chun-Li Zhang, Ph.D.
Assistant Professor, Molecular Biology
W.W. Caruth, Jr. Scholar in Biomedical Research
*Ralf Kittler, Ph.D.
Assistant Professor, McDermott Center
for Human Growth and Development
John L. Roach Scholar in Biomedical Research
Steven Kliewer, Ph.D.
Professor, Molecular Biology
Nancy B. and Jake L. Hamon Distinguished Chair
in Basic Cancer Research
*W. Lee Kraus, Ph.D.
Professor and Director, Green Center
for Reproductive Biology Sciences
Cecil H. and Ida Green Distinguished Chair in
Reproductive Biology Sciences
Michael White, Ph.D.
Professor, Cell Biology
'RANT!$OVE#HAIRFOR2ESEARCHIN/NCOLOGY4HE
Sherry Wigley Crow Cancer Research Endowed Chair
in Honor of Robert Lewis Kirby, M.D.
Beth Levine, M.D.
Professor, Internal Medicine–Center for
Autophagy Research
Charles Cameron Sprague Distinguished Chair in
Biomedical Science
Howard Hughes Medical Institute Investigator
Woodring Wright, M.D., Ph.D.
Professor, Cell Biology
Southland Financial Corporation
Distinguished Chair in Geriatrics
Wen Hong Li, Ph.D.
Associate Professor, Cell Biology
Southwestern Medical Foundation Scholar in
Medical Research
Yi Liu, Ph.D.
Professor, Physiology
Louise W. Kahn Scholar in Biomedical Research
Lawrence Lum, Ph.D.
Associate Professor, Cell Biology
Virginia Murchison Linthicum Scholar
in Medical Research
*James Malter, M.D.
Professor and Chairman, Pathology
The Senator Betty and Dr. Andy Andujar
Distinguished Chairmanship of Pathology
David Mangelsdorf, Ph.D.
Professor and Chairman, Pharmacology
$ISTINGUISHED#HAIRIN0HARMACOLOGY2AYMONDAND
Ellen Willie Distinguished Chair in Molecular Neuropharmacology in Honor of Harold B. Crasilneck, Ph.D.
Howard Hughes Medical Institute Investigator
Carole Mendelson, Ph.D.
Professor, Biochemistry
Gray Pearson, Ph.D.
Assistant Professor, Simmons Cancer Center
*Ryan Potts, Ph.D.
Assistant Professor, Physiology
Michael L. Rosenberg Scholar in Medical Research
Mike Rosen, Ph.D.
Professor, Biochemistry
Mar Nell and F. Andrew Bell Distinguished Chair
in Biochemistry
Howard Hughes Medical Institute Investigator
Lani Wu, Ph.D.
Associate Professor, Pharmacology
Cecil H. and Ida Green Scholar in Biomedical
Computational Science
Xian-Jin Xie, Ph.D.
Associate Professor, Clinical Sciences
Hongtao Yu, Ph.D.
Professor, Pharmacology
Michael L. Rosenberg Scholar in
Medical Research
Howard Hughes Medical Institute Investigatorexper
experimental therapeutics of
cancer program
*Kiyoshi Ariizumi, Ph.D.
Associate Professor, Dermatology
David Boothman, Ph.D.
Professor, Simmons Cancer Center
Robert B. and Virginia Payne Professorship
in Oncology
Rolf Brekken, Ph.D.
Associate Professor, Surgery
Effie Marie Cain Research Scholar
Kathlynn Brown, Ph.D.
Assistant Professor, Internal Medicine
Hematology/Oncology
Sandeep Burma, Ph.D.
Associate Professor, Radiation Oncology
Benjamin Chen, Ph.D.
Associate Professor, Radiation Oncology
David Chen, Ph.D.
Professor, Radiation Oncology
David A. Pistenmaa, M.D., Ph.D., Distinguished Chair
in Radiation Oncology
*Elliott Ross, Ph.D.
Professor, Pharmacology
Greer Garson and E.E. Fogelson Distinguished Chair
in Medical Research
*Kevin Choe, M.D., Ph.D.
Assistant Professor, Radiation Oncology
Pier Paolo Scaglioni, M.D.
