2010 – 2011 SCIENTIFIC R EPORT THE UNIVERSITY OF CHICAGO COMPREHENSIVE CANCER CENTER
THE UNIVERSITY OF CHICAGO COMPREHENSIVE CANCER CENTER 2010 – 2011 SCIENTIFIC R EPORT FROM THE DIRECTOR Dear Friends and Colleagues: It gives me great pleasure to present The University of Chicago Comprehensive Cancer Center’s 2010 – 2011 Scientific Report. The report serves as an account of the progress we have made during the past 2 years, an exciting time marked by growth and development. We have undertaken several initiatives to place personalized therapies at the forefront of clinical care, including the development of the Center for Personalized Therapeutics. The center incorporates broad genetic information into routine clinical practices to guide medical treatment decisions. We have also received renewed funding for the Pharmacogenomics of Anticancer Agents Research (PAAR) Group, which aims to improve the efficacy of cancer therapeutics. Another initiative is the 1000 Cancer Genome Project, which we launched to sequence the transcriptomes of 1000 tumors to identify new therapeutic targets and facilitate personalized treatment strategies. Adding to the repertoire of shared core facilities and further strengthening our population research efforts, we developed the Epidemiology and Research Recruitment Core (ERRC) to streamline specimen collection and implement processes for large-scale collection of interview data to ascertain individual variables and exposure history. The integration of these multiple dimensions allows investigators to conduct high-quality multidisciplinary population and clinical research studies. To serve our neighbors in the surrounding Chicago area better, in 2010 we established the Office of Community Engagement and Cancer Disparities (OCECD). The OCECD facilitates University-community partnerships through advocacy, education, and community-based research to decrease cancer health disparities, increase cancer knowledge in the community, and increase participation in clinical trials. Thus far, the OCECD has made steady progress in promoting breast cancer screening in Chicago’s black and Asian American communities. Our growth is reflected in the 81 new cancer researchers who have joined the Cancer Center over the past 5 years. These talented investigators have significantly enhanced our program with their high-quality expertise in the areas of translational and clinical oncology, surgical oncology, pediatric oncology, and population research. With a total cost of $93 million in peer-reviewed grant funding, our 220 researchers across six scientific programs have been pioneering the research and development outlined throughout the pages of this report. We continue to have the largest cancer clinical trials program in Illinois, with 900 patients enrolled into therapeutic clinical trials in 2010. We also hold leadership positions in several national clinical trials study groups, and we are one of only a handful of hospitals in the country that provides all three phases of clinical trials through programs funded by the National Cancer Institute. Our New Hospital Pavilion, soon to be completed, will further facilitate our distinguished clinical research efforts. I am pleased to say that the past 2 years have been exhilarating as we have grown and undertaken opportunities to explore new avenues in cancer research. I would like to thank our constituents for their generosity and support, without which this work would not be possible. While we celebrate our accomplishments, we hold fast to our mission to pursue the scientific efforts required to advance cancer care. With gratitude, Michelle M. Le Beau, PhD Arthur and Marian Edelstein Professor of Medicine Director, The University of Chicago Comprehensive Cancer Center Leadership and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Overview of The University of Chicago Comprehensive Cancer Center. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Accomplishments of Note . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Molecular Mechanisms of Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Table of Contents From the Director . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inside Cover Hematopoiesis and Hematological Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Immunology and Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 Advanced Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 Cancer Prevention and Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 Resources and Services . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 Highlights . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 UCCCC SCIENTIFIC REPORT 2010 – 2011 Pharmacogenomics and Experimental Therapeutics . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 1 UCCCC Leadership and Administration UCCCC LEADERSHIP AND ADMINISTRATION EXECUTIVE COMMITTEE Michelle M. Le Beau, PhD Director Arthur and Marian Edelstein Professor of Medicine Director, Cancer Cytogenetics Laboratory Marcy A. List, PhD Associate Director for Administration Scientific Director, Cancer Clinical Trials Office Marsha R. Rosner, PhD Co-Deputy Director for Basic Sciences UCCC SCIENTIFIC REPORT 2010 – 2011 Charles B. Huggins Professor Chair, Ben May Department for Cancer Research Professor of Neurobiology, Pharmacology, and Physiology Richard L. Schilsky, MD Co-Deputy Director for Clinical Sciences Professor of Medicine and Section Chief of Hematology/Oncology Habibul Ahsan, MBBS, MMedSc Associate Director for Population Research Professor of Health Studies, Medicine, and Human Genetics John Cunningham, MBBCh, MSc Professor of Pediatrics and Section Chief of Pediatric Hematology/Oncology Geoffrey L. Greene, PhD Associate Director for Basic Sciences Virginia and D.K. Ludwig Professor Associate Director, Ben May Department for Cancer Research Yves Lussier, MD φ Associate Director for Informatics Associate Professor of Medicine Director, Center for Biomedical Informatics 2 Mark J. Ratain, MD Associate Director for Clinical Sciences Walter Stadler, MD Fred C. Buffett Professor of Medicine and Surgery Leon O. Jacobson Professor of Medicine Associate Dean for Clinical Research Director, Center for Personalized Therapeutics Director, Genitourinary Program Director, Pharmacology Core Facility Gary Steinberg, MD Bruce and Beth White Family Professor of Surgery Ravi Salgia, MD, PhD Professor of Medicine Michael Vannier, MD Professor of Radiology Associate Director for Translational Sciences Ezra Cohen, MD Associate Professor of Medicine Associate Director for Education ADDITIONAL MEMBERS OF THE CANCER ADVISORY COMMITTEE Susan Cohn, MD Professor of Pediatric Hematology/Oncology Ralph Weichselbaum, MD Daniel K. Ludwig Professor and Chairman of Radiation & Cellular Oncology S. Diane Yamada, MD Professor of Obstetrics and Gynecology Chief, Section of Gynecological Oncology Everett E. Vokes, MD John E. Ultmann Professor and Chairman of Medicine Director, Pediatric Clinical Sciences Karen E. Kim, MD, MS Associate Professor of Medicine Director, Office of Community Engagement and Cancer Disparities Olufunmilayo Olopade, MBBS Walter L. Palmer Distinguished Service Professor of Medicine Associate Dean for Global Medicine Mitchell C. Posner, MD Thomas D. Jones Professor and Chief of General Surgery James Schilling, PhD Associate Director for Core Facilities Executive Director, Office of Shared Research Facilities Arieh Shalhav, MD Fritz and Mary Lee Duda Chair, Professor and Chief of Urology PROGRAM LEADERS MOLECULAR MECHANISMS OF CANCER Suzanne Conzen, MD Professor of Medicine Kay MacLeod, PhD Associate Professor, Ben May Department for Cancer Research HEMATOPOIESIS AND HEMATOLOGICAL MALIGNANCIES Wendy Stock, MD Professor of Medicine Director, Leukemia Program Michael Thirman, MD Associate Professor of Medicine IMMUNOLOGY AND CANCER Thomas Gajewski, MD, PhD Professor of Pathology and Medicine φ Dr. Lussier left UChicago in August 2011. EXTERNAL ADVISORY COMMITTEE M. Eileen Dolan, PhD Professor of Medicine James Willson, MD (Chair) Director, Harold Simmons Cancer Center Walter Stadler, MD Fred C. Buffett Professor of Medicine and Surgery Associate Dean for Clinical Research Director, Genitourinary Program ADVANCED IMAGING Lisa K. Simmons Distinguished Chair and Professor in Comprehensive Oncology The University of Texas Southwestern Medical Center at Dallas Gregory Karczmar, PhD Professor of Radiology Donald Berry, PhD Professor and Chair of Biostatistics Director, Magnetic Resonance Imaging and Spectroscopy Core Facility M.D. Anderson Cancer Center Heber MacMahon, MB, ChB Professor of Radiology Section Chief of Thoracic Radiology Habibul Ahsan, MBBS, MMedSc Associate Director for Population Research Professor of Health Studies, Medicine, and Human Genetics Brian Chiu, PhD Associate Professor of Health Studies Andrea King, PhD Professor of Psychiatry SENIOR STAFF Natalie Olinger Boden Director for Communications and Public Relations Mary Ellen Connellan, MA Executive Director, The University of Chicago Cancer Research Foundation Rajan Gopalakrishnan, MS Director for Informatics Hoyee Leong, PhD Director for Scientific Communications and Strategic Partnerships Christine Miller, MA Director for Finance Connie Skosey, RN, CCRP Director for Clinical Operations CEO, James Cancer Hospital & Solove Research Institute Professor of Cancer Research Professor of Surgery Duke University School of Medicine Gloria Petersen, PhD Purvis and Roberta Tabor Professor of Epidemiology Mayo Clinic College of Medicine Stephen E. Sallan, MD Chief of Staff Professor of Pediatrics Harvard Medical School Dana-Farber Cancer Institute Lawrence Schwartz, MD James Picker Professor and Chairman of Radiology Columbia University The Ohio State University Margaret R. Spitz, MD, MPH Professor of Epidemiology George T.Y. Chen, PhD Professor of Radiation Oncology Baylor College of Medicine Massachusetts General Hospital Daniel Sullivan, MD Professor of Radiology Mary B. Daly, MD, PhD Timothy R. Talbot Jr. Chair for Cancer Research Professor and Chair of Clinical Genetics Fox Chase Cancer Center Stan Gerson, MD Director, Comprehensive Cancer Center Asa & Patricia Shiverick and Jane Shiverick (Tripp) Professor of Hematological Oncology Case Western Reserve University Steven D. Gore, MD Professor of Oncology The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Duke University School of Medicine Marcy Bohm Waldinger, MHSA Chief Administrative Officer University of Michigan Comprehensive Cancer Center Michael J. Weber, PhD Director, Cancer Center Professor of Microbiology UCCCC SCIENTIFIC REPORT 2010 – 2011 CANCER PREVENTION AND CONTROL Michael A. Caligiuri, MD Director, Comprehensive Cancer Center H. Kim Lyerly, MD George Barth Geller Professor in Cancer Research UCCCC Leadership and Administration PHARMACOGENOMICS AND EXPERIMENTAL THERAPEUTICS University of Virginia Health System Michael J. Welch, PhD Professor of Radiology, Developmental Biology, Chemistry, and Biomedical Engineering Washington University School of Medicine Philip D. Greenberg, MD Professor of Medicine and Immunology University of Washington Scott J. Leischow, PhD Professor of Medicine and Public Health The University of Arizona 3 UCCCC SCIENTIFIC REPORT 2010 – 2011 Molecular Mechanisms of Cancer OVERVIEW 4 OUNDED IN 1973 UNDER THE LEADERSHIP OF JOHN E. Ultmann, MD, The University of Chicago Comprehensive Cancer Center (UCCCC) has a long tradition of transforming cancer care through innovative research in basic, translational, clinical, and population sciences. The UCCCC, designated as a National Cancer Institute (NCI) Cancer Center in 1974 with the award of the Cancer Center Support Grant (CCSG), has been recognized as a preeminent leader in research to prevent cancer, elucidate its complexities, and develop novel therapies for state-of-the-art patient care. Today, the UCCCC continues its reputation of excellence and innovation as one of only 40 NCI-designated comprehensive cancer centers in the nation, and one of only two such centers in Illinois. Through the continuous support of the NCI centers in the nation, and one of and the Biological Sciences Division over the only two such centers in Illinois. past 37 years, the UCCCC has strengthened and enhanced its mission to prevent, understand, and cure cancer. As a result of scientific accomplishments, our members are awarded approximately $99 million in research funding annually, with $33 million of this sum awarded by the NCI and over $23 million in non-peer-reviewed grants and contracts. The current funding base for the UCCCC, which includes 10 P01 and Center type grants, 9 U-series awards, and 2 SPORE/SCOR awards, represents a nearly 40% increase in total peer-reviewed grant support since 2006. UCCCC SCIENTIFIC REPORT 2010 – 2011 The UCCCC’s scientific community integrates 220 members across 20 academic departments and three University Divisions (Biological, Physical, and Social Sciences). Our members specialize in fields across the continuum of cancer research in a highly interactive environment. Research is organized around six established scientific programs including Molecular Mechanisms of Cancer, Hematopoiesis and Hematological Malignancies, Immunology and Cancer, Pharmacogenomics & Experimental Therapeutics, Advanced Imaging, and Cancer Prevention and Control. These Today, the UCCCC continues programs emphasize translational and interdis- its reputation of excellence and ciplinary research, and promote collaboration innovation as one of only 40 NCIamong a diverse and dedicated team of outdesignated comprehensive cancer standing researchers, physicians, and trainees. Overview F The UCCCC has been traditionally recognized for its strength in both basic and clinical research, with a strong emphasis in the areas of cell signaling, cancer genetics, and tumor immunology. For several decades, the UCCCC has been a leader in the characterization of hematological malignant diseases, the development of new treatment paradigms in head and neck cancer, and in experimental therapeutics and early phase clinical trials for cancer. In the last decade, we have gained international recognition for our programs in personalized oncology, particularly pharmacogenetics of anticancer agents, and the identification of patients at high risk for cancer, with an emphasis on minority populations. These successes highlight the UCCCC’s commitment to bringing new diagnostic tests, novel treatments, and interventions to prevent cancer into medical practice. 5 Accomplishments of Note Accomplishments of Note Personalized Therapeutics nThe UCCCC successfully renewed its NIH U01 Pharmacogenomics of Anticancer Agents Research (PAAR) Group award, which aims to improve the efficacy of anticancer drugs by defining how genetic variability impacts the variability in response to anticancer agents. nThe University, under the leadership of Dr. Mark Ratain, developed the Center for Personalized Therapeutics and is recruiting patients to a clinical study that incorporates broad genetic information into routine clinical practice to guide medical treatment decisions. nThe Laboratory for Molecular and Genomic Pathology (LMGP) is being developed to advance molecular testing in cancer diagnosis and treatment. nThe UCCCC launched the Chicago 1000 Cancer Genome Project in conjunction with the Institute for Genomics and Systems Biology (IGSB). Using the latest technologies in gene-sequencing and computational analysis, the transcriptomes of 1000 tumors are being sequenced to identify new therapeutic targets and facilitate personalized treatment strategies. UCCCC SCIENTIFIC REPORT 2010 – 2011 Population Research 6 nThe UCCCC established the Epidemiology and Research Recruitment Core to support population studies. nThe Office of Community Engagement and Cancer Disparities (OCECD), directed by Dr. Karen Kim, was established to facilitate University-community partnerships through advocacy, education, and community-based research to decrease cancer health disparities, increase cancer knowledge in the community, and increase participation in clinical trials. n900 patients were entered onto therapeutic trials in 2010. These clinical efforts focus on studies of new drugs, sequencing of multidisciplinary treatment, transplantation, organ preservation, and treatment intensification as strategies to increase cure rates and response. nThe Cancer Clinical Trials Office (CCTO) consolidated regulatory activities for all adult cancerrelated trials, developed “real-time”, web-based access for protocol priority trees, and developed interfaces between databases for clinical trials management to streamline the retrieval and transfer of clinical and patient demographic data. Accomplishments of Note Clinical Trials nThe UCCCC and The University of Chicago Medical Center (UCMC) developed the Clinical Cancer Programs Operations Group (CCPOG) to enhance clinical operations. Recruitment and Expansion nOver the past 5 years, 81 new talented cancer researchers joined the UCCCC, including faculty in translational and clinical oncology, pediatric oncology, surgical oncology, and population research. nConstruction of the New Hospital Pavilion, opening in 2013, will provide 1.2 million square feet of specialty care with a focus on cancer and advanced surgery. UCCCC SCIENTIFIC REPORT 2010 – 2011 nThe UCMC developed a new partnership with Silver Cross Hospital (New Lenox, IL) to build a 20,000-square-foot outpatient cancer treatment center scheduled to open in early 2012. 