Assistant Professor, Internal Medicine
Hematology/Oncology
Robert Collins, M.D.
Professor, Internal Medicine
Hematology/Oncology
Sydney and J.L. Huffines Distinguished Chair in Cancer
2ESEARCHIN(ONOROF%UGENE&RENKEL-$(,LOYD
and Willye V. Skaggs Professorship in Medical Research
*Sandra Schmid, Ph.D.
Professor and Chairman, Cell Biology
Cecil H. Green Distinguished Chair in Cellular and
Molecular Biology
*Joachim Seemann, Ph.D.
Associate Professor, Cell Biology
Virginia Murchison Linthicum Scholar in Medical Research
Jonathan Terman, Ph.D.
Associate Professor, Neuroscience
Rita C. and William P. Clements, Jr. Scholar
in Medical Research
*Mathukumalli Vidyasagar, Ph.D.
Professor, Bioengineering, University of Texas at Dallas
Changho Choi, Ph.D.
Associate Professor, Advanced Imaging Research Center
*Ian Corbin, Ph.D.
Assistant Professor, Advanced Imaging Research Center
David Euhus, M.D.
Professor, Surgery
Marilyn R. Corrigan Distinguished Chair in
Breast Cancer Surgery
W. Phil Evans, M.D.
Clinical Professor, Radiology
The George and Carol Poston Professorship
in Breast Cancer Research
71
members
*Art Frankel, M.D.
Professor, Internal Medicine
Jinming Gao, Ph.D.
Professor, Simmons Cancer Center
Robert Gerard, Ph.D.
Associate Professor, Molecular Biology
David Gerber, M.D.
Assistant Professor, Internal Medicine
Hematology/Oncology
Jer-Tsong Hsieh, Ph.D.
Professor, Urology
Dr. John McConnell Distinguished Chair in Prostate
Cancer Research
*Erik Knudsen, Ph.D.
Professor, Pathology
Dr. Charles T. Ashworth Professorship in Pathology
UT Translational STARS Award
*Theodora Ross, M.D., Ph.D.
Professor, Internal Medicine Hematology/Oncology
*EANNE!NN0LITT0ROFESSORSHIPIN"REAST#ANCER2ESEARCH
H. Ben and Isabelle T. Decherd Chair in Internal Medicine,
in Honor of Henry M. Winans, Sr., M.D.
Arthur Sagalowsky, M.D.
Professor, Urology
The Dr. Paul Peters Chair in Urology in Memory of
Rumsey and Louis Strickland
Debabrata Saha, Ph.D.
Assistant Professor, Radiation Oncology
*Jennifer Kohler, Ph.D.
Assistant Professor, Biochemistry
A. Dean Sherry, Ph.D.
Professor and Director, Advanced Imaging
Research Center
Cecil H. and Ida Green Distinguished Chair in
Systems Biology (UT Dallas)
*Padmakar Kulkarni, Ph.D.
Professor, Radiology
*Daniel Siegwart, Ph.D.
Assistant Professor, Simmons Cancer Center
*Robert Lenkinski, Ph.D.
Professor, Radiology
Charles A. and Elizabeth Ann Sanders Chair in TransLATIONAL2ESEARCH*ANAND"OB0ICKENS$ISTINGUISHED
Professorship in Medical Science, in Memory of Jerry
Knight Rymer and Annette Brannon Rymer and Mr. and
Mrs. W.L. Pickens
*Timothy Solberg, Ph.D.
Professor, Radiation Oncology
Barbara Crittenden Professorship in Cancer Research
*Cheryl Lewis, Ph.D.
Assistant Professor, Pathology
Yair Lotan, M.D.
Professor, Urology
Helen J. and Robert S. Strauss Professorship in Urology
*Weihua Mao, Ph.D.
Assistant Professor, Radiation Oncology
Elisabeth Martinez, Ph.D.
Assistant Professor, Pharmacology
*Rhonda Souza, M.D.
Professor, Internal Medicine
Digestive/Liver Diseases
Baran Sumer, M.D.
Assistant Professor, Otolaryngology
Xiankai Sun, Ph.D.
Associate Professor, Radiology
Dr. Jack Krohmer Professorship in Radiation Physics
Philip Thorpe, Ph.D.