7 MOLECULAR MECHANISMS OF CANCER PROGRAM LEADERS Kay Macleod, PhD Associate Professor . of the Ben May . Department for . Cancer Research 8 Suzanne D. Conzen, MD Professor of Medicine HE MOLECULAR MECHANISMS OF CANCER PROGRAM comprises a diverse group of 46 investigators conducting basic and translational research from 12 departments with specialties including chemistry, systems biology, drug discovery, and developmental biology. The Program supports a collaborative environment between basic scientists and clinical researchers who are dedicated to elucidating the basic cell signaling and molecular mechanisms of abnormal cell growth that could lead to the discovery of innovative Molecular Mechanisms of Cancer T anticancer treatments. Particular emphasis is placed on understanding cell cycle regulation in cancerous versus normal cells, mechanistic analysis of signal transduction and apoptotic pathways, determining the structural biology of key proteins involved in cancer etiology, T H E OV E R A L L G OA L S O F T H E P R O G R A M A R E TO : UCCCC SCIENTIFIC REPORT 2010 – 2011 and delineating developmental pathways relevant to cancer. ■■Elucidate the molecular mechanisms of tissue specific and cell type-specific gene expression; ■■Determine the cellular mechanisms underlying cell growth/ division and cell survival/death; ■■Understand the multifaceted mechanisms leading to cancer metastases; ■■Use large-scale, high-throughput, and systems biology approaches to understand cancer biology; and ■■Discover novel developmental pathways relevant to cancer cell signaling. 9 Molecular Mechanisms of Cancer PROGRAM MEMBERSHIP† Eric Beyer, MD, PhD Professor of Pediatrics David Boone, PhD Assistant Professor of Medicine Steven Chmura, MD, PhD Assistant Professor of Radiation & Cellular Oncology Suzanne Conzen, MD Professor of Medicine Wei Du, PhD Professor of the Ben May Department for Cancer Research UCCCC SCIENTIFIC REPORT 2010 – 2011 Nickolai Dulin, PhD Associate Professor of Medicine Kathleen Goss, PhD Assistant Professor of Surgery Geoffrey Greene, PhD Professor of the Ben May Department for Cancer Research Rex Haydon, MD, PhD Associate Professor of Surgery Tong-Chuan He, MD, PhD Associate Professor of Surgery Yu-Ying He, PhD Assistant Professor of Medicine Akira Imamoto, PhD Associate Professor of the Ben May Department for Cancer Research Richard Jones, PhD Assistant Professor of the Ben May Department for Cancer Research Shohei Koide, PhD Associate Professor of Biochemistry & Molecular Biology Stephen Kron, MD, PhD Professor of Molecular Genetics & Cell Biology Bruce Lahn, PhD Professor of Human Genetics Ernst Lengyel, MD, PhD Professor of Obstetrics & Gynecology Marsha Rosner, PhD Professor and Chair of the Ben May Department for Cancer Research Shutsung Liao, PhD Professor of the Ben May Department for Cancer Research Benoit Roux, PhD Professor of Biochemistry & Molecular Biology Anning Lin, PhD Professor of the Ben May Department for Cancer Research Ravi Salgia, MD, PhD Professor of Medicine Hue Luu, MD Assistant Professor of Surgery Kay Macleod, PhD Associate Professor of the Ben May Department for Cancer Research Elizabeth McNally, MD, PhD Professor of Medicine Ivan Moskowitz, MD, PhD Assistant Professor of Pediatrics Lucia Schuger, MD Professor of Pathology φStephen Skapek, MD Associate Professor of Pediatrics Julian Solway, MD Professor of Medicine Michael Spiotto, MD, PhD Instructor of Radiation & Cellular Oncology Milan Mrksich, PhD Professor of Chemistry Jonathan Staley, PhD Associate Professor of Molecular Genetics & Cell Biology Piers Nash, PhD Assistant Professor of the Ben May Department for Cancer Research Wei-Jen Tang, PhD Professor of the Ben May Department for Cancer Research Marcelo Nobrega, MD, PhD Assistant Professor of Human Genetics Jerrold Turner, MD, PhD Professor of Pathology Clifton Ragsdale, PhD Associate Professor of Neurobiology Ilaria Rebay, PhD Associate Professor of the Ben May Department for Cancer Research Jalees Rehman, MD Assistant Professor of Medicine Carrie Rinker-Schaeffer, PhD Professor of Surgery Donald Vander Griend, PhD Assistant Professor of Surgery Samuel Volchenboum, MD, PhD, MS Assistant Professor of Pediatrics Kevin White, PhD Professor of Human Genetics Yingming Zhao, PhD Professor of the Ben May Department for Cancer Research Bernard Roizman, ScD Professor of Molecular Genetics & Cell Biology Deborah Lang, PhD Assistant Professor of Medicine † Reflects all Program membership during 2010-2011 φ Individuals who are no longer at the UCCCC 10 Program Highlights† †Due to space constraints, only a small representative sample of Program highlights is presented here. TSC2 INACTIVATION SPECIFICALLY KILLS RBMUTANT CANCER CELLS PARP1 INHIBITOR ACCELERATES SENESCENCE IN IRRADIATED BREAST CANCER CELLS AND TUMORS (INTERPROGRAMMATIC) The antitumor effects of ionizing radiation (IR) are determined in part by persistent DNA doublestrand breaks (DSB). IR induces the modification of chromatin domains surrounding DSBs, known as IR-induced foci (IRIF), which are implicated in DNA damage signaling and repair. An early event in the DSB response is the recruitment and activation of poly(ADP-ribose) polymerase 1 (PARP1). Stephen Kron, MD, PhD, and Ralph Weichselbaum, MD (Pharmacogenomics and Exper- imental Therapeutics Program), monitored the effects of PARP inhibition following IR of breast cancer cells and tumors. DSB repair was blocked by ABT-888 (veliparib), a PARP inhibitor currently in clinical trials, resulting in enhanced IRIF persistence and accelerated tumor cell senescence compared to IR alone. These results support targeting DSBs with PARP inhibitors as a potential therapeutic strategy to enhance radiation effectiveness. (Efimova et al., Cancer Res 70:6277-82, 2010) GEOMETRIC CUES INFLUENCE DIFFERENTIATION OF MESENCHYMAL STEM CELLS (INTRAPROGRAMMATIC) While significant efforts have been made to understand the factors that influence the differentiation of mesenchymal stem cells (MSCs), the forces governing lineage commitment remain poorly understood. UCCCC SCIENTIFIC REPORT 2010 – 2011 Inactivation of the Retinoblastoma (Rb) tumor suppressor is a common event in most human cancers, but very few approaches have targeted this event for therapeutic effect. Wei Du, PhD, recently performed a genetic screen to identify genes that modulate the cell death effects of Rb inactivation in the developing eye of Drosophila. He observed that inactivation of Tsc2 resulted in synergistic killing of tumor cells that are inactivated for pRb in both cell culture and in xenograft models. The synthetic lethality between loss of Rb and loss of Tsc2 was explained by the requirement for pRb to mitigate against oxidative stress resulting from increased protein synthesis and de novo lipid synthesis in Tsc2 mutant cells. These results suggest that inactivation of Tsc2 in Rb-deficient cancers could reduce tumor burden and be therapeutically relevant. (Li et al., Cancer Cell 17:469-80, 2010) Molecular Mechanisms of Cancer Publications 11 Molecular Mechanisms of Cancer UCCCC SCIENTIFIC REPORT 2010 – 2011 12 MSCs may be involved in the stromal support or etiology of several cancers. Bruce Lahn, PhD, and Milan Mrksich, PhD, demonstrated that cell shape can influence the differentiation of MSCs to distinct lineages. Cells exposed to a mixture of adipogenic and osteogenic differentiation cues showed differential commitment depending on adhesive area, subcellular curvature, and aspect ratio. The results indicated that geometric features that increased myosin contractility promoted osteogenesis, whereas shapes of identical area that disrupted contractility favored adipogenesis. These results indicate that geometric shaping can influence the factors that direct MSC fate that in turn are relevant to understanding the behavior of mesenchymal-like tumor cells and metastasis. (Kilian et al., PNAS 107:4872-7, 2010) RAC3 IS A NEW PROONCOGENIC PARTNER OF ERα IN BREAST CANCER Estrogen receptor alpha (ERα) plays an important role in breast cancer development and response to hormone-based therapies. Geoffrey Greene, PhD, discovered a unique role for RAC3, a Rho family GTPase, as an ERα coactivator. In a combination of overexpression, chemical inhibition, and siRNA knockdown assays, RAC3 was necessary for full ERα-induced expression of genes involved in cell proliferation, migration, and invasion. Furthermore, RAC3 overexpression in ERα-positive breast cancers correlated with a significant decrease in recurrence-free survival and an increase in the odds ratio for metastastic events. These results indicate a novel function for Rhofamily GTPases and a potential new therapeutic target for breast cancers expressing ERα. (Walker et al., Oncogene 30:1984-94, 2011) GENETIC ANALYSIS OF WHOLEGENOME DATA REVEALS DRIVING MUTATIONS OF A HEPATOCELLULAR CARCINOMA A central issue in cancer genomics is understanding the dynamics of tumor growth in relation to underlying somatic mutations. Cancer mutations are classified as driver mutations when they contribute directly to tumorigenesis and are critical for understanding the molecular biology of cancers. Using a cell-population genetic approach, Chung-I Wu, PhD, in collaboration with Kevin White, PhD, analyzed a case of hepatocellular carcinoma (HCC) to identify candidate driver mutations. Nine different sections from three tumors and seven additional sections from adjacent non-tumor tissues were sampled and subjected to exon and whole-genome sequencing. Four evolutionary lineages of tumor cells were defined from validated somatic mutations. These lineages were derived from three driver mutations affecting cell cycle control and apoptosis, which were functionally distinct from mutations that accumulated earlier. The distinct functions between these mutations suggest that genetic interactions underlie tumor growth. (Tao et al., PNAS 108:12042-7, 2011) C-MET AND VEGFR-2 ACTIVITY ARE REQUIRED FOR OVARIAN CANCER METASTASIS (INTERPROGRAMMATIC) Targeted therapies have not yet been approved for the treatment of ovarian cancer. Ernst Lengyel, MD, PhD, S. Diane Yamada, MD (Pharmacogenomics and Experimental Therapeutics Program), and colleagues investigated the efficacy and mechanism of action of foretinib, an orally available multikinase inhibitor of c-Met and vascular endothelial growth factor receptor-2 (VEGFR2) against ovarian cancer growth. Foretinib blocked tumorigenesis and reduced invasive tumor growth in genetic and xenograft mouse models by inhibiting c-Met activation, inducing cell cycle arrest, reducing ovarian cancer cell adhesion and migration, and inducing anoikis. This study provides a rationale for further clinical development of foretinib as a targeted therapeutic for ovarian cancer. (Zillhardt et al., Clin Cancer Res 17:4042-51, 2011) Grants UVA-INDUCED SKIN CANCER INVOLVES PTEN SUPPRESSION Ultraviolet (UV) radiation is the major environmental risk factor for non-melanoma skin cancer. Yu-Ying He, PhD, the recipient of an R01 award from the National Institutes of Health, has demonstrated that PTEN is a critical suppressor for human and mouse skin cancer and aims to determine the molecular consequences of UVA-induced PTEN down-regulation. This work will provide new insights into the molecular basis for UVA contribution in skin carcinogenesis. CHRONIC STRESS IMPACTS BREAST CANCER OUTCOME Mechanisms that underlie the role of chronic stress in breast cancer are poorly understood. Suzanne Conzen, MD, and Martha McClintock, PhD (Cancer Prevention and Control Program) were awarded an R01 grant from the National Cancer Institute to uncover novel stress-induced mechanisms affecting mammary tumor growth using rodent models of breast cancer previously developed to study the impact of chronic social isolation. Completion of these studies will help identify preventive interventions aimed at the identified biological processes for women who are at high risk of social isolation. TRNA IS A POTENTIAL BREAST CANCER THERAPEUTIC AGENT Funded by the Department of Defense Breast Cancer Program, Marsha Rosner, PhD, is developing ORGANOTYPIC 3-DIMENSIONAL CULTURE IS ADAPTED FOR HIGHTHROUGHPUT SCREENING Current drug screening strategies rely on cell lines cultured on plastic, which are poorly representative of the tumor microenvironment. Ernst Lengyel, MD, PhD, developed an organotypic 3D culture derived from primary human mesothelial cells, fibroblasts, and extracellular matrix. When co-cultured with primary ovarian cancer cells, the 3D culture mimics early events that occur in adhesion, invasion, and metastasis. Dr. Lengyel was awarded an R21 grant from the National Institutes of Health to establish a robust and reproducible high-throughput drug screening assay using this 3D culture system. Successful adaptation of the system will facilitate the identification of new therapeutic compounds and serve as a proof-of-concept for using organotypic cultures for other drug screens. ADVANCED MULTI-COLOR CONFOCAL AND FRAP-SAC MICROSCOPE ENHANCES IMAGING CAPABILITIES Jerrold Turner, MD, PhD, received an S10 shared instrument grant from the National Center for Research Resources to acquire the Marianas Real Time Confocal SDC microscopy system for incorporation into the Integrated Microscopy Core Facility, which serves over 165 laboratories at The University of Chicago and multiple collaborative users from neighboring institutions. The highspeed system provides users with new features including SAC, FRET, and FRAP, has simultaneous two-color imaging capabilities, and serves as an additional multicolor confocal platform for live samples. Molecular Mechanisms of Cancer a new class of RNA-based agents to treat breast tumors. Dr. Rosner has engineered specific transfer RNAs (tRNAs) that are mischarged, or have incompatibly charged amino acid and decoding capacity, which leads to the synthesis of mutated proteins that can fold incorrectly and induce apoptosis. This potential new therapeutic approach targets an essential part of the cellular machinery, making it extremely difficult for tumor cells to evolve and develop resistance to this approach. UCCCC SCIENTIFIC REPORT 2010 – 2011 13 Featured Faculty Profiles† UCCCC SCIENTIFIC REPORT 2010 – 2011 Molecular Mechanisms of Cancer †Due to space constraints, only a small representative sample of Program members is presented here. GEOFFREY GREENE, PHD Professor of the Ben May Department for Cancer Research Dr. Geoffrey Greene’s laboratory studies the molecular mechanisms by which steroids and SERMs regulate development, differentiation, cellular proliferation and survival in hormone-responsive tissues and cancers, via one or both of the two estrogen receptor subtypes, ERα and ERβ. Projects in his laboratory have direct relevance and application to breast cancer genesis, progression, treatment and prevention, as well as to the development of compounds that can be used for hormone replacement therapy in postmenopausal women. The overall objective of Dr. Greene’s research is to determine the molecular distinctions between estrogen agonism and antagonism in hormone-dependent tissues and cancers, and to use this information to identify, develop, and characterize novel compounds that can be used for hormone replacement therapy and as breast cancer chemoprevention and chemotherapeutic agents. Natural and synthetic ligands regulate diverse signaling and transcriptional networks via one or both of two estrogen receptor subtypes, ERα and ERβ. Geoffrey Greene, PhD The structural and functional events underlying ligand-specific coregulator recruitment and resultant transcriptional activation or repression are complex and still not well defined for both ERs. However, the development of diverse ER subtype-selective ligands has provided powerful molecular tools to study the linkage between ligand and transcription. Detailed structure-function information for the two ERs, a major focus of Dr. Greene’s laboratory, has proved useful both for understanding as well as designing ligands with tissue- and pathway-selective behaviors. Structural information for ERα and ERβ ligand-binding domains (LBDs) occupied by some of these ligands has helped define the relationship between receptor ligand positioning and the formation of different cofactor-binding surfaces. Combined with knowledge gained from extensive genomic and proteomic mapping studies of ER target genes and interacting proteins for both ER subtypes, it should be possible to improve breast cancer treatment and prevention strategies. In recent work, Dr. Greene’s laboratory identified RAC3 as a novel ERα co-regulator. RAC3 is a Rho family small GTPase that is associated with cytoskeletal rearrangement.1 Notably, RAC3 appears to be necessary for full ERα transcriptional activity and promotes proliferation and migration in ERα-positive breast cancer cells. In addition, RAC3 overexpression in ERα-positive breast cancers correlates with a significant decrease in recurrence-free survival and a significant increase in the odds ratio of metastasis. Dr. Greene is exploring RAC3 as a potential therapeutic target in ERα-positive breast cancers that become therapy resistant. 1 Walker MP, Zhang M, Le TP, Wu P, Lainé M, Greene GL. RAC3 is a pro-migratory co-activator of ERα. Oncogene 30:19841994, 2011. 14 Professor of the Ben May Department for Cancer Research Dr. Yingming Zhao’s research aims to develop new proteomics and chemical biology approaches for studying protein post-translational modification (PTM) pathways. He applies these technologies, in conjunction with those in biochemistry and molecular and cell biology, to discover and characterize new PTM pathways that have important implications in cancer. Dr. Zhao’s laboratory has recently described the identification and verification of a previously unreported form of PTM, lysine succinylation.1 The succinyllysine residue was initially identified by mass spectrometry and then exhaustively verified by various chemical and biochemical methods. They further showed that lysine succinylation is evolutionarily conserved, and that this PTM dynamically responds to different physiological conditions and exhibits different profiles among cancer cell lines. The high abundance of succinyllysine and the roles of other known lysine modifications in cancer biology suggest that lysine succinylation may also play a role in cancer. Dysregulation of histone modifications is intimately associated with cancer progression. Dr. Zhao’s group has identified 67 novel histone marks, a discovery that increases the current number of known histone marks by about 70%.2 They verified one of the newly identified marks, lysine crotonylation (Kcr), as a novel, evolutionarily conserved histone PTM. The unique structure and genomic localization of histone Kcr suggest that it is mechanistically and functionally different from histone lysine acetylation. These results dramatically extend the repertoire of histone PTM sites and reveal new insights into epigenetic regulations. UCCCC SCIENTIFIC REPORT 2010 – 2011 A major focus of the Zhao group is quantitative proteomics and the functional analysis of SIRT1, a protein that plays an important role in cancer and aging. To characterize networks regulated by SIRT1, Dr. Zhao’s laboratory identified and quantified 4623 Lys acetylation sites in 1800 Lys acetylation proteins, representing the largest Lys acetylome reported to date. A total of 486 Lys acetylation sites were enhanced more than 100% in response to SIRT1 knockout, notably among proteins involved in DNA damage response, cell cycle, Notch signaling, and RNA splicing pathways. The results indicate that SIRT1 targets mainly nonhistone proteins, but may indirectly regulate Yingming Zhao, PhD the acetylation levels of many additional substrates, including histones, through modulation of acetylase activity. These efforts provide key insights into mechanisms of SIRT1 functions and offer biomarker candidates for clinical evaluation of SIRT1-activator compounds. Molecular Mechanisms of Cancer YINGMING ZHAO, PHD 1 Zhang Z, Tan M, Xie Z, Dai L, Chen Y, Zhao Y. Identification of lysine succinylation as a new post-translational modification. Nat Chem Biol 7:58-63, 2011. 2 Tan M, Luo H, Lee S, Jin F, Yang JS, Montellier E, Buchou T, Cheng Z, Rousseaux S, Rajagopal N, Lu Z, Ye Z, Zhu Q, Wysocka J, Ye Y, Khochbin S, Ren B, Zhao Y. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 146:1016-1028, 2011. 15 Molecular Mechanisms of Cancer WEI DU, PHD Professor of the Ben May Department for Cancer Research Dr. Wei Du’s laboratory uses an in vivo approach to investigate the coordination of cell proliferation with differentiation during normal animal development, as well as how cells and tissues behave in response to specific genetic alterations that are frequently observed in cancer. Many of the genes that participate in these aspects of biology are well-conserved between mammals and the fruit fly Drosophila melanogaster. The fly model is an experimentally tractable and relatively simple genetic model system. Work in the Du laboratory aims to understand how genes from distinct signaling pathways work together to achieve proper tissue development and homeostasis, and to integrate discoveries from the fly with the more complex mouse and human model systems. This approach has yielded several novel findings over the past decade that have contributed to our understanding of developmental processes and tumor biology. UCCCC SCIENTIFIC REPORT 2010 – 2011 Wei Du, PhD The Retinoblastoma (Rb) tumor suppressor is frequently inactivated in a variety of cancers, so understanding how Rb-deficient cells rely on the activities of distinct genes to grow and survive could lead to novel therapeutic targeting that specifically kills tumor cells but not normal tissue. One such target identified by a genetic screen in the Du laboratory is Tsc2, which was found to be important for cell survival in the absence of Rb in both flies and human cells cultured under stress conditions.1 Inactivation of Tsc2 specifically kills Rb-deficient cells, a phenotype that depends on elevated levels of oxidative stress, and prevents tumor formation when xenografted into mice. Ongoing work on this project aims to understand the sensitivity of these cells to various other forms of stress, and seeks to identify methods to enhance or mimic this “synthetic lethal” effect of targeting Tsc2 activity in cells lacking Rb. Another major goal of the Du laboratory is to utilize the developing fly retina as a model to understand how cells coordinate a differentiation program with cell cycle arrest. Recent work on this project showed that expression of Atonal is dynamically controlled by a network of eye-specific genes, called the retinal determination factors, in collaboration with genes involved in diverse developmental programs. Previous results showed that the transition from a proliferative progenitor state to a quiescent differentiated state during retinal development involves Atonal activity, which controls expression of the CIP/KIP ortholog and cell cycle inhibitor Dacapo. Further studies into how specific developmental genes function together with the retinal determination factors during eye development are currently under way. 1 Li B, Gordon GM, Du CH, Xu J, Du W. Specific killing of Rb mutant cancer cells by inactivating TSC2. Cancer Cell 17:469-480, 2010. 16 Professor of Obstetrics/Gynecology Dr. Ernst Lengyel’s clinical practice focuses on the surgical treatment of primary and recurrent ovarian cancer. His research aims to understand ovarian cancer tumor biology and translate findings into novel therapeutic treatments that will significantly improve the survival of those with this devastating disease. Ovarian cancer is the 5th leading cause of cancer deaths among women in the United States and has the highest mortality rate of all gynecologic malignancies. Following malignant transformation of ovarian surface epithelial cells, tumor cells detach from the ovary and attach to the peritoneum or omentum, but rarely leave the peritoneal cavity.1 The disease is often diagnosed at a late stage when tumor cells have disseminated within the peritoneal cavity. Despite aggressive treatment, more than two thirds of all patients succumb to their disease within 5 years. Dr. Lengyel’s group uses primary and cultured ovarian cancer cell lines and mouse models of ovarian cancer (xenograft, genetic). They have also assembled 12 tissue microarrays using primary and metastatic ovarian tumor samples obtained from 200 patients. These samples are linked to a database containing prospective clinicopathologic and survival data on all patients with ovarian cancer that have undergone operations at The University of Chicago since 1992. His laboratory collaborates with gynecologic pathologists from the Department of Pathology as well as researchers from the Department of Biochemistry and Molecular Biology. Recent work has demonstrated that the receptor tyrosine kinase c-Met may be a good therapeutic target for breast and ovarian cancers, and that integrins can activate c-Met in a ligand-independent manner.2-4 Similarly, he has shown that targeting the urokinase plasminogen activator receptor (u-PAR) pathway in ovarian cancers is effective in preclinical studies.5 Dr. Lengyel is also exploring new MRI contrast agents to differentiate benign from malignant ovarian tumors in collaboration with Northwestern University’s Division of Hematology/Oncology. 1 UCCCC SCIENTIFIC REPORT 2010 – 2011 Projects in Dr. Lengyel’s laboratory aim to: 1) understand the early steps of ovarian cancer metastasis to the peritoneum and omentum and characterize Ernst Lengyel, MD, PhD tumor-stroma interactions during metastasis; 2) characterize and test new treatment targets in pre-clinical models; 3) investigate new agents to delay or inhibit the development of ovarian cancer; and 4) study the role of miRNAs in ovarian cancer metastasis. Molecular Mechanisms of Cancer ERNST LENGYEL, MD, PHD Lengyel E. Ovarian cancer development and metastasis. Am J Pathol 177:1053-1064, 2010. 2 Zillhardt M, Park SM, Romero I, Sawada K, Montag AG, Krausz T, Yamada SD, Peter ME, Lengyel E. Foretinib (GSK1363089) an orally available multi-kinase inhibitor of c-Met and VEGFR-2, blocks proliferation, induces anoikis, and impairs ovarian cancer metastasis. Clin Cancer Res 17:4042-4051, 2011. Zillhardt M, Christensen J, Lengyel E. An orally available small molecule inhibitor of c-Met, PF-2341066, reduces tumor burden in a pre-clinical model of ovarian cancer metastasis. Neoplasia 12:1-10, 2010. 3 Mitra AK, Sawada K, Tiwari P, Mui K, Gwin K, Lengyel E. Ligand independent activation of c-Met by fibronectin a5b1-integrin regulates ovarian cancer invasion and metastasis. Oncogene 30:1566-1576, 2011. 4 5 Kenny HA, Leonhardt P, Ladanyi A, Yamada SD, Montag AG, Im HK, Jagadeeswaran S, Shaw DE, Mazar AP, Lengyel E. Targeting the urokinase plasminogen activator receptor inhibits ovarian cancer metastasis. Clin Cancer Res 17:459-471, 2011. 17 Molecular Mechanisms of Cancer UCCCC SCIENTIFIC REPORT 2010 – 2011 RAVI SALGIA, MD, PHD Professor of Medicine Dr. Ravi Salgia, a physician-scientist with particular expertise in lung cancer, is the director of the Thoracic Oncology Program at The University of Chicago. He has been a clinical thoracic oncologist for nearly two decades and led research efforts to study key pathways in lung cancer and the potential for novel therapeutics. Early in his career, Dr. Salgia was the first to identify the inhibition of c-Kit with imatinib in vitro as well as the modulation of topoisomerase-I by c-Kit modulation. He has developed and participated in numerous clinical protocols, and has been instrumental in bringing together investigators from diverse fields to collaborate on lung cancer studies. Dr. Salgia’s laboratory was the first to identify the role of c-Met in lung cancer. Specifically, his laboratory identified particular mutations in the juxtamembrane and semaphorin domains of c-Met. His group also showed the regulation of the cytoskeleton with the juxtamembrane mutations of c-Met, especially as related to the focal adhesion protein paxillin. Furthermore, Ravi Salgia, MD, PhD Dr. Salgia has determined the biological functions of the c-Met/hepatocyte growth factor, as well as the potential for novel therapeutic inhibition. Through this work, a number of clinical trials have come to fruition. Aside from his expertise in tyrosine kinases, cytoskeletal regulation, topoisomerase-I, and downstream signal transduction molecules, Dr. Salgia and his group have initiated studies to determine the role of EPH receptors and reactive oxygen species in lung cancer. Dr. Salgia and colleagues have developed a comprehensive thoracic oncology database that combines clinical data with genomic and proteomic data obtained from various tumor tissues collected from patients with non-small cell lung cancer.1 This database will aid in the identification of potential therapeutic targets for thoracic malignancies. In recent studies, Dr. Salgia and his collaborators have demonstrated the potential for MST1R, a member of the MET receptor tyrosine kinase family, as a therapeutic target in gastroesophageal cancer, and also PKC-β and VEGFR2 as therapeutic targets in malignant pleural mesothelioma.2,3 1 Surati M, Robinson M, Nandi S, Faoro L, Demchuk C, Rolle CE, Kanteti R, Ferguson BD, Hasina R, Gangadhar TC, Salama AK, Arif Q, Kirchner C, Mendonca E, Campbell N, Limvorasak S, Villaflor V, Hensing TA, Krausz T, Vokes EE, Husain AN, Ferguson MK, Karrison TG, Salgia R. Proteomic characterization of non-small cell lung cancer in a comprehensive translational thoracic oncology database. J Clin Bioinforma 1:1-11, 2011. 2 Catenacci DV, Cervantes G, Yala S, Nelson EA, El-Hashani E, Kanteti R, El Dinali M, Hasina R, Brägelmann J, Seiwert T, Sanicola M, Henderson L, Grushko TA, Olopade O, Karrison T, Bang YJ, Kim WH, Tretiakova M, Vokes E, Frank DA, Kindler HL, Huet H, Salgia R. RON (MST1R) is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma. Cancer Biol Ther 12:9-46, 2011. 3 Loganathan S, Kanteti R, Siddiqui SS, El-Hashani E, Tretiakova M, Vigneswaran H, Cervantes G, Natarajan V, Husain AN, Vokes EE, Kindler HL, Salgia R. Role of protein kinase C β and vascular endothelial growth factor receptor in malignant pleural mesothelioma: Therapeutic implications and the usefulness of Caenorhabditis elegans model organism. J Carcinog 10:4, 2011. 18 Assistant Professor of the Ben May Department for Cancer Research Dr. Richard Jones’ laboratory is focused on understanding the role of receptor tyrosine kinase signaling networks in breast cancer. His group is developing and applying large scale protein analysis methods for monitoring the abundance, modification, and localization of signaling proteins and transcription factors involved in breast cancer progression. The specific aims of his research are to: 1) characterize the phosphorylationdependent protein interactions between ErbB receptors and their downstream mediators; 2) characterize the dynamic changes in protein abundance and modification that occur in tumor cells stimulated by members of the ErbB family; and 3) use computation modeling methods to describe the relationships between proteins in signaling networks and between proteins and cell behaviors, especially migration and invasion. Ciaccio MF, Wagner JP, Chuu C-P, Lauffenburger DA, Jones RB. Systems analysis of EGF receptor signaling dynamics with microwestern arrays. Nat Methods 7:148–155, 2010. 1 2 Liu J, Kuo WL, Seiwert TY, Lingen M, Ciaccio MF, Jones RB, Rosner MR, Cohen EEW. Effect of complementary pathway blockade on efficacy of combination enzastaurin and rapamycin. Head Neck 33:1774-1782, 2011. 3 Chevrier N, Mertins P, Artyomov MN, Shalek AK, Garber M, Iannacone M, Ciaccio MF, Gat-Viks I, Eisenhaure TM, Clauser KR, Yosef N, Tonti E, Robinson J, Sutton A, Andersen MS, Root DE, von Andrian U, Jones RB, Park H, Carr SA, Regev A, Amit I, Hacohen H. Systematic discovery of TLR signaling components delineates viral-sensing circuits. Cell 147:853-867, 2011. UCCCC SCIENTIFIC REPORT 2010 – 2011 In the past year, the Jones laboratory has described the application of the Richard Jones, PhD micro-western array methodology in building statistical models of ErbB 1 receptor tyrosine kinase coactivation networks in cervical carcinoma cells. They have additionally used this methodology to assist others in understanding the role of targeting multiple signaling pathways in head and neck cancer, and in understanding conflicting cell signals in dendritic cells.2,3 Dr. Jones has also recently described the use of novel protein analysis methodologies for understanding complex biological systems.4 Molecular Mechanisms of Cancer RICHARD JONES, PHD 4 Hause RJ, Kim HD, Leung K, Jones RB. Targeted protein-omic methods are bridging the gap between proteomics and hypothesisdriven protein analysis approaches. Expert Rev Proteomics 8:565-575, 2011. 19 Molecular Mechanisms of Cancer KAY MACLEOD, PHD Associate Professor of the Ben May Department for Cancer Research Work in Dr. Kay Macleod’s laboratory explores the role of autophagy and mitochondrial function in cancer.1 Her work centers on two main avenues of investigation: 1) the role of BNip3 and other regulators of mitochondrial function and integrity in tumor cell metabolism and progression to metastasis, and 2) the role of autophagy in regulating tumor cell migration and invasion, and how autophagy influences metastasis in vivo. UCCCC SCIENTIFIC REPORT 2010 – 2011 Kay Macleod, PhD The goals of Dr. Macleod’s research are focused on understanding how these processes modulate breast cancer progression to metastasis through the use of mouse models of breast cancer and primary human breast cancer cells in collaboration with clinical oncologists. Using these in vivo approaches and leveraging molecular, biochemical, and cell biological techniques, Dr. Macleod’s research aims to understand how tumors subvert normal responses to nutrient deprivation to promote cell migration/invasion and to activate oxidative stress responses that promote tumor growth and metastasis. For example, the Macleod laboratory has shown that BNip3 promotes mitochondrial integrity, reduces oxidative stress and suppresses mammary tumor metastasis by inhibiting Hif-1a stabilization and reducing tumor angiogenesis.2 Furthermore, BNip3 inhibits tumor cell proliferation by regulating mitochondrial fragmentation in a cell cycle-dependent manner.3 They have also shown that autophagy promotes tumor cell migration/invasion in vitro and cancer metastasis in vivo through effects on focal adhesion activity.4 By understanding how these processes contribute to cancer metastasis, the goal will be to determine how inhibiting autophagy or aspects of mitochondrial function can prevent breast cancer metastasis. Along these lines, Dr. Macleod has shown that autophagy-inducing drugs synergize with agents that cause endoplasmic reticulum stress, resulting in enhanced tumor cell killing in vitro and in vivo.5 1 Glick D, Barth S, Macleod KF. Autophagy: Cellular & Molecular Mechanisms. J Pathol 221:3-12, 2010. 2 Tracy K, Chen H, Gwinn K, Zhang Y, Rehmann J, Dorn GW II, Macleod KF. Suppression of metastasis by BNIP3 through effects on mitochondrial function and ROS. Genes Dev (under review). 3 Barth S, Zhou Y, Yang J, Zhao Y, Macleod KF. Cdk regulation of BNIP3 modulates mitochondrial ROS production during cell cycle. Mol Cell Biol (under review). 4 Sharifi M, Olson L, Chen H, Collier C, Mui S, Macleod KF. Autophagy promotes cell motility and tumor metastasis through effects on focal adhesion maturation. Cancer Res (in preparation). 5 De Raedt T, Walton Z, Lucas J, Li D, Chen Y, Maertens O, Jeong SM, Bronson RT, Normant E, Haigis MC, Manning BD, Wong K-K, Macleod KF, Cichowski, K. Developing an mTOR-inhibitor based combination cancer therapy. Cancer Cell, 2011 (in press). 