Professor, Pharmacology
The Serena S. Simmons Distinguished
Chair in Cancer Immunopharmacology
Ralph Mason, Ph.D.
Professor, Radiology
David Wang, M.D., Ph.D.
Assistant Professor, Internal Medicine
Hematology/Oncology
David Miller, M.D.
Professor, Obstetrics and Gynecology
Amy and Vernon E. Faulconer Distinguished Chair in Medical
3CIENCE$ALLAS&OUNDATION#HAIRIN'YNECOLOGIC/NCOLOGY
*E. Sally Ward, Ph.D.
Professor, Immunology
Paul and Betty Meek-FINA Professorship
in Molecular Immunology
Jerry Niederkorn, Ph.D.
Professor, Ophthalmology
Royal C. Miller Chair in Age-Related Macular Degeneration
2ESEARCH'EORGE!AND.ANCY03HUTT0ROFESSORSHIPIN
Medical Science
James K.V. Willson, M.D.
Professor and Director, Simmons
Cancer Center
The Lisa K. Simmons Distinguished Chair in
Comprehensive Oncology
*Tej Pandita, Ph.D.
Professor, Radiation Oncology
Naomi Winick, M.D.
Professor, Pediatrics
Lowe Foundation Professorship in
Pediatric Neuro-Oncology
*Ivan Pedrosa, M.D.
Associate Professor, Radiology
Jack Reynolds, M.D., Chair in Radiology
Fangyu Peng, M.D., Ph.D.
Associate Professor, Radiology
Claus Roehrborn, M.D.
Professor and Chairman, Urology
S.T. Harris Family Chair in Medical Science,
IN(ONOROF*OHN$-C#ONNELL-$%%
Fogelson and Greer Garson Fogelson
Distinguished Chair in Urology
72
*Neil Rofsky, M.D.
Professor and Chairman, Radiology
Effie and Wofford Cain Distinguished Chair in
Diagnostic Imaging
*John Yordy, M.D., Ph.D.
Assistant Professor, Radiation Oncology
Dawen Zhao, M.D., Ph.D.
Associate Professor, Radiology
lung cancer program
Hsienchang (Thomas) Chiu, M.D.
Assistant Professor, Internal Medicine
Hak Choy, M.D.
Professor and Chairman, Radiation Oncology
The Nancy B. & Jake L. Hamon Distinguished
Chair in Therapeutic Oncology Research
J. Michael DiMaio, M.D.
Professor, Thoracic Surgery
Laurence and Susan Hirsch/Centex
Distinguished Chair in Heart Disease
Jonathan Dowell, M.D.
Associate Professor, Internal Medicine
Hematology/Oncology
Boning Gao, Ph.D.
Assistant Professor, Pharmacology
Christine Garcia, M.D., Ph.D.
Associate Professor, McDermott Center
for Human Growth and Development
Adi Gazdar, M.D.
Professor, Pathology
W. Ray Wallace Distinguished Chair in Molecular
Oncology Research
Luc Girard, Ph.D.
Assistant Professor, Pharmacology
Sandra Hofmann, M.D., Ph.D.
Professor, Internal Medicine
Hematology/Oncology
*Puneeth Iyengar, M.D.
Assistant Professor, Radiation Oncology
*David Johnson, M.D., Ph.D.
Professor and Chairman, Internal Medicine
Donald W. Seldin Distinguished Chair in
Internal Medicine
*Kemp Kernstine, M.D., Ph.D.
Professor and Chairman, Thoracic Surgery
Robert Tucker Hayes Foundation Distinguished Chair
in Cardiothoracic Surgery
*James Kim, M.D., Ph.D.
Assistant Professor, Internal Medicine
Hematology/Oncology
*Zhi-Ping Liu, Ph.D.
Assistant Professor, Internal Medicine Cardiology
John Minna, M.D.
Professor, Internal Medicine and Pharmacology
Director, Hamon Center for Therapeutic
Oncology Research
Sarah M. and Charles E. Seay Distinguished Chair
in Cancer Research
Max L. Thomas Distinguished Chair in Molecular
Pulmonary Oncology
Joan Schiller, M.D.
Professor, Internal Medicine
Chief, Hematology/Oncology Division
Andrea L. Simmons Distinguished Chair
in Cancer Research
Jerry Shay, Ph.D.
Professor, Cell Biology
The Southland Financial Corporation
Distinguished Chair in Geriatrics
Michael Story, Ph.D.
Associate Professor, Radiation Oncology
Robert Timmerman, M.D.
Professor, Radiation Oncology
Effie Marie Cain Distinguished Chair in
Cancer Therapy Research
Yang Xie, Ph.D.
Assistant Professor, Clinical Sciences
population science and cancer
control program
Chul Ahn, Ph.D.
Professor, Clinical Sciences
*Ruben Amarasingham, M.D.
Assistant Professor, Internal Medicine
General Medicine
disease oriented team
(DOT) members
Patrick Leavey, M.D. (Pediatrics)
Associate Professor, Pediatrics
Ramzi Abdulrahman, M.D. (NeuroOnc)
Associate Professor, Radiation Oncology
A. Marilyn Leitch, M.D. (Breast)
Professor, Surgery
S.T. Harris Family Distinguished Chair in Breast
Surgery, in Honor of A. Marilyn Leitch, M.D.
*Kevin Albuquerque, M.D. (GynOnc)
Associate Professor, Radiation Oncology
Larry Anderson, M.D., Ph.D. (Heme)
Assistant Professor, Internal Medicine
Hematology/Oncology
Victor Aquino, M.D. (Pediatrics)
Associate Professor, Pediatrics
Yull Arriaga, M.D. (GI)
Assistant Professor, Internal Medicine
Keith Argenbright, M.D.
Associate Professor, Simmons Cancer Center
Glen Balch, M.D. (GI)
Assistant Professor, Surgery
Bijal Balasubramanian, M.B.B.S.,
Ph.D., M.P.H.
Assistant Professor, Epidemiology, Human Genetics
and Environmental Sciences,
UT School of Public Health–Dallas
*Muhammad Beg, M.D. (GI)
Assistant Professor, Internal Medicine
Michael Businelle, Ph.D.
Assistant Professor, Health Promotion and Behavioral
Sciences, UT School of Public Health–Dallas
*Ethan Halm, M.D., M.P.H.
Professor, Internal Medicine
General Medicine
Walter Family Distinguished Chair in Internal Medicine
in Honor of Albert D. Roberts, M.D.
Heidi Hamann, Ph.D.
Assistant Professor, Psychiatry
Stephen Inrig, Ph.D.
Assistant Professor, Clinical Sciences
Darla Kendzor, Ph.D.
Assistant Professor, Health Promotion and Behavioral
Sciences, UT School of Public Health–Dallas
Simon Craddock Lee, Ph.D., M.P.H.
Assistant Professor, Clinical Sciences
*Jorge Marrero, M.D., M.S.
Professor, Internal Medicine
*Mary Elizabeth Paulk, M.D.
Associate Professor, Internal Medicine
General Medicine
*Sandi Pruitt, Ph.D., M.P.H.
Assistant Professor, Clinical Sciences
Roshni Rao, M.D.
Associate Professor, Surgery
Kerem Shuval, Ph.D., M.P.H.
Assistant Professor, Epidemiology, Human Genetics
and Environmental Sciences, UT School of Public
Health–Dallas
Amit Singal, M.D.
Assistant Professor, Internal Medicine
Dedman Family Scholar in Clinical Care
Celette Sugg Skinner, Ph.D.
Professor, Clinical Sciences
Chief, Division of Behavioral and
Communications Sciences
Jasmin Tiro, Ph.D., M.P.H.
Assistant Professor, Clinical Sciences
*Adam Yopp, M.D.
Assistant Professor, Surgical Oncology
Daniel Bowers, M.D. (Pediatrics)
Associate Professor, Pediatrics
Jeffrey Cadeddu, M.D. (GU)
Professor, Urology
Ralph C. Smith, M.D. Distinguished Chair in
Minimally Invasive Urologic Surgery
*Kevin Courtney, M.D., Ph.D. (GU)
Assistant Professor, Internal Medicine
Hematology/Oncology
Eugene Frenkel, M.D. (GU)
Professor, Internal Medicine
Elaine Dewey Sammons Distinguished Chair in Cancer
2ESEARCHIN(ONOROF%UGENE0&RENKEL-$
!+ENNETH0YE0ROFESSORSHIPIN#ANCER2ESEARCH
Raymond D. and Patsy R. Nasher Distinguished Chair in
Cancer Research, in Honor of Eugene P. Frenkel, M.D.