20 Assistant Professor of Pediatrics Dr. Volchenboum’s laboratory is focused on using quantitative proteomics to study pediatric solid tumors. Neuroblastoma is the most common pediatric solid tumor and is responsible for 15% of deaths in children from cancer. Despite aggressive multimodal therapy, most children with high-stage neuroblastoma will die from their disease. The most powerful non-clinical prognostic indicator of aggressive disease is amplification of the MYCN oncogene. Using SILAC labeling and mass spectrometry-based proteomics, Dr. Volchenboum is probing for differences between neuroblastoma cell lines that over-express the MYCN oncogene and those that do not. Differentially expressed proteins are confirmed by antibody-based methods. The initial findings from this algorithm development were recently published (Mol Cell Proteomics 8:2011, 2009). In this study, Dr. Volchenboum’s laboratory demonstrated that spectral deconvolution through comparison of stable isotope-labeled and unlabeled peptides facilitated the classification of fragmentation ions as shifting or non-shifting. Next, they demonstrated that they could compare these groups of ions to the theoretical fragmentation pattern of the Mascot search engine-identified peptide to corroborate peptide identification. The algorithm significantly improved the sensitivity and specificity of the mass spectrometry analysis when compared to the Mascot search engine. A follow-up study using these methods on data from breast cancer cell lines is now being prepared for submission, and another manuscript describing the algorithm for identification of peptides directly from fragmentation spectra is in the final stages of development. UCCCC SCIENTIFIC REPORT 2010 – 2011 Dr. Volchenboum’s laboratory is incorporating biological pathway analysis to integrate proteomic and genomic expression data to understand the signaling pathways perturbed as a result of MYCN amplification and over-expression. Identification of important signaling pathways may lead to the development Samuel Volchenboum, . MD, PhD, MS of new targeted therapeutics. Another major scientific interest is the development of algorithms to facilitate high-throughput proteomic analysis. The current state-of-the-art methods for analysis of mass spectrometry data are highly inefficient, owing to off-line analysis that prevents modulation of data collection during the run with consequent low sensitivity and narrow dynamic range. Furthermore, current methods for protein identification rely on statistical analysis and are prone to a high false positive rate. Using stable isotope-labeled proteomic data, Dr. Volchenboum is developing methods for rapid confirmation of peptide identity based on spectral deconvolution and comparison to the fragmentation pattern of the search engine-identified peptide. They are currently extending these methods to permit rapid peptide identification directly from the captured spectra. By increasing the sensitivity and specificity of mass spectrometry-based proteomics, analysis of patient samples such as tumor biopsies or serum may be performed in real-time, rapidly enough for clinically relevant decision-making. Molecular Mechanisms of Cancer SAMUEL VOLCHENBOUM, MD, PHD, MS 21 Selected Publications Molecular Mechanisms of Cancer * : Intraprogrammatic Collaboration # : Interprogrammatic Collaboration BEYER, ERIC, MD, PHD Allen MJ, Gemel J, Beyer EC, Lal R. Atomic force microscopy of Connexin40 gap junction hemichannels reveals calcium-dependent three-dimensional molecular topography and open-closed conformations of both the extracellular and cytoplasmic faces. J Biol Chem 286:22139-46, 2011. PMC3121358 Lichtenstein A, Minogue PJ, Beyer EC, Berthoud VM. Autophagy: a pathway that contributes to connexin degradation. J Cell Sci 124:910-20, 2011. PMC3048889 UCCCC SCIENTIFIC REPORT 2010 – 2011 BOONE, DAVID, PHD Mitra S, Sammani S, Wang T, Boone DL, Meyer NJ, Dudek SM, MorenoVinasco L, Garcia JG, Jacobson JR. Role of GADD45a in Akt Phosphorylation and Ubiquitination Following Mechanical Stress-Induced Vascular Injury. Am J Respir Crit Care Med, 2011 (Epub ahead of print). # Lodolce JP, Kolodziej LE, Rhee L, Kariuki SN, Franek BS, McGreal NM, Logsdon MF, Bartulis SJ, Perera MA, Ellis NA, Adams EJ, Hanauer SB, Jolly M, Niewold TB, Boone DL. African-derived genetic polymorphisms in TNFAIP3 mediate risk for autoimmunity. J Immunol 184:7001-9, 2010. Bishop BL, Lodolce JP, Kolodziej LE, Boone DL, Tang WJ. The role of anthrolysin O in gut epithelial barrier disruption during Bacillus anthracis infection. Biochem Biophys Res Commun 394:254-9, 2010. CHMURA, STEVEN, MD, PHD # Nichols MA, Mell LK, Hasselle MD, Karrison TG, MacDermed D, Meriwether A, Witt ME, Weichselbaum RR, Chmura SJ. Outcomes in black patients with early breast cancer treated with breast conservation therapy. Int J Radiat Oncol Biol Phys 79:392-9, 2011. # Mell LK, Jeong JH, Nichols MA, Polite BN, Weichselbaum RR, Chmura SJ. Predictors of competing mortality in early breast cancer. Cancer 116:5365-73, 2010. CONZEN, SUZANNE, MD # Gehlert S, Murray A, Sohmer D, McClintock M, Conzen S, Olopade O. The importance of transdisciplinary collaborations for understanding and resolving health disparities. Soc Work Public Health 25:408-22, 2010. # Szmulewitz RZ, Chung E, Al-Ahmadie H, Daniel S, Kocherginsky M, Razmaria A, Zagaja GP, Brendler CB, Stadler WM, Conzen SD. Serum/glucocorticoidregulated kinase 1 expression in primary human prostate cancers. Prostate, 2011 (Epub ahead of print). Melhem-Bertrandt A, Chavez-Macgregor M, Lei X, Brown EN, Lee RT, MericBernstam F, Sood AK, Conzen SD, Hortobagyi GN, Gonzalez-Angulo AM. Beta-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer. J Clin Oncol 29:2645-52, 2011. PMC3139371 Rizvi SA, Liu S, Chen Z, Skau C, Pytynia M, Kovar DR, Chmura SJ, Kozmin SA. Rationally simplified bistramide analog reversibly targets actin polymerization and inhibits cancer progression in vitro and in vivo. J Am Chem Soc 132:7288-90, 2010. # Jansen SA, Conzen SD, Fan X, Markiewicz E, Krausz T, Newstead GM, Karczmar GS. In vivo MRI of early stage mammary cancers and the normal mouse mammary gland. NMR Biomed 24:880-7, 2011. # Li J, Chaudhary A, Chmura SJ, Pelizzari C, Rajh T, Wietholt C, Kurtoglu M, Aydogan B. A novel functional CT contrast agent for molecular imaging of cancer. Phys Med Biol 55:4389-97, 2010. DU, WEI, PHD # Aydogan B, Li J, Rajh T, Chaudhary A, Chmura SJ, Pelizzari C, Wietholt C, Kurtoglu M, Redmond P. AuNP-DG: 22 deoxyglucose-labeled gold nanoparticles as X-ray computed tomography contrast agents for cancer imaging. Mol Imaging Biol 12:463-7, 2010. * # Li B, Wang CZ, He TC, Yuan CS, Du W. Antioxidants potentiate American ginseng-induced killing of colorectal cancer cells. Cancer Lett 289:62-70, 2010. PMC2824022 * # Li B, Zhao J, Wang CZ, Searle J, He TC, Yuan CS, Du W. Ginsenoside Rh2 induces apoptosis and paraptosis-like cell death in colorectal cancer cells through activation of p53. Cancer Lett 301:185-92, 2011. PMC3022099 Searle JS, Li B, Du W. Targeting Rb mutant cancers by inactivating TSC2. Oncotarget 1:228-32, 2010. PMC2920149 Li B, Gordon GM, Du CH, Xu J, Du W. Specific killing of Rb mutant cancer cells by inactivating TSC2. Cancer Cell 17:469-80, 2010. PMC2873973 DULIN, NICKOLAI, PHD # O’Sullivan JA, Zloza A, Kohlhapp FJ, Moore TV, Lacek AT, Dulin NO, Guevara-Patino JA. Priming with very low-affinity peptide ligands gives rise to CD8(+) T-cell effectors with enhanced function but with greater susceptibility to transforming growth factor (TGF) betamediated suppression. Cancer Immunol Immunother 60:1543-51, 2011. GOSS, KATHLEEN, PHD # Zhu H, Dougherty U, Robinson V, Mustafi R, Pekow J, Kupfer S, Li YC, Hart J, Goss K, Fichera A, Joseph L, Bissonnette M. EGFR Signals Downregulate Tumor Suppressors miR-143 and miR-145 in Western Diet-Promoted Murine Colon Cancer: Role of G1 Regulators. Mol Cancer Res 9:960-75, 2011. # Khramtsov AI, Khramtsova GF, Tretiakova M, Huo D, Olopade OI, Goss KH. Wnt/beta-catenin pathway activation is enriched in basal-like breast cancers and predicts poor outcome. Am J Pathol 176:2911-20, 2010. GREENE, GEOFFREY, PHD Liu H, Bockhorn J, Dalton R, Chang YF, Qian D, Zitzow LA, Clarke MF, Greene GL. Removal of lactate dehydrogenaseelevating virus from human-in-mouse breast tumor xenografts by cell-sorting. J Virol Methods 173:266-70, 2011. PMC3086718 Walker MP, Zhang M, Le TP, Wu P, Laine M, Greene GL. RAC3 is a pro-migratory co-activator of ERalpha. Oncogene 30:1984-94, 2011. PMC3084334 HAYDON, REX, MD, PHD Zuo GW, Kohls CD, He BC, Chen L, Zhang W, Shi Q, Zhang BQ, Kang Q, Luo J, Luo X, Wagner ER, Kim SH, Restegar F, Haydon RC, Deng ZL, Luu HH, He TC, Luo Q. The CCN proteins: important signaling mediators in stem cell differentiation and tumorigenesis. Histol Histopathol 25:795-806, 2010. PMC2922104 Chen L, Jiang W, Huang J, He BC, Zuo GW, Zhang W, Luo Q, Shi Q, Zhang BQ, Wagner ER, Luo J, Tang M, Wietholt C, Luo X, Bi Y, Su Y, Liu B, Kim SH, He CJ, Hu Y, Shen J, Rastegar F, Huang E, Gao Y, Gao JL, Zhou JZ, Reid RR, Luu HH, Haydon RC, He TC, Deng ZL. Insulinlike growth factor 2 (IGF-2) potentiates BMP-9-induced osteogenic differentiation and bone formation. J Bone Miner Res 25:2447-59, 2010. * Avedian RS, Haydon RC, Peabody TD. Multiplanar osteotomy with limited wide margins: a tissue preserving surgical technique for high-grade bone sarcomas. Clin Orthop Relat Res 468:2754-64, 2010. PMC3049617 # Wagner ER, He BC, Chen L, Zuo GW, Zhang W, Shi Q, Luo Q, Luo X, Liu B, Luo J, Rastegar F, He CJ, Hu Y, Boody B, Luu HH, He TC, Deng ZL, Haydon RC. Therapeutic Implications of PPARgamma in Human Osteosarcoma. PPAR Res 2010:956427, 2010. PMC2825651 # He BC, Chen L, Zuo GW, Zhang W, Bi Y, Huang J, Wang Y, Jiang W, Luo Q, Shi Q, Zhang BQ, Liu B, Lei X, Luo J, Luo X, Wagner ER, Kim SH, He CJ, Hu Y, Shen J, Zhou Q, Rastegar F, Deng ZL, Luu HH, He TC, Haydon RC. Synergistic antitumor effect of the activated PPARgamma and retinoid receptors on HE, TONG-CHUAN, MD, PHD Wagner ER, Zhu G, Zhang BQ, Luo Q, Shi Q, Huang E, Gao Y, Gao JL, Kim SH, Rastegar F, Yang K, He BC, Chen L, Zuo GW, Bi Y, Su Y, Luo J, Luo X, Huang J, Deng ZL, Reid RR, Luu HH, Haydon RC, He TC. The therapeutic potential of the Wnt signaling pathway in bone disorders. Curr Mol Pharmacol 4:14-25, 2011. * # Rastegar F, Gao JL, Shenaq D, Luo Q, Shi Q, Kim SH, Jiang W, Wagner ER, Huang E, Gao Y, Shen J, Yang K, He BC, Chen L, Zuo GW, Luo J, Luo X, Bi Y, Liu X, Li M, Hu N, Wang L, Luther G, Luu HH, Haydon RC, He TC. Lysophosphatidic acid acyltransferase beta (LPAATbeta) promotes the tumor growth of human osteosarcoma. PLoS One 5:e14182, 2010. PMC2995727 # Wagner ER, Luther G, Zhu G, Luo Q, Shi Q, Kim SH, Gao JL, Huang E, Gao Y, Yang K, Wang L, Teven C, Luo X, Liu X, Li M, Hu N, Su Y, Bi Y, He BC, Tang N, Luo J, Chen L, Zuo G, Rames R, Haydon RC, Luu HH, He TC. Defective osteogenic differentiation in the development of osteosarcoma. Sarcoma 2011:325238, 2011. PMC3061279 HE, YU-YING, PHD * Han W, Ming M, He TC, He YY. Immunosuppressive cyclosporin A activates AKT in keratinocytes through PTEN suppression: implications in skin carcinogenesis. J Biol Chem 285:1136977, 2010. PMC2857015 Ming M, Han W, Maddox J, Soltani K, Shea CR, Freeman DM, He YY. UVBinduced ERK/AKT-dependent PTEN suppression promotes survival of epidermal keratinocytes. Oncogene 29:492-502, 2010. PMC2813408 Ming M, Feng L, Shea CR, Soltani K, Zhao B, Han W, Smart RC, Trempus CS, He YY. PTEN Positively Regulates UVBInduced DNA Damage Repair. Cancer Res 71:5287-95, 2011. PMC3148338 Han W, Ming M, He YY. Caffeine promotes ultraviolet B-induced apoptosis in human keratinocytes without complete DNA repair. J Biol Chem 286:22825-32, 2011. PMC3123050 Ming M, Shea CR, Feng L, Soltani K, He YY. UVA induces lesions resem- bling seborrheic keratoses in mice with keratinocyte-specific PTEN downregulation. J Invest Dermatol 131:1583-6, 2011. PMC3116047 Ming M, Shea CR, Guo X, Li X, Soltani K, Han W, He YY. Regulation of global genome nucleotide excision repair by SIRT1 through xeroderma pigmentosum C. PNAS 107:22623-8, 2010. PMC3012476 Lei X, Liu B, Han W, Ming M, He YY. UVB-Induced p21 degradation promotes apoptosis of human keratinocytes. Photochem Photobiol Sci 9:1640-8, 2010. PMC3035101 IMAMOTO, AKIRA, PHD Seo JH, Wood LJ, Agarwal A, O’Hare T, Elsea CR, Griswold IJ, Deininger MW, Imamoto A, Druker BJ. A specific need for CRKL in p210BCR-ABL-induced transformation of mouse hematopoietic progenitors. Cancer Res 70:7325-35, 2010. PMC2940946 JONES, RICHARD, PHD Ciaccio MF, Wagner JP, Chuu CP, Lauffenburger DA, Jones RB. Systems analysis of EGF receptor signaling dynamics with microwestern arrays. Nat Methods 7:148-55, 2010. PMC2881471 * # Liu J, Kuo WL, Seiwert TY, Lingen M, Ciaccio MF, Jones RB, Rosner MR, Cohen EE. Effect of complementary pathway blockade on efficacy of combination enzastaurin and rapamycin. Head Neck, 2011 (Epub ahead of print). * Liu BA, Jablonowski K, Shah EE, Engelmann BW, Jones RB, Nash PD. SH2 domains recognize contextual peptide sequence information to determine selectivity. Mol Cell Proteomics 9:2391-404, 2010. 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Role of protein kinase C beta and vascular endothelial growth factor receptor in malignant pleural mesothelioma: Therapeutic implications and the usefulness of Caenorhabditis elegans model organism. J Carcinog 10:4, 2011. PMC3049271 TANG, WEI-JEN, PHD Guo Q, Manolopoulou M, Bian Y, Schilling AB, Tang WJ. Molecular basis for the recognition and cleavages of IGF-II, TGF-alpha, and amylin by human insulin-degrading enzyme. J Mol Biol 395:430-43, 2010. PMC2813390 Ralat LA, Kalas V, Zheng Z, Goldman RD, Sosnick TR, Tang WJ. Ubiquitin is a novel substrate for human insulin-degrading enzyme. J Mol Biol 406:454-66, 2011. PMC3064465 Ralat LA, Guo Q, Ren M, Funke T, Dickey DM, Potter LR, Tang WJ. Insulin-degrading enzyme modulates the natriuretic peptide-mediated signaling response. J Biol Chem 286:4670-9, 2011. PMC3039328 27 Molecular Mechanisms of Cancer UCCCC SCIENTIFIC REPORT 2010 – 2011 Ren M, Guo Q, Guo L, Lenz M, Qian F, Koenen RR, Xu H, Schilling AB, Weber C, Ye RD, Dinner AR, Tang WJ. Polymerization of MIP-1 chemokine (CCL3 and CCL4) and clearance of MIP-1 by insulindegrading enzyme. EMBO J 29:3952-66, 2010. PMC3020635 Ivancic D, Katzman RB, Grimm G, Lee G, Fryer J, Nusrat A, Turner JR, Barrett TA. Epithelial NF-kappaB enhances transmucosal fluid movement by altering tight junction protein composition after T cell activation. Am J Pathol 176:158-67, 2010. PMC2797878 TURNER, JERROLD, MD, PHD VANDER GRIEND, DONALD, PHD Raleigh DR, Boe DM, Yu D, Weber CR, Marchiando AM, Bradford EM, Wang Y, Wu L, Schneeberger EE, Shen L, Turner JR. Occludin S408 phosphorylation regulates tight junction protein interactions and barrier function. J Cell Biol 193:56582, 2011. PMC3087007 Vander Griend DJ, D’Antonio J, Gurel B, Antony L, Demarzo AM, Isaacs JT. Cell-autonomous intracellular androgen receptor signaling drives the growth of human prostate cancer initiating cells. Prostate 70:90-9, 2010. PMC2788041 * # Chen L, Park SM, Tumanov AV, Hau A, Sawada K, Feig C, Turner JR, Fu YX, Romero IL, Lengyel E, Peter ME. CD95 promotes tumour growth. Nature 465:492-6, 2010. PMC2879093 Yu D, Marchiando AM, Weber CR, Raleigh DR, Wang Y, Shen L, Turner JR. MLCK-dependent exchange and actin binding region-dependent anchoring of ZO-1 regulate tight junction barrier function. PNAS 107:8237-41, 2010. PMC2889526 Marchiando AM, Shen L, Graham WV, Weber CR, Schwarz BT, Austin JR 2nd, Raleigh DR, Guan Y, Watson AJ, Montrose MH, Turner JR. Caveolin1-dependent occludin endocytosis is required for TNF-induced tight junction regulation in vivo. J Cell Biol 189:111-26, 2010. PMC2854371 Weber CR, Raleigh DR, Su L, Shen L, Sullivan EA, Wang Y, Turner JR. Epithelial myosin light chain kinase activation induces mucosal interleukin-13 expression to alter tight junction ion selectivity. J Biol Chem 285:12037-46, 2010. PMC2852941 Raleigh DR, Marchiando AM, Zhang Y, Shen L, Sasaki H, Wang Y, Long M, Turner JR. Tight junction-associated MARVEL proteins marveld3, tricellulin, and occludin have distinct but overlapping functions. Mol Biol Cell 21:1200-13, 2010. PMC2847524 # Pekow JR, Hetzel JT, Rothe JA, Hanauer SB, Turner JR, Hart J, Noffsinger A, Huo D, Rubin DT. Outcome after surveillance of low-grade and indefinite dysplasia in patients with ulcerative colitis. Inflamm Bowel Dis 16:1352-6, 2010. PMC3046461 Tang Y, Clayburgh DR, Mittal N, Goretsky T, Dirisina R, Zhang Z, Kron M, 28 D’Antonio JM, Vander Griend DJ, Antony L, Ndikuyeze G, Dalrymple SL, Koochekpour S, Isaacs JT. Loss of androgen receptor-dependent growth suppression by prostate cancer cells can occur independently from acquiring oncogenic addiction to androgen receptor signaling. PLoS One 5:e11475, 2010. PMC2900211 WHITE, KEVIN, PHD # Stoddart A, McNerney ME, Bartom E, Bergerson R, Young DJ, Qian Z, Wang J, Fernald AA, Davis EM, Larson RA, White KP, Le Beau MM. Genetic pathways leading to therapy-related myeloid neoplasms. Mediterr J Hematol Infect Dis 3:e2011019, 2011. PMC3113274 # Godley LA, Cunningham J, Dolan ME, Huang RS, Gurbuxani S, McNerney ME, Larson RA, Leong H, Lussier Y, Onel K, Odenike O, Stock W, White KP, Le Beau MM. An integrated genomic approach to the assessment and treatment of acute myeloid leukemia. Semin Oncol 38:21524, 2011. Negre N, Brown CD, Shah PK, Kheradpour P, Morrison CA, Henikoff JG, Feng X, Ahmad K, Russell S, White RA, Stein L, Henikoff S, Kellis M, White KP. A comprehensive map of insulator elements for the Drosophila genome. PLoS Genet 6:e1000814, 2010. PMC2797089 Tao Y, Ruan J, Yeh SH, Lu X, Wang Y, Zhai W, Cai J, Ling S, Gong Q, Chong Z, Qu Z, Li Q, Liu J, Yang J, Zheng C, Zeng C, Wang HY, Zhang J, Wang SH, Hao L, Dong L, Li W, Sun M, Zou W, Yu C, Li C, Liu G, Jiang L, Xu J, Huang H, Li C, Mi S, Zhang B, Chen B, Zhao W, Hu S, Zhuang SM, Shen Y, Shi S, Brown C, White KP, Chen DS, Chen PJ, Wu CI. Rapid growth of a hepatocellular carcinoma and the driving mutations revealed by cell-population genetic analysis of whole-genome data. PNAS 108:12042-7, 2011. PMC3141952 Al-Dhaheri M, Wu J, Skliris GP, Li J, Higashimato K, Wang Y, White KP, Lambert P, Zhu Y, Murphy L, Xu W. CARM1 is an important determinant of ERalpha-dependent breast cancer cell differentiation and proliferation in breast cancer cells. Cancer Res 71:2118-28, 2011. PMC3076802 ZHAO, YINGMING, PHD Lee S, Chen Y, Luo H, Wu AA, Wilde M, Schumacker PT, Zhao Y. The first global screening of protein substrates bearing protein-bound 3,4-Dihydroxyphenylalanine in Escherichia coli and human mitochondria. J Proteome Res 9:5705-14, 2010. PMC2974785 Zhang Z, Tan M, Xie Z, Dai L, Chen Y, Zhao Y. Identification of lysine succinylation as a new post-translational modification. Nat Chem Biol 7:58-63, 2011. PMC3065206 Zeng SX, Li Y, Jin Y, Zhang Q, Keller DM, McQuaw CM, Barklis E, Stone S, Hoatlin M, Zhao Y, Lu H. Structure-specific recognition protein 1 facilitates microtubule growth and bundling required for mitosis. Mol Cell Biol 30:935-47, 2010. PMC2815565 Selected Major Grants and Awards INVESTIGATOR TITLE PROJECT START DATE END DATE TOTAL ANNUAL COST 6/15/2010 5/31/2014 7/1/2010 CLASS FUNDING AGENCY $481,585 R01 National Heart, Lung, and Blood Institute 6/30/2015 $411,843 R01 National Institutes . of Health Connexons in cardiovcascular cell communication ERIC BEYER Biology of lens intercellular communication SUZANNE CONZEN Identifying mechanisms linking stress biology to human breast cancer 6/20/2011 4/30/2016 $319,238 R01 National Cancer Institute SUZANNE CONZEN The role of SGK1 in triple-negative breast cancer resistance to treatment 9/30/2010 8/31/2012 $185,250 R21 National Cancer Institute WEI DU A novel approach to target Rb . mutant cancers 4/1/2011 3/31/2016 $319,238 R01 National Cancer Institute WEI DU Specific killing of prostate cancers with inactivated Rb pathway 3/1/2010 3/31/2013 $234,000 N/A Department of Defense GEOFFREY GREENE Structure-function analysis of ER in the presence of TSEC mixtures 8/31/2010 8/31/2011 $254,118 N/A Pfizer, Inc. GEOFFREY GREENE Multi-domain assembly of nuclear estrogen receptors: structural . insights into ER-positive breast . cancer therapeutics 4/1/2011 3/31/2013 $236,334 N/A Department of Defense BRUCE LAHN Development of the replica barcode selection assay 9/1/2010 8/31/2012 $234,000 R21 National Institutes . of Health BRUCE LAHN Investigating the role of gene occlusion in cellular aging 10/1/2010 9/30/2014 $234,000 N/A The Ellison Medical Foundation DEBORAH LANG The role of PAX3 in melanoma metastasis 7/1/2011 6/30/2015 $125,000 N/A American Cancer Society ERNST LENGYEL Adaptation of an organotypic . 3 dimensional culture for highthroughput screening 7/1/2011 6/30/2012 $156,000 R21 National Institutes . of Health MILAN MRKSICH Nanomaterials for cancer diagnostics and therapeutics 9/21/2010 7/31/2015 $157,104 N/A National Cancer Institute MARSHA ROSNER tRNA as therapeutic agent of . breast cancer 7/1/2010 7/31/2012 $214,499 N/A Department of Defense MARSHA ROSNER tRNA and its activation targets . as biomarkers and regulators of . breast cancer 9/1/2010 8/31/2012 $206,374 N/A Department of Defense RAVI SALGIA Testing c-Met antibody and SMI efficacy 3/5/2010 9/4/2011 $112,099 N/A Lilly, Eli & Company RAVI SALGIA The role of CXCR4 inhibition in combination with cytotoxic chemotherapy in lung cancer: . pre-clinical modeling and proposed clinical study 9/7/2010 9/6/2012 $105,000 N/A Lilly, Eli & Company RAVI SALGIA Testing c-Met antibody and SMI efficacy 3/5/2010 9/4/2011 $112,099 N/A Lilly, Eli & Company STEPHEN SKAPEK Molecular targeting in nonrhabdomyosarcoma soft tissue sarcoma 7/1/2011 6/30/2013 $120,111 N/A St. Baldrick's Foundation UCCCC SCIENTIFIC REPORT 2010 – 2011 ERIC BEYER Molecular Mechanisms of Cancer The Molecular Mechanisms of Cancer Program has a funding base of $22,314,658 in annual total costs (current as of July 2011). This sum includes $7,260,372 in NCI funding and $11,077,184 in other NIH funding. Due to space constraints, only selected new awards since January 1, 2010 of $100,000 or greater in annual total costs are listed here. 29 UCCCC SCIENTIFIC REPORT 2010 – 2011 Molecular Mechanisms of Cancer HEMATOPOIESIS AND HEMATOLOGICAL MALIGNANCIES PROGRAM LEADERS Wendy Stock, MD Professor of Medicine 30 Michael Thirman, MD Associate Professor of Medicine HE HEMATOPOIESIS AND HEMATOLOGICAL MALIGNANCIES Program focuses on the cytogenetic and molecular analysis of hematological malignant diseases. The Program brings together a collaborative group of 28 members spanning three academic departments with an integrated focus on basic, translational, and clinical research. Members of this program have successfully identified genes involved in both normal hematopoiesis and the pathogenesis of leukemias and lymphomas, and translated their findings into novel molecularly targeted therapeutic approaches for hematological malignancies. ■■Determine mechanisms of hematopoiesis; ■■Define molecular and genetic risk groups in leukemia and lymphoma; UCCCC SCIENTIFIC REPORT 2010 – 2011 M E M B E R S O F T H E H E M ATO P O I E S I S A N D H E M ATO LO G I C A L M A L I G N A N C I E S P R O G R A M S E E K TO : Hematopoiesis and Hematological Malignancies T ■■Develop and characterize animal models of leukemia and lymphoma; and ■■Develop novel risk-adapted clinical trials for hematologic malignancies. 31 UCCCC SCIENTIFIC REPORT 2010 – 2011 Hematopoiesis and Hematological Malignancies PROGRAM MEMBERSHIP† John Anastasi, MD Associate Professor of Pathology φJames Nachman, MD Professor of Pediatrics Andrew Artz, MD Assistant Professor of Medicine Olatoyosi Odenike, MD Assistant Professor of Medicine Beverly Baron, MD Associate Professor of Pathology Kenan Onel, MD, PhD Associate Professor of Pediatrics Jianjun Chen, PhD Assistant Professor of Medicine Janet Rowley, MD, DSc Professor of Medicine Kenneth Cohen, MD Assistant Professor of Medicine Dorothy Sipkins, MD, PhD Assistant Professor of Medicine John Cunningham, MBBCh, MSc Professor of Pediatrics Sonali Smith, MD Associate Professor of Medicine Jill de Jong, MD, PhD Assistant Professor of Pediatrics Wendy Stock, MD Professor of Medicine Lucy Godley, MD, PhD Associate Professor of Medicine Michael Thirman, MD Associate Professor of Medicine Fotini Gounari, PhD, DSc Assistant Professor of Medicine φKoen van Besien, MD Professor of Medicine Sandeep Gurbuxani, MBBS, PhD Assistant Professor of Pathology James Vardiman, MD Professor of Pathology Barbara Kee, PhD Associate Professor of Pathology Amittha Wickrema, PhD Associate Professor of Medicine Richard Larson, MD Professor of Medicine φYanming Zhang, MD Assistant Professor of Medicine Michelle Le Beau, PhD Professor of Medicine Todd Zimmerman, MD Associate Professor of Medicine Susana Marino, MD, PhD Associate Professor of Pathology Jennifer McNeer, MD Assistant Professor of Pediatrics † Reflects all Program membership during 2010-2011 φ Individuals who are no longer at the UCCCC 32 Program Highlights† †Due to space constraints, only a small representative sample of Program highlights is presented here. MIR-17-92 MAY SERVE AS A THERAPEUTIC TARGET IN MLLREARRANGED ACUTE LEUKEMIA (INTRAPROGRAMMATIC) TEMSIROLIMUS SHOWS ACTIVITY IN NON-MANTLE CELL NON-HODGKIN LYMPHOMA SUBTYPES (INTRA/ INTERPROGRAMMATIC) Although the rapamycin (mTOR) pathway is a validated target in mantle cell lymphoma, it has not been extensively evaluated in other lymphomas. In collaboration with Dr. Koen van Besien, Pharmacogenomics and Experimental Therapeutics Program members Drs. Theodore Karrison and Everett Vokes, Sonali Smith, MD, conducted a phase II trial to examine the response rate of temsirolimus in patients with relapsed aggressive and indolent lymphomas. Temsirolimus, a water soluble rapalog, is currently approved for the treatment of metastatic renal cell carcinoma. Patients with diffuse large B-cell lymphoma (DLBCL) or transformed follicular lymphoma showed an overall and complete response rate of 28.1% and 12.5%, respectively, while patients with follicular lymphoma showed rates of 53.8% and 25.6%, respectively, with mild toxicity. These results support further evaluation of the mTOR pathway as a therapeutic target in these diseases. (Smith et al., J Clin Oncol 28:4740-6, 2010) UCCCC SCIENTIFIC REPORT 2010 – 2011 The microRNA (miR)-17-92 cluster is frequently overexpressed in mixed lineage leukemia (MLL)-rearranged acute leukemias. Jianjun Chen, PhD, and colleagues including Drs. Michael Thirman and Janet Rowley, demonstrated that MLL fusion proteins exhibit stronger direct binding to the miR-17-92 locus than wild-type MLL. Forced expression of the miR-17-92 cluster significantly increased the tertiary colony formation capacity of normal mouse bone marrow progenitor cells, and cooperated with MLL fusion proteins in transforming these cells. The investigators also identified over 360 potential miR-17-92 target genes, which are significantly enriched during cell differentiation, hematopoiesis, apoptosis, and the cell cycle. These results indicate that miR-17-92 may play an essential role in the development of MLL-associated leukemias, and suggest that this cluster may serve as a potential target for therapeutic intervention. (Mi et al., PNAS 107:3710-5, 2010) kowitz (Molecular Mechanisms of Cancer Program), constructed transgenic mice expressing DNMT3B7, a truncated DNMT3B isoform commonly found in cancer cells, to determine its effect on DNA methylation. DNMT3B7 transgenic mice exhibited altered embryonic development including lymphopenia. When bred with Eμ-Myc transgenic mice, DNMT3B7 expression accelerated lymphomagenesis, increased global DNA methylation, and led to increased chromosomal rearrangements. These data suggest that truncated DNMT3B isoforms can contribute to the redistribution of DNA methylation that occurs in cancer. (Shah et al., Cancer Res 70:5840-50, 2010) Hematopoiesis and Hematological Malignancies Publications DNMT3B7 DISRUPTS EMBRYONIC DEVELOPMENT AND ACCELERATES LYMPHOMAGENESIS (INTRA/ INTERPROGRAMMATIC) Mechanisms by which cancer cells acquire epigenetic changes, including abnormal methylation patterns, are not well understood. Cancer cells commonly express aberrant DNA methyltransferase 3B transcripts. Lucy Godley, MD, PhD, and colleagues including Drs. Michelle Le Beau, John Anastasi, and Ivan Mos- 33 Hematopoiesis and Hematological Malignancies UCCCC SCIENTIFIC REPORT 2010 – 2011 ARSENIC TRIOXIDE IMPROVES SURVIVAL FOR ADULTS WITH APL (INTRAPROGRAMMATIC) Arsenic trioxide is an effective treatment for patients with relapsed acute promyelocytic leukemia (APL). In a randomized phase III trial, Richard Larson, MD, and Wendy Stock, MD, examined the efficacy of arsenic trioxide consolidation in 481 patients with APL in first remission. Eventfree survival and disease-free survival were significantly improved for patients assigned to arsenic trioxide consolidation (80% and 90%, respectively) compared to patients assigned to standard consolidation therapy (63% and 70%, respectively) at 3 years. These data demonstrate that the addition of arsenic trioxide consolidation to standard induction and consolidation therapy significantly improves event-free and disease-free survival in adults with newly diagnosed APL. (Powell et al., Blood 116:3751-7, 2010) HIGH-DOSE CYTARABINE/ MITOXANTRONE FOLLOWED BY HEMATOPOIETIC STEM CELL TRANSPLANT IS A NEW TREATMENT APPROACH FOR T-MN (INTRA/ INTERPROGRAMMATIC) A standard remission induction and post-remission therapy for patients with therapy-related myeloid neoplasms (t-MN) does not exist. Lucy Godley, MD, PhD, and Richard Larson, MD, along with Hematopoiesis and Hematological Malignancies Program members including Drs. Odenike, Artz, van Besien, Zhang, Le Beau, and Stock, and Dr. Christopher Daugherty (Pharmacogenomics and Experimental Therapeutics Program), developed a uniform prospective treatment approach for patients with t-MN. Using a single induction regimen of high-dose cytarabine and mitoxan 34 trone, followed by hematopoietic cell transplant whenever possible, the investigators observed a complete remission rate of 66%, partial remission rate of 16%, and overall response rate of 82%. Furthermore, autologous stem cells that provided durable and adequate graft function were collected from selected patients in remission from t-MN. The overall approach was well-tolerated and efficacious, even in older patients and those with comorbidities, allowing support for curative treatment strategies. (Godley et al., Leuk Lymphoma 51:995-1006, 2010) VARIANTS AT 6Q21 IMPLICATE PRDM1 IN THE ETIOLOGY OF THERAPY-INDUCED SECOND MALIGNANCIES AFTER HODGKIN LYMPHOMA (INTERPROGRAMMATIC) Kenan Onel, MD, PhD, along with Drs. R. Stephanie Huang (Pharmacogenomics and Experimental Therapeutics Program), and Olufunmilayo Olopade (Cancer Prevention and Control Program), discovered two genetic variations on chromosome band 6q21 that can predict the risk for developing secondary cancers in pediatric patients undergoing radiation therapy for Hodgkin lymphoma. Hematopoiesis and Hematological Malignancies UCCCC SCIENTIFIC REPORT 2010 – 2011 Nearly 20% of these patients develop secondary cancers within 30 years of treatment. Dr. Onel performed a genome-wide association study and found that secondary cancers were strongly associated with genetic variations resulting in decreased expression of PRDM1 gene and impaired induction of PRDM1 after radiation exposure. These findings indicate a role for PRDM1 as a radiation-responsive tumor suppressor and will facilitate the understanding of secondary tumor development in cancer patients treated with radia- tion therapy. (Best et al., Nat Med 17:941-3, 2011) Grants NUCLEAR ARCHITECTURE OF LEUKEMIA STEM CELLS FACILITATES GENETIC ANALYSIS OF T-AML Through funding from the Cancer Research Foundation (CRF), John Cunningham, MBBCh, MSc, is exploring the nuclear architecture of therapy-related acute myeloid leukemia (t-AML) stem cells and determining whether it contributes to the initiation and progression of leukemia as well as the resistance of leukemic stem cells to chemotherapy. By analyzing the distribution and modification of histones, a map of gene regulatory regions in both normal leukemic stem cells is being developed. These efforts will enhance the ability to analyze complex gene regulatory networks that regulate t-AML and facilitate the identification of novel therapeutic targets. 35 Hematopoiesis and Hematological Malignancies UCCCC SCIENTIFIC REPORT 2010 – 2011 36 THE MIR-17-92 CLUSTER ENHANCES ACUTE MYELOID LEUKEMIA A cluster of microRNAs (miRNAs), the mir-17-92, contains seven miRNAs that are highly expressed in malignant lymphomas and frequently overexpressed in various acute leukemias. Jianjun Chen, PhD, through R01 funding from the National Cancer Institute, is investigating the mechanisms by which miRNAs in this cluster may regulate the proliferation and differentiation of hematopoietic progenitor cells. These studies will facilitate the identification of target genes that contribute towards leukemogenesis. EFFORTS UNDER WAY TO IDENTIFY FUSION TRANSCRIPTS IN LEUKEMIA Structural aberrations in the cancer genome are used as genetic markers for diagnosis, treatment, and prognosis. Janet Rowley, MD, DSc, and colleagues from Northshore University Health System and The University of Texas were awarded an RC1 grant from the National Cancer Institute to perform a systematic analysis to identify fusion transcripts and their chromosomal structural aberrations in acute myeloid leukemia (AML). The study will allow the identification of new candidate genes involved in AML as well as genetic markers for improved clinical diagnosis and treatment. Featured Faculty Profiles† †Due to space constraints, only a small representative sample of Program members is presented here. Assistant Professor of Medicine The goal of Dr. Andrew Artz’s research is to improve outcomes among older adults with hematologic disorders by using individualized treatment strategies. A second area of active investigation aims to characterize otherwise unexplained anemia to identify patients who may harbor an occult or impending hematologic malignancy. Dr. Artz has established a unique Geriatric Anemia Clinic that allows clinicians to carefully phenotype patients, provide samples for a biorepository, and perform interventional trials. He has recently reported that approximately 7.5% of older anemic adults have an underlying hematologic malignancy, and that myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) account for half of these malignancies.1 Moreover, approximately 15% of the remaining anemia patients have blood or marrow findings suggesting a precursor lesion to MDS (i.e., early MDS). Along with his collaborator, Amittha Wickrema, PhD, Dr. Artz is searching for biomarkers to establish new diagnostic tools for earlier diagnosis and treatment of MDS or AML. Finally, through an NIHfunded consortium, they have initiated a series of clinical trials to study unexplained anemia in the elderly. Interventions aimed at early MDS will be tested in the near future. UCCCC SCIENTIFIC REPORT 2010 – 2011 Allogeneic hematopoietic cell transplantation (HCT) remains the major modality to eradicate high-risk and relapsed hematologic malignancies, but its extension to older adults is limited because of transplant-related morbidity and mortality. Dr. Artz’s research employs established tools (e.g., biomarkers, geriatric assessment) to detect subtle health impairments in elderly patients as novel predictors of acute toxicities after curative intent transplantation for adults 50 to 75 years of age. His research demonstrates that the presence of comorbid conditions and mild functional limitations are predicative of worse tolerance. He and his colleagues have also reported that pre-transplant elevated c-reactive protein (CRP) and possibly IL-6 track closely with transplant-associated morbidity and mortality. Dr. Artz and his colleagues have recently completed a prospective comprehensive geriatric assessment Andrew Artz, MD (CGA) of 140 adults (50 years of age or older) undergoing HCT. Their preliminary data reveal a wide range of limitations by CGA among patients with good performance status. In addition, self-reported measures of quality of life strongly predict transplant-related mortality independent of standard measures while evidence of frailty, adjusted for disease status, tracked with greater relapse. Ongoing work will delineate the essential novel prognostic factors for tolerance and study interventions targeted at patients at high risk for poor tolerance and/or specific limitations. Hematopoiesis and Hematological Malignancies ANDREW ARTZ, MD Artz AS, Thirman MJ. Unexplained anemia predominates despite an intensive evaluation in a racially diverse cohort of older adults from a referral anemia clinic. J Gerontol A Biol Sci Med Sci 66:925-932, 2011. 