Dan Garwood, M.D. (Breast)
Associate Professor, Radiation Oncology
Barbara Haley, M.D. (Breast)
Professor, Internal Medicine
Charles Cameron Sprague, M.D. Chair in
Clinical Oncology
*Raquibul Hannan, M.D., Ph.D. (GU)
Assistant Professor, Radiation Oncology
Amy Harker-Murray, M.D. (Breast)
Assistant Professor, Internal Medicine
Randall Hughes, M.D. (Head & Neck)
Associate Professor, Internal Medicine
James Huth, M.D. (Melanoma)
Professor, Surgery
The Occidental Chemical Chair in Cancer Research
Payal Kapur, M.D. (GU)
Associate Professor, Pathology
Jenny Li, MD (Breast)
Assistant Professor, Internal Medicine
John Mansour, M.D. (GI)
Assistant Professor, Surgery
Vitaly Margulis, M.D. (GU)
Assistant Professor, Urology
Jeffrey Meyer, M.D. (GI)
Assistant Professor, Radiation Oncology
Bruce Mickey, M.D. (NeuroOnc)
Professor, Neurological Surgery
William Kemp Clark Chair of Neurological Surgery
Harris Naina, M.D. (Heme)
Assistant Professor, Internal Medicine
Lucien Nedzi, M.D. (Head & Neck)
Associate Professor, Radiation Oncology
David Pistenmaa, M.D., Ph.D. (GU)
Professor, Radiation Oncology
David Bruton Jr. Professorship in Clinical
Cancer Research
Zora Rogers, M.D. (Pediatrics)
Professor, Pediatrics
Cynthia Rutherford, M.D. (Heme)
Professor, Internal Medicine
Barrett Family Professorship in Cancer Research
Venetia Sarode, M.D. (Breast)
Associate Professor, Pathology
Rohit Sharma, M.D. (Melanoma)
Assistant Professor, Surgery
Ann Spangler, M.D. (Breast)
Assistant Professor, Radiation Oncology
Masaya Takahashi, Ph.D. (Lung)
Associate Professor, Advanced Imaging
Research Center
Stan Taylor, M.D. (Melanoma)
Professor, Dermatology
J.B. Howell Professorship in Melanoma Education
and Detection
*Gomika Udugamasooriya, Ph.D. (GU)
Assistant Professor, Advanced Imaging
Research Center
Udit Verma, M.D. (GI)
Associate Professor, Internal Medicine
Madhuri Vusirikala, M.D. (Heme)
Associate Professor, Internal Medicine
Dawn Klemow-Reed, M.D. (Breast)
Assistant Professor, Internal Medicine
Sirisha Karri, M.D. (GI)
Assistant Professor, Internal Medicine
Saad Khan, M.D. (Head & Neck)
Assistant Professor, Internal Medicine
Nathan Kim, M.D., Ph.D. (GU)
Assistant Professor, Radiation Oncology
Prasad Koduru, Ph.D. (Heme)
Professor, Pathology
73
senior leadership
Harold C. Simmons Comprehensive Cancer Center
Annual Report 2012
President
Daniel K. Podolsky, M.D.
Director
James K.V. Willson, M.D.
Associate Director
Tim Strawderman, Ph.D.
Writer
Karen Patterson
Creative Director
Shayne Washburn
Designers
Art Garcia
Magdalena Zawojska
Photographers
Brian Coats
David Gresham
Charles Ford
Additional Photos/Images Provided As Follows:
Page 12: Image courtesy of MacMillan Laboratory
Page 14: Illustration A: By Kevin Gardner and Richard Bruick
Page 14: Image B: Courtesy of Jason Key
Page 17: Image A: By Damaris Foping
Page 17: Image B: Analyses and image by Hyunseck Kim and Michael White
Page 17: Image C: By Tadeusz F. Molinski
Page 22: By Mehau Kulyk / Photo Researchers, Inc.