1 37 Hematopoiesis and Hematological Malignancies UCCCC SCIENTIFIC REPORT 2010 – 2011 LUCY GODLEY, MD, PHD Associate Professor of Medicine The goal of Dr. Lucy Godley’s research is to understand the molecular basis of bone marrow malignancies. The specific aims of her research are to: 1) understand the pathways that lead to altered patterns of DNA methylation/ hydroxymethylation in human bone marrow cancers; and 2) learn what predisposes patients with inherited RUNX1 mutations to develop leukemia. By understanding the molecular basis of these pathways, her hope is to develop rational therapies that will be more effective and less toxic for patients. Epigenetic changes, including modifications of histone proteins and cytosine bases in DNA, alter chromatin structure to regulate gene transcription. Cancer cells are characterized by abnormal patterns of DNA methylation/ hydroxymethylation. Work in Dr. Godley’s laboratory focuses on elucidating mechanisms that control these modifications within cancer cells. She has shown that cancer cells exhibit aberrant splicing of the DNMT3B gene, producing DNMT3B transcripts containing premature stop codons that encode Lucy Godley, MD, PhD truncated proteins lacking the catalytic domain. Using mass spectrometry and a chemical labeling method developed in Dr. Chuan He’s laboratory (Pharmacogenomics and Experimental Therapeutics Program), her laboratory has detected low levels of hydroxymethylcytosine in several subtypes of acute myeloid leukemia (AML), including those with TET2 or IDH1/2 mutations. They have also observed that treatment of leukemia cells with so-called “hypomethylating agents” actually increases levels of hydroxymethylation. As a result, they are testing whether this effect could drive the clinical efficacy of these drugs. In recent findings, Dr. Godley demonstrated that a truncated DNMT3B isoform found in human cancer cells can alter Myc-driven tumorigenesis.1 Her laboratory has shown that other tumors driven by Myc or MYC family members are very sensitive to DNA methylation. Dr. Godley and her collaborators have also demonstrated that AMLs with TET2 or IDH1/2 mutations have increased levels of DNA methylation.2 They have expanded their findings and shown that these leukemias also have less hydroxymethylation. Current work is focused on the identification of affected genes. Shah MY, Vasanthakumar A, Barnes NY, Figueroa ME, Kamp A, Hendrick C, Ostler KR, Davis EM, Lin S, Anastasi J, Le Beau MM, Moskowitz IP, Melnick A, Pytel P, Godley LA. DNMT3B7, a truncated DNMT3B isoform expressed in human tumors, disrupts embryonic development and accelerates lymphomagenesis. Cancer Res 70:5840-5850, 2010. 1 Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, Li Y, Bhagwat N, Vasanthakumar A, Fernandez HF, Tallman MS, Sun Z, Wolniak K, Peeters JK, Liu W, Choe SE, Fantin VR, Paietta E, Löwenberg B, Licht JD, Godley LA, Delwel R, Valk PJ, Thompson CB, Levine RL, Melnick A. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18:553-567, 2010. 2 38 Assistant Professor of Pathology Dr. Sandeep Gurbuxani’s long-standing interest is to uncover the mechanisms of resistance to chemotherapy-induced cell death in acute leukemias. Specifically, his laboratory is investigating how glucocorticoids induce cell death in acute lymphoblastic leukemia (ALL). Synthetic glucocorticoids, such as dexamethasone and prednisone, have been used for treating ALL for over 5 decades. Indeed, sensitivity to glucocorticoids is the most important predictor of treatment outcome in ALL patients. In spite of the extensive use and crucial impact on outcome, the mechanism of glucocorticoid-induced cell death is poorly understood. A lack of understanding of these mechanisms has also hampered the capacity to overcome the phenomenon of resistance to glucocorticoid-mediated cell death in a small but significant minority of de novo ALL patients as well as in the vast majority of ALL patients at the time of relapse. Dr. Gurbuxani’s laboratory is using two strategies to identify the mechanisms of glucocorticoidinduced cell death. Both of these approaches are influenced by current knowledge about the physiological role of endogenous glucocorticoids. Since glucocorticoids mediate their effects by a GR-mediated transcriptional program, Dr. Gurbuxani is determining whether the activated GR influences the transcription of a unique set of genes in ALL cells. In a second set of experiments, he is determining the effect of glucocorticoids on the metabolism of ALL cells. The cell death observed in ALL cells may possibly be a consequence of catastrophic perturbations in cellular metabolism that result in depletion of essential housekeeping molecules. In the long run, Dr. Gurbuxani expects to exploit the information obtained from these experiments for developing targeted therapy for ALL that is refractory to glucocorticoid-mediated cell death. UCCCC SCIENTIFIC REPORT 2010 – 2011 Of note, the phenomenon of cell death in response to glucocorticoid exposure Sandeep Gurbuxani, MBBS, PhD is observed only in limited tissue types, the most important being immature lymphoid cells. Interestingly, endogenous glucocorticoids secreted by the adrenal cortex control a myriad of cellular functions, most notably glucose metabolism. Glucocorticoids mediate their effects by binding to the glucocorticoid receptor (GR), a transcription factor of the nuclear receptor family. Once activated, the GR generates a response that involves both transactivation and transrepression. Hematopoiesis and Hematological Malignancies SANDEEP GURBUXANI, MBBS, PHD 39 Hematopoiesis and Hematological Malignancies AMITTHA WICKREMA, PHD Associate Professor of Medicine Dr. Amittha Wickrema’s research program focuses on the molecular mechanisms underlying normal and malignant hematopoiesis. Specifically, he studies the epigenetic, transcriptional, and post-translational regulatory circuits that guide blood stem cells in the commitment and terminal differentiation to red blood cells. UCCCC SCIENTIFIC REPORT 2010 – 2011 Amittha Wickrema, PhD Over the years, Dr. Wickrema’s laboratory has developed a unique human cellular model for studying the commitment, proliferation, and terminal differentiation of blood stem cells to erythroid progenitors, erythroblasts, and reticulocytes. This model is unique because it recapitulates in vitro the normal program driven by specific cytokines and a stringent feeding regimen. They have utilized this primary human model to define signaling pathways and cytokine requirements critical for cell survival, proliferation, and terminal differentiation. These studies not only revealed the molecular basis of human erythroblast differentiation, but also identified the pathways essential for enucleation.1-3 Most recently, Dr. Wickrema’s laboratory uncovered osteopontin (OPN), a cytokine associated with bone development, to be involved in the regulation of erythroblast actin cytoskeleton.4 This initial finding led them to investigate the role of OPN in the regulation of mature red blood cell homeostasis under normal and pathologic conditions. Serum OPN levels are highly elevated in many clinical conditions, including cancer and sickle cell disease. Current studies include investigation of the role played by OPN in the regulation of mature red blood cell deformability and metabolic flux, which are key characteristics for the long-term survival of red blood cells. These studies also include examination of the impact of elevated OPN on oxidative stress in sickle red blood cells. Dr. Wickrema’s second area of investigation focuses on adaptation of the human erythroblast model to culture and force differentiation of myelodysplastic stem/erythroid progenitors as a tool for early diagnosis as well as for studying candidate genes associated with the pathogenesis of myelodysplastic syndromes (MDS). MDS represents a group of pre-malignant diseases that quickly proceeds to becoming malignant. Most patients with MDS are initially diagnosed with anemia, and approximately 25% of patients with unexplained anemia develop MDS. Current efforts in the laboratory include identification of genetic aberrations in very early MDS stem/erythroid cells and the functional consequence of these aberrations in disrupting either commitment survival and/or terminal differentiation, including globin synthesis and enucleation. This project is being carried out in collaboration with Drs. Andrew Artz and Amit Verma, a physician scientist and long-time collaborator at Albert Einstein University. Wickrema A, Uddin S, Sharma A, Chen F, Alsayed Y, Ahmad S, Sawyer ST, Krystal G, Yi T, Nishada K, Hibi M, Hirano T, Platanias LC. Engagement of Gab1 and Gab2 in erythropoietin signaling. J Biol Chem 274:24469-24474, 1999. 1 Mahmud DL, G-Amlak M, Deb DK, Platanias LC, Uddin S, Wickrema A. Phosphorylation of forkhead transcription factors by erythropoietin and stem cell factor prevents acetylation and their interaction with coactivator p300 in erythroid progenitor cells. Oncogene 21:1556-1562, 2002. 2 3 Uddin S, Ah-Kang J, Ulaszek J, Mahmud D, Wickrema A. Differentiation stage-specific activation of p38 mitogen-activated protein kinase isoforms in primary human erythroid cells. PNAS 101:147-512, 2004. Kang JA, Zhou Y, Weis TL, Liu H, Ulaszek J, Satgurunathan N, Zhou L, van Besien K, Crispino J, Verma A, Low PS, Wickrema A. Osteopontin regulates actin cytoskeleton and contributes to cell proliferation in primary erythroblasts. J Biol Chem 283:6997-7006, 2008. 4 40 Hematopoiesis and Hematological Malignancies MICHAEL THIRMAN, MD Associate Professor of Medicine Dr. Michael Thirman’s laboratory focuses on the role of MLL and its partner proteins in the development of acute leukemia. He has cloned the ELL gene and its interacting factors, EAF1 and EAF2. Using model systems, Dr. Thirman’s laboratory analyzes the pathways that mediate leukemogenesis and seeks to translate this knowledge into the development of novel treatment strategies. MLL encodes a histone methyltransferase that is critical in maintaining gene expression during embryonic development and hematopoiesis. 11q23 translocations result in the formation of chimeric MLL fusion proteins that act as potent drivers of acute leukemia. However, it remains unclear what portion of the leukemic genome is under the direct control of MLL fusions. Independent expression profiling studies on primary patient samples and cellular leukemic models have revealed a smaller number of genes (∼100) which are differentially expressed in MLL-rearranged leukemias. Collectively, these studies do not provide a clear picture regarding what portion of the genome is directly controlled by MLL fusion proteins. Michael Thirman, MD UCCCC SCIENTIFIC REPORT 2010 – 2011 To address these important issues, Dr. Thirman’s laboratory undertook two parallel strategies, including mapping MLL binding in multiple human leukemia patient-derived cell lines, and a combined location and expression profiling analysis in an MLL-ENL–inducible system.1 By comparing patient-derived leukemic cell lines, they observed that MLL fusion-bound genes are a small subset recognized by wild-type MLL. In an inducible MLL-ENL model, MLL fusion protein binding and changes in H3K79 methylation are limited to a specific portion of the genome, whereas wild-type MLL distributes to a much larger set of gene loci. Surprisingly, among 223 MLL-ENL-bound genes, only 12 demonstrate a significant increase in mRNA expression on induction of the fusion protein. Among target genes whose expression is strongly influenced by MLL-ENL, Dr. Thirman’s laboratory has identified key developmental regulators that potentially contribute to the development of MLL-associated leukemia. These include HOXA9 and its cofactor, MEIS1, which have previously been identified as targets of MLL fusion genes. In addition, Dr. Thirman has identified the transcription factors EYA1, SIX1, and SIX4 as direct MLL-ENL targets. EYA proteins form heterodimers with members of the SIX protein family. They found that Eya1 has the capacity to immortalize hematopoietic progenitor cells in vitro and collaborates with Six1 in hematopoietic transformation assays. Altogether, the data suggest that MLL fusions contribute to the development of acute leukemia through direct activation of a small set of target genes. 1 Wang Q, Wu G, Mi S, He F, Wu J, Dong J, Luo RT, Mattison R, Kaberlein J, Prabhakar S, Ji H, Thirman MJ. MLL fusion proteins preferentially regulate a subset of wild type MLL target genes in the leukemic genome. Blood 117:6895-9605, 2011. 41 Hematopoiesis and Hematological Malignancies UCCCC SCIENTIFIC REPORT 2010 – 2011 RICHARD LARSON, MD Professor of Medicine The goal of Dr. Richard Larson’s research program is to understand the determinants of response to treatment in patients with acute leukemia. The methods include prospective clinical trials, evaluation of novel therapeutic agents, and correlation of cytogenetic and molecular markers that identify biologically distinct subsets of leukemia. A primary focus of Dr. Larson’s work has been to understand the etiology of therapy-related leukemia. It is now well-recognized that leukemia sometimes occurs as a therapy-related myeloid neoplasm (t-MN) in patients who have previously received cytotoxic therapy or ionizing radiation therapy (RT). The exact mechanism of the leukemogenic transformation remains to be determined. This disorder arises as a direct consequence of mutational events induced by the primary treatment. The outcomes for these patients have been historically poor compared to people who develop acute myeloid leukemia (AML) de novo. Currently comprising 10%-20% of all cases of AML, t-MN Richard Larson, MD is relatively resistant to conventional leukemia therapies and is associated with short survival times. Median life expectancy from diagnosis is about 8-10 months in most cases.1 Although the spectrum of cytogenetic abnormalities in t-AML is similar to AML de novo, the frequency of unfavorable cytogenetics, such as a complex karyotype or deletion or loss of chromosomes 5 and/or 7, is considerably higher in t-MN. Two distinct groups of patients with t-MN have been described. The more common subtype, seen in about 75% of patients, typically occurs 5-7 years after first exposure to alkylating agents or radiation, is often preceded by a myelodysplastic syndrome, and is frequently accompanied by clonal cytogenetic abnormalities such as the loss of all or part of chromosomes 5 or 7. Mutations of the TP53 tumor suppressor gene are also common. The risk is related to total cumulative exposure over time to alkylating agents. In contrast, among individuals who develop t-AML after treatment with topoisomerase II inhibitors, the latency period to the development of t-AML is often only 1-3 years, antecedent MDS is rare, and gene rearrangements involving MLL at 11q23 or RUNX1/AML1 at 21q22 are common. It is now well-recognized that acute promyelocytic leukemia (APL) and other subtypes of AML with balanced translocations sometimes occur as a t-MN in patients who have previously received cytotoxic therapy or ionizing radiation therapy. In general, t-MN patients should be encouraged to participate in prospective clinical trials that are appropriately designed for other AML patients with similar cytogenetic abnormalities. Patients who have an HLA-matched donor should be considered for allogeneic hematopoietic cell transplantation, although patients with favorable karyotypes such as t(15;17) and inv(16) may do well with conventional intensive chemotherapy.2,3 1 Larson RA, Le Beau MM. Prognosis and therapy of therapy-related acute promyelocytic leukemia and other “good risk” acute myeloid leukemias. Mediterr J Hematol Infect Dis 3: e2011032, 2011. 2 Larson, RA. Therapy-related myeloid neoplasms. Haematologica 94:454-459, 2009. Godley LA, Njiaju UO, Green M, Weiner H, Lin S, Odenike O, Rich ES, Artz A, Van Besien K, Daugherty CK, Zhang Y, Le Beau MM, Stock W, Larson RA. Treatment of therapy-related myeloid neoplasms with high-dose cytarabine/mitoxantrone followed by hematopoietic stem cell transplant. Leuk Lymphoma 5:995-1006, 2010. 