Joan Schiller, M.D., and James K.V. Willson, M.D.
Page 24: Illustration A: By Ralph DeBerardinis
Page 24: Illustration B: Shutterstock
Simmons Cancer Center
James K.V. Willson, M.D., $IRECTOR
!SSOCIATE$EANFOR/NCOLOGY0ROGRAMS
0ROFESSOROF)NTERNAL-EDICINE
The Lisa K. Simmons Distinguished Chair
in Comprehensive Oncology
Joan Schiller, M.D., $EPUTY$IRECTOR
#HIEFOF(EMATOLOGY/NCOLOGY
0ROFESSOROF)NTERNAL-EDICINE
Andrea L. Simmons Distinguished
Chair in Cancer Research
Chul Ahn, Ph.D., Associate Director for
"IOSTATISTICSAND"IOINFORMATICS0ROFESSOR
of Clinical Sciences
David Boothman, Ph.D., Associate
$IRECTORFOR4RANSLATIONAL2ESEARCH
0ROFESSOROF0HARMACOLOGY2OBERT"
and Virginia Payne Professorship
in Oncology
Hak Choy, M.D., Associate Director for
2ADIATION/NCOLOGY0ROFESSORAND#HAIR
OF2ADIATION/NCOLOGY.ANCY"AND
Jake L. Hamon Distinguished Chair in
Therapeutic Oncology Research
David Euhus, M.D., Associate Director
FOR#LINICAL2ESEARCH0ROFESSOROF3URGERY
Co-Director of the Mary L. Brown Breast
Cancer Genetics and Risk Assesment
0ROGRAM-ARILYN2#ORRIGAN$ISTINGUISHED
Chair in Breast Cancer Surgery
Jerry Shay, Ph.D., Associate Director
FOR4RAININGAND%DUCATION0ROFESSOR
OF#ELL"IOLOGY3OUTHLAND&INANCIAL
Corporation Distinguished Chair
in Geriatrics
Celette Sugg Skinner, Ph.D., Associate
Director for Cancer Control and Population
3CIENCE0ROFESSOROF#LINICAL3CIENCES
Chief of the Division of Behavioral and
Communications Sciences
Stephen X. Skapek, M.D., Director
OF0EDIATRIC(EMATOLOGY/NCOLOGY
0ROFESSOROF0EDIATRICS#HILDRENS#ANCER
Fund Distinguished Professorship in
Pediatric Oncology Research
Michael White, Ph.D., Associate Director
FOR"ASIC3CIENCE0ROFESSOROF#ELL"IOLOGY
Sherry Wigley Crow Cancer Research
Endowed Chair, in Honor of Robert Lewis
+IRBY-$'RANT!$OVE#HAIRFOR
Research in Oncology
Page 26: Image A: By Raghu Chivukula and Joshua Mendell
Page 26: Images B, Top and Bottom: By Janaiah Kota and Joshua Mendell
Page 26: Image C, Left and Right: By Janaiah Kota and Joshua Mendell
Page 28: Image Courtesy of Cancer Genetics Program
Page 31: Image Courtesy of Cancer Genetics Program
Page 32: Image By Brekken Laboratory
Page 34: Images A, B, C: By Brekken Laboratory
Page 36: Image A: Courtesy of Lum Laboratory
Page 40: By Sidney Moulds / Photo Researchers, Inc.
Stephanie Clayton, M.H.S.M., Associate
Vice President for Cancer Programs
Page 42: Image A, Top and Bottom: By Xiumei Huang
Tim Strawderman, Ph.D., Associate
Director for Research Administration
Page 44: Image B: Courtesy of Minna Laboratory - R.M. Carstens, K.E. Huffman
Page 42: Illustration B: By Chase W. Kessinger
Page 50: Photo by Pr. M. Brauner
Page 59: Graphs Courtesy of Helen Hobbs, M.D.
Page 60: iStock
Page 64: Images A and B: Courtesy of Moncrief Cancer Institute
74
75
76
77
78
© 2013 UT Southwestern Medical Center. MKT 1119
Dallas, Texas 75390-9125
214-645-HOPE (4673)
simmonscancercenter.org