3 42 Selected Publications * : Intraprogrammatic Collaboration # : Interprogrammatic Collaboration * Stoddart A, Tennant TR, Fernald AA, Anastasi J, Brodsky FM, Le Beau MM. The clathrin-binding domain of CALMAF10 alters the phenotype of myeloid neoplasms in mice. Oncogene 2011 (Epub ahead of print). * # Shah MY, Vasanthakumar A, Barnes NY, Figueroa ME, Kamp A, Hendrick C, Ostler KR, Davis EM, Lin S, Anastasi J, Le Beau MM, Moskowitz IP, Melnick A, Pytel P, Godley LA. DNMT3B7, a truncated DNMT3B isoform expressed in human tumors, disrupts embryonic development and accelerates lymphomagenesis. Cancer Res 70:5840-50, 2010. PMC2905468 * Smith SM, Anastasi J, Cohen KS, Godley LA. The impact of MYC expression in lymphoma biology: beyond Burkitt lymphoma. Blood Cells Mol Dis 45:317-23, 2010. ARTZ, ANDREW, MD * Locke FL, Artz A, Rich E, Zhang Y, van Besien K, Stock W. Feasibility of clofarabine cytoreduction before allogeneic transplant conditioning for refractory AML. Bone Marrow Transplant 45:16928, 2010. * # Godley LA, Njiaju UO, Green M, Weiner H, Lin S, Odenike O, Rich ES, Artz A, Van Besien K, Daugherty CK, Zhang Y, Le Beau MM, Stock W, Larson RA. Treatment of therapy-related myeloid neoplasms with high-dose cytarabine/ mitoxantrone followed by hematopoietic stem cell transplant. Leuk Lymphoma 51:995-1006, 2010. * Artz AS, Thirman MJ. Unexplained anemia predominates despite an intensive evaluation in a racially diverse cohort of older adults from a referral anemia clinic. J Gerontol A Biol Sci Med Sci 66:925-32, 2011. * # O’Donnell PH, Artz AS, Undevia SD, Pai RK, Del Cerro P, Horowitz S, Godley LA, Hart J, Innocenti F, Larson RA, Odenike OM, Stock W, Van Besien K. Phase I study of dose-escalated busulfan with fludarabine and alemtuzumab as conditioning for allogeneic hematopoietic stem cell transplant: reduced clearance at high doses and occurrence of late sinusoidal obstruction syndrome/veno-occlusive disease. Leuk Lymphoma 51:2240-9, 2010. Hurria A, Cirrincione CT, Muss HB, Kornblith AB, Barry W, Artz AS, Schmieder L, Ansari R, Tew WP, Weckstein D, Kirshner J, Togawa K, Hansen K, Katheria V, Stone R, Galinsky I, Postiglione J, Cohen HJ. Implementing a geriatric assessment in cooperative group clinical cancer trials: CALGB 360401. J Clin Oncol 29:1290-6, 2011. PMC3083997 * van Besien K, Kenkre V, Artz AS. T-celldepleted reduced-intensity conditioning transplantation for lymphoma: do donor lymphocyte infusions really matter? J Clin Oncol 29:e243, 2011. Liu H, Artz AS. Reduction of imatinib absorption after gastric bypass surgery. Leuk Lymphoma 52:310-3, 2011. BARON, BEVERLY, MD Armand P, Kim HT, Zhang MJ, Perez WS, Dal Cin PS, Klumpp TR, Waller EK, Litzow MR, Liesveld JL, Lazarus HM, Artz AS, Gupta V, Savani BN, McCarthy PL, Cahn JY, Schouten HC, Finke J, Ball ED, Aljurf MD, Cutler CS, Rowe * Baron BW, Hyjek E, Gladstone B, Thirman MJ, Baron JM. PDCD2, a protein whose expression is repressed by BCL6, induces apoptosis in human cells by activation of the caspase cascade. Blood Cells Mol Dis 45:169-75, 2010. CHEN, JIANJUN, PHD Xiong Y, Li Z, Ji M, Tan AC, Bemis J, Tse JV, Huang G, Park J, Ji C, Chen J, Bemis LT, Bunting KD, Tse W. MIR29B regulates expression of MLLT11 (AF1Q), an MLL fusion partner, and low MIR29B expression associates with adverse cytogenetics and poor overall survival in AML. Br J Haematol 153:753-7, 2011. Du W, Li J, Sipple J, Chen J, Pang Q. Cytoplasmic FANCA-FANCC complex interacts and stabilizes the cytoplasmdislocalized leukemic nucleophosmin protein (NPMc). J Biol Chem 285:3743644, 2010. PMC2988349 * Mi S, Li Z, Chen P, He C, Cao D, Elkahloun A, Lu J, Pelloso LA, Wunderlich M, Huang H, Luo RT, Sun M, He M, Neilly MB, Zeleznik-Le NJ, Thirman MJ, Mulloy JC, Liu PP, Rowley JD, Chen J. Aberrant overexpression and function of the miR-17-92 cluster in MLL-rearranged acute leukemia. PNAS 107:3710-5, 2010. PMC2840429 Wang Y, Li Z, He C, Wang D, Yuan X, Chen J, Jin J. MicroRNAs expression signatures are associated with lineage and survival in acute leukemias. Blood Cells Mol Dis 44:191-7, 2010. PMC2829339 * Chen J, Odenike O, Rowley JD. Leukaemogenesis: more than mutant genes. Nat Rev Cancer 10:23-36, 2010. PMC2972637 UCCCC SCIENTIFIC REPORT 2010 – 2011 * Wang J, Fernald AA, Anastasi J, Le Beau MM, Qian Z. Haploinsufficiency of Apc leads to ineffective hematopoiesis. Blood 115:3481-8, 2010. JM, Antin JH, Isola LM, Di Bartolomeo P, Camitta BM, Miller AM, Cairo MS, Stockerl-Goldstein K, Sierra J, Savoie ML, Halter J, Stiff PJ, Nabhan C, Jakubowski AA, Bunjes DW, Petersdorf EW, Devine SM, Maziarz RT, Bornhauser M, Lewis VA, Marks DI, Bredeson CN, Soiffer RJ, Weisdorf DJ. Classifying cytogenetics in patients with acute myelogenous leukemia in complete remission undergoing allogeneic transplantation: A Center for International Blood and Marrow Transplant Research Study. Biol Blood Marrow Transplant, 2011 (Epub ahead of print). Hematopoiesis and Hematological Malignancies ANASTASI, JOHN, MD COHEN, KENNETH, MD * # Kenkre VP, Horowitz S, Artz AS, Liao C, Cohen KS, Godley LA, Kline JP, Smith SM, Stock W, van Besien K. T-celldepleted allogeneic transplant without donor leukocyte infusions results in excellent long-term survival in patients with multiply relapsed Lymphoma. Predictors for survival after transplant relapse. Leuk Lymphoma 52:214-22, 2011. Batchelor TT, Duda DG, di Tomaso E, Ancukiewicz M, Plotkin SR, Gerstner E, Eichler AF, Drappatz J, Hochberg FH, Benner T, Louis DN, Cohen KS, Chea H, Exarhopoulos A, Loeffler JS, Moses MA, Ivy P, Sorensen AG, Wen PY, Jain RK. Phase II study of cediranib, an oral panvascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with 43 UCCCC SCIENTIFIC REPORT 2010 – 2011 Hematopoiesis and Hematological Malignancies recurrent glioblastoma. J Clin Oncol 28:2817-23, 2010. PMC2903316 # Meng Y, Beckett MA, Liang H, Mauceri HJ, van Rooijen N, Cohen KS, Weichselbaum RR. Blockade of tumor necrosis factor alpha signaling in tumor-associated macrophages as a radiosensitizing strategy. Cancer Res 70:1534-43, 2010. Horowitz NS, Penson RT, Duda DG, di Tomaso E, Boucher Y, Ancukiewicz M, Cohen KS, Berlin S, Krasner CN, Moses MA, Jain RK. Safety, efficacy, and biomarker exploration in a phase II study of bevacizumab, oxaliplatin, and gemcitabine in recurrent Mullerian carcinoma. Clin Ovarian Cancer Other Gynecol Malig 4:26-33, 2011. PMC3151740 Cohen KS. Angiogenesis and multiple myeloma: is there a role for angiogenic biomarkers in the context of autologous stem cell transplant? Leuk Lymphoma 52:1173-5, 2011. CUNNINGHAM, JOHN, MBBCH, MSC * # Godley LA, Cunningham J, Dolan ME, Huang RS, Gurbuxani S, McNerney ME, Larson RA, Leong H, Lussier Y, Onel K, Odenike O, Stock W, White KP, Le Beau MM. An integrated genomic approach to the assessment and treatment of acute myeloid leukemia. Semin Oncol 38:215-24, 2011. # Zheng Y, Zhao YD, Gibbons M, Abramova T, Chu PY, Ash JD, Cunningham JM, Skapek SX. Tgfbeta signaling directly induces Arf promoter remodeling by a mechanism involving Smads 2/3 and p38 MAPK. J Biol Chem 285:35654-64, 2010. PMC2975190 Sundaresan NR, Pillai VB, Wolfgeher D, Samant S, Vasudevan P, Parekh V, Raghuraman H, Cunningham JM, Gupta M, Gupta MP. The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy. Sci Signal 4:ra46, 2011. DE JONG, JILL, MD, PHD de Jong JL, Burns CE, Chen AT, Pugach E, Mayhall EA, Smith AC, Feldman HA, Zhou Y, Zon LI. Characterization of immune-matched hematopoietic transplantation in zebrafish. Blood 117:4234-42, 2011. PMC3087475 44 GODLEY, LUCY, MD, PHD * # Shah MY, Vasanthakumar A, Barnes NY, Figueroa ME, Kamp A, Hendrick C, Ostler KR, Davis EM, Lin S, Anastasi J, Le Beau MM, Moskowitz IP, Melnick A, Pytel P, Godley LA. DNMT3B7, a truncated DNMT3B isoform expressed in human tumors, disrupts embryonic development and accelerates lymphomagenesis. Cancer Res 70:5840-50, 2010. PMC2905468 * # Godley LA, Njiaju UO, Green M, Weiner H, Lin S, Odenike O, Rich ES, Artz A, Van Besien K, Daugherty CK, Zhang Y, Le Beau MM, Stock W, Larson RA. Treatment of therapy-related myeloid neoplasms with high-dose cytarabine/ mitoxantrone followed by hematopoietic stem cell transplant. Leuk Lymphoma 51:995-1006, 2010. # Yang Q, Tian Y, Ostler KR, Chlenski A, Guerrero LJ, Salwen HR, Godley LA, Cohn SL. Epigenetic alterations differ in phenotypically distinct human neuroblastoma cell lines. BMC Cancer 10:286, 2010. PMC2897803 * Churpek JE, Garcia JS, Madzo J, Jackson SA, Onel K, Godley LA. Identification and molecular characterization of a novel 3’ mutation in RUNX1 in a family with familial platelet disorder. Leuk Lymphoma 51:1931-5, 2010. # Song CX, Szulwach KE, Fu Y, Dai Q, Yi C, Li X, Li Y, Chen CH, Zhang W, Jian X, Wang J, Zhang L, Looney TJ, Zhang B, Godley LA, Hicks LM, Lahn BT, Jin P, He C. Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine. Nat Biotechnol 29:68-72, 2011. PMC3107705 Godley LA, Mondragon A. Molecular biology. Preference by exclusion. Science 331:1017-8, 2011. Moran-Crusio K, Reavie L, Shih A, AbdelWahab O, Ndiaye-Lobry D, Lobry C, Figueroa ME, Vasanthakumar A, Patel J, Zhao X, Perna F, Pandey S, Madzo J, Song C, Dai Q, He C, Ibrahim S, Beran M, Zavadil J, Nimer SD, Melnick A, Godley LA, Aifantis I, Levine RL. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20:11-24, 2011. Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, Li Y, Bhagwat N, Vasanthakumar A, Fernandez HF, Tallman MS, Sun Z, Wolniak K, Peeters JK, Liu W, Choe SE, Fantin VR, Paietta E, Lowenberg B, Licht JD, Godley LA, Delwel R, Valk PJ, Thompson CB, Levine RL, Melnick A. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18:553-67, 2010. GOUNARI, FOTINI, PHD, DSC Hu MG, Deshpande A, Schlichting N, Hinds EA, Mao C, Dose M, Hu GF, Van Etten RA, Gounari F, Hinds PW. CDK6 kinase activity is required for thymocyte development. Blood 117:6120-31, 2011. PMC3122937 Khazaie K, Blatner NR, Khan MW, Gounari F, Gounaris E, Dennis K, Bonertz A, Tsai FN, Strouch MJ, Cheon E, Phillips JD, Beckhove P, Bentrem DJ. The significant role of mast cells in cancer. Cancer Metastasis Rev 30:45-60, 2011. * De Keersmaecker K, Real PJ, Gatta GD, Palomero T, Sulis ML, Tosello V, Van Vlierberghe P, Barnes K, Castillo M, Sole X, Hadler M, Lenz J, Aplan PD, Kelliher M, Kee BL, Pandolfi PP, Kappes D, Gounari F, Petrie H, Van der Meulen J, Speleman F, Paietta E, Racevskis J, Wiernik PH, Rowe JM, Soulier J, Avran D, Cave H, Dastugue N, Raimondi S, Meijerink JP, CordonCardo C, Califano A, Ferrando AA. The TLX1 oncogene drives aneuploidy in T cell transformation. Nat Med 16:1321-7, 2010. PMC2974790 GURBUXANI, SANDEEP, MBBS, PHD Huang QQ, Perlman H, Huang Z, Birkett R, Kan L, Agrawal H, Misharin A, Gurbuxani S, Crispino JD, Pope RM. FLIP: a novel regulator of macrophage differentiation and granulocyte homeostasis. Blood 116:4968-77, 2010. PMC3012591 # Ferguson SD, Musleh W, Gurbuxani S, Shafizadeh SF, Lesniak MS. Intracranial mucosa-associated lymphoid tissue (MALT) lymphoma. J Clin Neurosci 17:666-9, 2010. Gao Z, Huang Z, Olivey HE, Gurbuxani S, Crispino JD, Svensson EC. FOG-1-mediated recruitment of NuRD is required for cell lineage re-enforcement during haematopoiesis. EMBO J 29:457-68, 2010. PMC2824465 Small S, Keerthivasan G, Huang Z, Gurbuxani S, Crispino JD. Overexpression of survivin initiates hematologic malignan- lism. J Biol Chem 285:32596-605, 2010. PMC2952262 * # Godley LA, Cunningham J, Dolan ME, Huang RS, Gurbuxani S, McNerney ME, Larson RA, Leong H, Lussier Y, Onel K, Odenike O, Stock W, White KP, Le Beau MM. An integrated genomic approach to the assessment and treatment of acute myeloid leukemia. Semin Oncol 38:215-24, 2011. Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C, Pasquini R, Clark RE, Hochhaus A, Hughes TP, Gallagher N, Hoenekopp A, Dong M, Haque A, Larson RA, Kantarjian HM. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 362:2251-9, 2010. KEE, BARBARA, PHD * Kolitz JE, George SL, Marcucci G, Vij R, Powell BL, Allen SL, DeAngelo DJ, Shea TC, Stock W, Baer MR, Hars V, Maharry K, Hoke E, Vardiman JW, Bloomfield CD, Larson RA. P-glycoprotein inhibition using valspodar (PSC-833) does not improve outcomes for patients younger than age 60 years with newly diagnosed acute myeloid leukemia: Cancer and Leukemia Group B study 19808. Blood 116:1413-21, 2010. PMC2938834 # Verykokakis M, Boos MD, Bendelac A, Adams EJ, Pereira P, Kee BL. Inhibitor of DNA binding 3 limits development of murine slam-associated adaptor proteindependent “innate” gammadelta T cells. PLoS One 5:e9303, 2010. PMC2824806 # Verykokakis M, Boos MD, Bendelac A, Kee BL. SAP protein-dependent natural killer T-like cells regulate the development of CD8(+) T cells with innate lymphocyte characteristics. Immunity 33:203-15, 2010. PMC2933745 * De Keersmaecker K, Real PJ, Gatta GD, Palomero T, Sulis ML, Tosello V, Van Vlierberghe P, Barnes K, Castillo M, Sole X, Hadler M, Lenz J, Aplan PD, Kelliher M, Kee BL, Pandolfi PP, Kappes D, Gounari F, Petrie H, Van der Meulen J, Speleman F, Paietta E, Racevskis J, Wiernik PH, Rowe JM, Soulier J, Avran D, Cave H, Dastugue N, Raimondi S, Meijerink JP, CordonCardo C, Califano A, Ferrando AA. The TLX1 oncogene drives aneuploidy in T cell transformation. Nat Med 16:1321-7, 2010. PMC2974790 LARSON, RICHARD, MD * Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood 116:3751-7, 2010. PMC2981533 # Fernandes MS, Reddy MM, Croteau NJ, Walz C, Weisbach H, Podar K, Band H, Carroll M, Reiter A, Larson RA, Salgia R, Griffin JD, Sattler M. Novel oncogenic mutations of CBL in human acute myeloid leukemia that activate growth and survival pathways depend on increased metabo- Becker H, Marcucci G, Maharry K, Radmacher MD, Mrozek K, Margeson D, Whitman SP, Wu YZ, Schwind S, Paschka P, Powell BL, Carter TH, Kolitz JE, Wetzler M, Carroll AJ, Baer MR, Caligiuri MA, Larson RA, Bloomfield CD. Favorable prognostic impact of NPM1 mutations in older patients with cytogenetically normal de novo acute myeloid leukemia and associated gene- and microRNA-expression signatures: a Cancer and Leukemia Group B study. J Clin Oncol 28:596-604, 2010. PMC2815994 Lin TS, Donohue KA, Byrd JC, Lucas MS, Hoke EE, Bengtson EM, Rai KR, Atkins JN, Link BK, Larson RA. Consolidation therapy with subcutaneous alemtuzumab after fludarabine and rituximab induction therapy for previously untreated chronic lymphocytic leukemia: final analysis of CALGB 10101. J Clin Oncol 28:4500-6, 2010. PMC2988639 Baer MR, George SL, Sanford BL, Mrozek K, Kolitz JE, Moore JO, Stone RM, Powell BL, Caligiuri MA, Bloomfield CD, Larson LE BEAU, MICHELLE, PHD Wong JC, Zhang Y, Lieuw KH, Tran MT, Forgo E, Weinfurtner K, Alzamora P, Kogan SC, Akagi K, Wolff L, Le Beau MM, Killeen N, Shannon K. Use of chromosome engineering to model a segmental deletion of chromosome band 7q22 found in myeloid malignancies. Blood 115:452432, 2010. PMC2881500 * Wang J, Fernald AA, Anastasi J, Le Beau MM, Qian Z. Haploinsufficiency of Apc leads to ineffective hematopoiesis. Blood 115:3481-8, 2010. Mohrin M, Bourke E, Alexander D, Warr MR, Barry-Holson K, Le Beau MM, Morrison CG, Passegue E. Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis. Cell Stem Cell 7:174-85, 2010. PMC2924905 * # Shah MY, Vasanthakumar A, Barnes NY, Figueroa ME, Kamp A, Hendrick C, Ostler KR, Davis EM, Lin S, Anastasi J, Le Beau MM, Moskowitz IP, Melnick A, Pytel P, Godley LA. DNMT3B7, a truncated DNMT3B isoform expressed in human tumors, disrupts embryonic development and accelerates lymphomagenesis. Cancer Res 70:5840-50, 2010. PMC2905468 # Palakodeti A, Lucas I, Jiang Y, Young DJ, Fernald AA, Karrison T, Le Beau MM. Impaired replication dynamics at the FRA3B common fragile site. Hum Mol Genet 19:99-110, 2010. PMC2800779 UCCCC SCIENTIFIC REPORT 2010 – 2011 Ramirez K, Kee BL. Multiple hats for natural killers. Curr Opin Immunol 22:193-8, 2010. Marcucci G, Maharry K, Wu YZ, Radmacher MD, Mrozek K, Margeson D, Holland KB, Whitman SP, Becker H, Schwind S, Metzeler KH, Powell BL, Carter TH, Kolitz JE, Wetzler M, Carroll AJ, Baer MR, Caligiuri MA, Larson RA, Bloomfield CD. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol 28:2348-55, 2010. PMC2881719 RA. Escalation of daunorubicin and addition of etoposide in the ADE regimen in acute myeloid leukemia patients aged 60 years and older: Cancer and Leukemia Group B Study 9720. Leukemia 2 5:800-7, 2011. Hematopoiesis and Hematological Malignancies cies in vivo. Leukemia 24:1920-6, 2010. PMC2978276 * Stoddart A, Tennant TR, Fernald AA, Anastasi J, Brodsky FM, Le Beau MM. The clathrin-binding domain of CALMAF10 alters the phenotype of myeloid neoplasms in mice. Oncogene, 2011 (Epub ahead of print). Link DC, Schuettpelz LG, Shen D, Wang J, Walter MJ, Kulkarni S, Payton JE, Ivanovich J, Goodfellow PJ, Le Beau M, Koboldt DC, Dooling DJ, Fulton RS, Bender RH, Fulton LL, Delehaunty KD, Fronick CC, Appelbaum EL, Schmidt H, Abbott R, O’Laughlin M, Chen K, McLellan MD, Varghese N, Nagarajan R, Heath S, Graubert TA, Ding L, Ley TJ, Zambetti GP, Wilson RK, Mardis ER. Identification of a novel TP53 cancer 45 UCCCC SCIENTIFIC REPORT 2010 – 2011 Hematopoiesis and Hematological Malignancies susceptibility mutation through wholegenome sequencing of a patient with therapy-related AML. JAMA 305:156876, 2011. Jones L, Wei G, Sevcikova S, Phan V, Jain S, Shieh A, Wong JC, Li M, Dubansky J, Maunakea ML, Ochoa R, Zhu G, Tennant TR, Shannon KM, Lowe SW, Le Beau MM, Kogan SC. Gain of MYC underlies recurrent trisomy of the MYC chromosome in acute promyelocytic leukemia. J Exp Med 207:2581-94, 2010. PMC2989761 MARINO, SUSANA, MD, PHD Woolfrey A, Klein JP, Haagenson M, Spellman S, Petersdorf E, Oudshoorn M, Gajewski J, Hale GA, Horan J, Battiwalla M, Marino SR, Setterholm M, Ringden O, Hurley C, Flomenberg N, Anasetti C, Fernandez-Vina M, Lee SJ. HLA-C antigen mismatch is associated with worse outcome in unrelated donor peripheral blood stem cell transplantation. Biol Blood Marrow Transplant 17:885-92, 2011. PMC3071866 Valcarcel D, Sierra J, Wang T, Kan F, Gupta V, Hale GA, Marks DI, McCarthy PL, Oudshoorn M, Petersdorf EW, Ringden O, Setterholm M, Spellman SR, Waller EK, Gajewski JL, Marino SR, Senitzer D, Lee SJ. One-antigen mismatched related versus HLA-matched unrelated donor hematopoietic stem cell transplantation in adults with acute leukemia: Center for International Blood and Marrow Transplant Research results in the era of molecular HLA typing. Biol Blood Marrow Transplant 17:640-8, 2011. * Marino SR, Lin S, Maiers M, Haagenson M, Spellman S, Klein JP, Binkowski TA, Lee SJ, van Besien K. Identification by random forest method of HLA class I amino acid substitutions associated with lower survival at day 100 in unrelated donor hematopoietic cell transplantation. Bone Marrow Transplant, 2011 (Epub ahead of print). PMC3128239 NACHMAN, JAMES, MD * Gaynon PS, Angiolillo AL, Carroll WL, Nachman JB, Trigg ME, Sather HN, Hunger SP, Devidas M. Long-term results of the children’s cancer group studies for childhood acute lymphoblastic leukemia 1983-2002: a Children’s Oncology Group Report. Leukemia 24:285-97, 2010. PMC2906139 * Matloub Y, Bostrom BC, Hunger SP, Stork LC, Angiolillo A, Sather H, La M, 46 Gastier-Foster JM, Heerema NA, Sailer S, Buckley PJ, Thomson B, Cole C, Nachman JB, Reaman G, Winick N, Carroll WL, Devidas M, Gaynon PS. Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Blood 118:243-51, 2011. PMC3138679 * Nachman JB. Osteonecrosis in childhood ALL. Blood 117:2298-9, 2011. ODENIKE, OLATOYOSI, MD * Chen J, Odenike O, Rowley JD. Leukaemogenesis: more than mutant genes. Nat Rev Cancer 10:23-36, 2010. PMC2972637 * # Godley LA, Njiaju UO, Green M, Weiner H, Lin S, Odenike O, Rich ES, Artz A, Van Besien K, Daugherty CK, Zhang Y, Le Beau MM, Stock W, Larson RA. Treatment of therapy-related myeloid neoplasms with high-dose cytarabine/ mitoxantrone followed by hematopoietic stem cell transplant. Leuk Lymphoma 51:995-1006, 2010. * # O’Donnell PH, Artz AS, Undevia SD, Pai RK, Del Cerro P, Horowitz S, Godley LA, Hart J, Innocenti F, Larson RA, Odenike OM, Stock W, Van Besien K. Phase I study of dose-escalated busulfan with fludarabine and alemtuzumab as conditioning for allogeneic hematopoietic stem cell transplant: reduced clearance at high doses and occurrence of late sinusoidal obstruction syndrome/veno-occlusive disease. Leuk Lymphoma 51:2240-9, 2010. * Kantarjian HM, Padmanabhan S, Stock W, Tallman MS, Curt GA, Li J, Osmukhina A, Wu K, Huszar D, Borthukar G, Faderl S, Garcia-Manero G, Kadia T, Sankhala K, Odenike O, Altman JK, Minden M. Phase I/II multicenter study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of AZD4877 in patients with refractory acute myeloid leukemia. Invest New Drugs, 2011 (Epub ahead of print). * van Besien K, Schouten V, Parsad S, Smith S, Odenike O, Artz A. Allogeneic Stem Cell Transplantation in Renal failure. Engraftment and prolonged survival, but high incidence of neurologic toxicity. Leuk Lymphoma, 2011 (Epub ahead of print). ONEL, KENAN, MD, PHD * Churpek JE, Garcia JS, Madzo J, Jackson SA, Onel K, Godley LA. Identification and molecular characterization of a novel 3’ mutation in RUNX1 in a family with familial platelet disorder. Leuk Lymphoma 51:1931-5, 2010. # Tan YH, Krishnaswamy S, Nandi S, Kanteti R, Vora S, Onel K, Hasina R, Lo FY, El-Hashani E, Cervantes G, Robinson M, Hsu HS, Kales SC, Lipkowitz S, Karrison T, Sattler M, Vokes EE, Wang YC, Salgia R. CBL is frequently altered in lung cancers: its relationship to mutations in MET and EGFR tyrosine kinases. PLoS One 5:e8972, 2010. PMC2813301 # Best T, Li D, Skol AD, Kirchhoff T, Jackson SA, Yasui Y, Bhatia S, Strong LC, Domchek SM, Nathanson KL, Olopade OI, Huang RS, Mack TM, Conti DV, Offit K, Cozen W, Robison LL, Onel K. Variants at 6q21 implicate PRDM1 in the etiology of therapy-induced second malignancies after Hodgkin’s lymphoma. Nat Med 17:941-3, 2011. # Sucheston L, Witonsky DB, Hastings D, Yildiz O, Clark VJ, Di Rienzo A, Onel K. Natural selection and functional genetic variation in the p53 pathway. Hum Mol Genet 20:1502-8, 2011. PMC3063984 ROWLEY, JANET, MD, DSC # Schreiber H, Rowley JD, Rowley DA. Targeting mutations predictably. Blood 118:830-1, 2011. Chandra HS, Heisterkamp NC, Hungerford A, Morrissette JJ, Nowell PC, Rowley JD, Testa JR. Philadelphia Chromosome Symposium: commemoration of the 50th anniversary of the discovery of the Ph chromosome. Cancer Genet 204:171-9, 2011. PMC3092778 * Mi S, Li Z, Chen P, He C, Cao D, Elkahloun A, Lu J, Pelloso LA, Wunderlich M, Huang H, Luo RT, Sun M, He M, Neilly MB, Zeleznik-Le NJ, Thirman MJ, Mulloy JC, Liu PP, Rowley JD, Chen J. Aberrant overexpression and function of the miR-17-92 cluster in MLL-rearranged acute leukemia. PNAS 107:3710-5, 2010. PMC2840429 * Chen J, Odenike O, Rowley JD. Leukaemogenesis: more than mutant genes. Nat Rev Cancer 10:23-36, 2010. PMC2972637 SIPKINS, DOROTHY, MD, PHD Boyerinas B, Sipkins DA. HSPCs in the balance: The vascular niche. Cell Stem Cell 7:645-6, 2010. SMITH, SONALI, MD Smith SM. AIDS-related BL and CD4 count: a clue? Blood 116:5435-6, 2010. # Chiu BC, Kwon S, Evens AM, Surawicz T, Smith SM, Weisenburger DD. Dietary intake of fruit and vegetables and risk of non-Hodgkin lymphoma. Cancer Causes Control 22:1183-95, 2011. * Ramsdale E, van Besien K, Smith SM. Personalized treatment of lymphoma: promise and reality. Semin Oncol 38:225-35, 2011. * # Smith SM, van Besien K, Karrison T, Dancey J, McLaughlin P, Younes A, Smith S, Stiff P, Lester E, Modi S, Doyle LA, Vokes EE, Pro B. Temsirolimus has activity in non-mantle cell non-Hodgkin’s lymphoma subtypes: The University of Chicago phase II consortium. J Clin Oncol 28:4740-6, 2010. PMC3020703 * # Poire X, Kline J, Grinblatt D, Zimmerman T, Conner K, Muhs C, Gajewski T, Van Besien K, Smith SM. Phase II study of immunomodulation with granulocytemacrophage colony-stimulating factor, interleukin-2, and rituximab following autologous stem cell transplant in patients with relapsed or refractory lymphomas. Leuk Lymphoma 51:1241-50, 2010. * Evens AM, David KA, Helenowski I, Nelson B, Kaufman D, Kircher SM, Gimelfarb A, Hattersley E, Mauro LA, Jovanovic B, Chadburn A, Stiff P, Winter JN, Mehta J, Van Besien K, Gregory S, Gordon LI, Shammo JM, Smith SE, Smith SM. Multicenter analysis of 80 solid organ transplantation recipients with post-transplantation lymphoproliferative disease: outcomes and prognostic factors in the modern era. J Clin Oncol 28:1038-46, 2010. PMC2834429 STOCK, WENDY, MD * # Godley LA, Njiaju UO, Green M, Weiner H, Lin S, Odenike O, Rich ES, Artz A, Van Besien K, Daugherty CK, Zhang Y, Le Beau MM, Stock W, Larson RA. Treatment of therapy-related myeloid neoplasms with high-dose cytarabine/ mitoxantrone followed by hematopoietic Slovak ML, Bedell V, Lew D, Albain KS, Ellis GK, Livingston RB, Martino S, Perez EA, Hortobagyi GN, Sher D, Stock W. Screening for clonal hematopoiesis as a predictive marker for development of therapy-related myeloid neoplasia (t-MN) following neoadjuvant therapy for breast cancer: a Southwest Oncology Group study (S0012). Breast Cancer Res Treat 119:391-8, 2010. PMC3024910 * Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood 116:3751-7, 2010. PMC2981533 * Locke FL, Artz A, Rich E, Zhang Y, van Besien K, Stock W. Feasibility of clofarabine cytoreduction before allogeneic transplant conditioning for refractory AML. Bone Marrow Transplant 45:1692-8, 2010. Stock W. Adolescents and young adults with acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program 2010:21-9, 2010. * # Kenkre VP, Horowitz S, Artz AS, Liao C, Cohen KS, Godley LA, Kline JP, Smith SM, Stock W, van Besien K. T-celldepleted allogeneic transplant without donor leukocyte infusions results in excellent long-term survival in patients with multiply relapsed Lymphoma. Predictors for survival after transplant relapse. Leuk Lymphoma 52:214-22, 2011. * # Godley LA, Cunningham J, Dolan ME, Huang RS, Gurbuxani S, McNerney ME, Larson RA, Leong H, Lussier Y, Onel K, Odenike O, Stock W, White KP, Le Beau MM. An integrated genomic approach to the assessment and treatment of acute myeloid leukemia. Semin Oncol 38:215-24, 2011. * # O’Donnell PH, Artz AS, Undevia SD, Pai RK, Del Cerro P, Horowitz S, Godley LA, Hart J, Innocenti F, Larson RA, Odenike OM, Stock W, Van Besien K. Phase I study of dose-escalated busulfan with fludarabine and alemtuzumab as conditioning for allogeneic hematopoietic stem cell transplant: reduced clearance at high doses and occurrence of late sinusoidal obstruction syndrome/veno-occlusive disease. Leuk Lymphoma 51:2240-9, 2010. THIRMAN, MICHAEL, MD * Artz AS, Thirman MJ. Unexplained anemia predominates despite an intensive evaluation in a racially diverse cohort of older adults from a referral anemia clinic. J Gerontol A Biol Sci Med Sci 66:925-32, 2011. Wang QF, Wu G, Mi S, He F, Wu J, Dong J, Luo RT, Mattison R, Kaberlein JJ, Prabhakar S, Ji H, Thirman MJ. MLL fusion proteins preferentially regulate a subset of wild-type MLL target genes in the leukemic genome. Blood 117:6895-905, 2011. PMC3128481 * Baron BW, Hyjek E, Gladstone B, Thirman MJ, Baron JM. PDCD2, a protein whose expression is repressed by BCL6, induces apoptosis in human cells by activation of the caspase cascade. Blood Cells Mol Dis 45:169-75, 2010. * Mi S, Li Z, Chen P, He C, Cao D, Elkahloun A, Lu J, Pelloso LA, Wunderlich M, Huang H, Luo RT, Sun M, He M, Neilly MB, Zeleznik-Le NJ, Thirman MJ, Mulloy JC, Liu PP, Rowley JD, Chen J. Aberrant overexpression and function of the miR-17-92 cluster in MLL-rearranged acute leukemia. PNAS 107:3710-5, 2010. PMC2840429 VAN BESIEN, KOEN, MD * van Besien K, Schouten V, Parsad S, Smith S, Odenike O, Artz A. Allogeneic stem cell transplantation in renal failure. Engraftment and prolonged survival, but high incidence of neurologic toxicity. Leuk Lymphoma, 2011 (Epub ahead of print). Greinix HT, van Besien K, Elmaagacli AH, Hillen U, Grigg A, Knobler R, Parenti D, Reddy V, Theunissen K, Michallet M, Flowers ME. Progressive improvement in cutaneous and extracutaneous chronic graft-versus-host disease after a 24-week course of extracorporeal photopheresisResults of a crossover randomized study. Biol Blood Marrow Transplant, 2011 (Epub ahead of print). UCCCC SCIENTIFIC REPORT 2010 – 2011 * Smith SM, Anastasi J, Cohen KS, Godley LA. The impact of MYC expression in lymphoma biology: beyond Burkitt lymphoma. Blood Cells Mol Dis 45:317-23, 2010. stem cell transplant. Leuk Lymphoma 51:995-1006, 2010. Hematopoiesis and Hematological Malignancies Fowler N, Kahl BS, Lee P, Matous JV, Cashen AF, Jacobs SA, Letzer J, Amin B, Williams ME, Smith S, Saleh A, Rosen P, Shi H, Parasuraman S, Cheson BD. Bortezomib, bendamustine, and rituximab in patients with relapsed or refractory follicular lymphoma: The phase II VERTICAL Study. J Clin Oncol 29:3389-95, 2011. * # O’Donnell PH, Artz AS, Undevia SD, Pai RK, Del Cerro P, Horowitz S, Godley LA, Hart J, Innocenti F, Larson RA, Odenike OM, Stock W, Van Besien K. Phase I study of dose-escalated busulfan with fludarabine and alemtuzumab as conditioning for allogeneic hematopoietic stem cell transplant: reduced clearance at high doses and occurrence of late sinusoidal obstruction syndrome/veno-occlusive disease. Leuk Lymphoma 51:2240-9, 2010. 47 Hematopoiesis and Hematological Malignancies UCCCC SCIENTIFIC REPORT 2010 – 2011 * # Kenkre VP, Horowitz S, Artz AS, Liao C, Cohen KS, Godley LA, Kline JP, Smith SM, Stock W, van Besien K. T-celldepleted allogeneic transplant without donor leukocyte infusions results in excellent long-term survival in patients with multiply relapsed lymphoma. Predictors for survival after transplant relapse. Leuk Lymphoma 52:214-22, 2011. * Marino SR, Lin S, Maiers M, Haagenson M, Spellman S, Klein JP, Binkowski TA, Lee SJ, van Besien K. Identification by random forest method of HLA class I amino acid substitutions associated with lower survival at day 100 in unrelated donor hematopoietic cell transplantation. Bone Marrow Transplant, 2011 (Epub ahead of print). PMC3128239 Shaughnessy PJ, Bolwell BJ, van Besien K, Mistrik M, Grigg A, Dodds A, Prince HM, Durrant S, Ilhan O, Parenti D, Gallo J, Foss F, Apperley J, Zhang MJ, Horowitz MM, Abhyankar S. Extracorporeal photopheresis for the prevention of acute GVHD in patients undergoing standard myeloablative conditioning and allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 45:1068-76, 2010. * # Poire X, Kline J, Grinblatt D, Zimmerman T, Conner K, Muhs C, Gajewski T, Van Besien K, Smith SM. Phase II study of immunomodulation with granulocytemacrophage colony-stimulating factor, interleukin-2, and rituximab following autologous stem cell transplant in patients with relapsed or refractory lymphomas. Leuk Lymphoma 51:1241-50, 2010. Martin PJ, Storer BE, Carpenter PA, Couriel DR, Flowers ME, Gupta V, Hsu JW, Jagasia M, Kitko CL, Maziarz RT, Rowley SD, Shaughnessy PJ, van Besien K, Weisdorf D, Lee SJ. Comparison of short-term response and long-term outcomes after initial systemic treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant 17:124-32, 2011. PMC2974028 VARDIMAN, JAMES, MD Mesa RA, Green A, Barosi G, Verstovsek S, Vardiman J, Gale RP. MPN-associated myelofibrosis (MPN-MF). Leuk Res 35:12-3, 2011. 48 * Kolitz JE, George SL, Marcucci G, Vij R, Powell BL, Allen SL, DeAngelo DJ, Shea TC, Stock W, Baer MR, Hars V, Maharry K, Hoke E, Vardiman JW, Bloomfield CD, Larson RA. P-glycoprotein inhibition using valspodar (PSC-833) does not improve outcomes for patients younger than age 60 years with newly diagnosed acute myeloid leukemia: Cancer and Leukemia Group B study 19808. Blood 116:1413-21, 2010. PMC2938834 WICKREMA, AMITTHA, PHD Wickrema A. Will cord blood stem cells come to the rescue of keratinocyte growth factor? Leuk Lymphoma 52:1423-4, 2011. Zhou L, Opalinska J, Sohal D, Yu Y, Mo Y, Bhagat T, Abdel-Wahab O, Fazzari M, Figueroa M, Alencar C, Zhang J, Kambhampati S, Parmar S, Nischal S, Hueck C, Suzuki M, Freidman E, Pellagatti A, Boultwood J, Steidl U, Sauthararajah Y, Yajnik V, McMahon C, Gore SD, Platanias LC, Levine R, Melnick A, Wickrema A, Greally JM, Verma A. Aberrant epigenetic and genetic marks are seen in myelodysplastic leukocytes and reveal Dock4 as a candidate pathogenic gene on chromosome 7q. J Biol Chem 286:2521123, 2011. PMC3137092 Zhou L, McMahon C, Bhagat T, Alencar C, Yu Y, Fazzari M, Sohal D, Heuck C, Gundabolu K, Ng C, Mo Y, Shen W, Wickrema A, Kong G, Friedman E, Sokol L, Mantzaris I, Pellagatti A, Boultwood J, Platanias LC, Steidl U, Yan L, Yingling JM, Lahn MM, List A, Bitzer M, Verma A. Reduced SMAD7 leads to overactivation of TGF-beta signaling in MDS that can be reversed by a specific inhibitor of TGF-beta receptor I kinase. Cancer Res 71:955-63, 2011. PMC3032816 Keerthivasan G, Small S, Liu H, Wickrema A, Crispino JD. Vesicle trafficking plays a novel role in erythroblast enucleation. Blood 116:3331-40, 2010. PMC2995360 ZHANG, YANMING, MD * Locke FL, Artz A, Rich E, Zhang Y, van Besien K, Stock W. Feasibility of clofarabine cytoreduction before allogeneic transplant conditioning for refractory AML. Bone Marrow Transplant 45:1692-8, 2010. * # Godley LA, Njiaju UO, Green M, Weiner H, Lin S, Odenike O, Rich ES, Artz A, Van Besien K, Daugherty CK, Zhang Y, Le Beau MM, Stock W, Larson RA. Treatment of therapy-related myeloid neoplasms with high-dose cytarabine/ mitoxantrone followed by hematopoietic stem cell transplant. Leuk Lymphoma 51:995-1006, 2010. Kim YC, Jung YC, Chen J, Alhasan AH, Kaewsaard P, Zhang Y, Ma S, Rosen S, Wang SM. Evidences showing wide presence of small genomic aberrations in chronic lymphocytic leukemia. BMC Res Notes 3:341, 2010. PMC3016268 ZIMMERMAN, TODD, MD Lin RJ, Curran JJ, Zimmerman TM, Song J, Niewold TB, Sweiss NJ. Lenalidomide for the treatment of cryoglobulinemia and undifferentiated spondyloarthropathy in a patient with multiple myeloma. J Clin Rheumatol 16:90-1, 2010. * # Poire X, Kline J, Grinblatt D, Zimmerman T, Conner K, Muhs C, Gajewski T, Van Besien K, Smith SM. Phase II study of immunomodulation with granulocytemacrophage colony-stimulating factor, interleukin-2, and rituximab following autologous stem cell transplant in patients with relapsed or refractory lymphomas. Leuk Lymphoma 51:1241-50, 2010. Jakubowiak AJ, Griffith KA, Reece DE, Hofmeister CC, Lonial S, Zimmerman TM, Campagnaro EL, Schlossman RL, Laubach JP, Raje NS, Anderson T, Mietzel MA, Harvey CK, Wear SM, Barrickman JC, Tendler CL, Esseltine DL, Kelley SL, Kaminski MS, Anderson KC, Richardson PG. Lenalidomide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone in newly diagnosed multiple myeloma: a phase 1/2 Multiple Myeloma Research Consortium trial. Blood 118:535-43, 2011. Somlo G, Lashkari A, Bellamy W, Zimmerman TM, Tuscano JM, O’Donnell MR, Mohrbacher AF, Forman SJ, Frankel P, Chen HX, Doroshow JH, Gandara DR. Phase II randomized trial of bevacizumab versus bevacizumab and thalidomide for relapsed/refractory multiple myeloma: a California Cancer Consortium trial. Br J Haematol 154:533-5, 2011. Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C, Schinzel AC, Harview CL, Brunet JP, Ahmann GJ, Adli M, Anderson KC, Ardlie KG, Auclair D, Baker A, Bergsagel PL, Bernstein BE, Drier Y, Fonseca R, Gabriel SB, Hofmeister CC, Jagannath S, Jakubowiak AJ, Krishnan A, Levy J, Liefeld T, Lonial S, Mahan S, Mfuko B, Monti S, Perkins LM, Onofrio R, Pugh TJ, Rajkumar SV, Ramos AH, Siegel DS, Sivachenko A, Stewart AK, Trudel S, Vij R, Voet D, Winckler W, Zimmerman T, Carpten J, Trent J, Hahn WC, Garraway LA, Meyerson M, Lander ES, Getz G, Golub TR. Initial genome sequencing and analysis of multiple myeloma. Nature 471:467-72, 2011. Selected Major Grants and Awards INVESTIGATOR TITLE PROJECT START DATE END DATE TOTAL ANNUAL COST CLASS FUNDING AGENCY The role of miR-126 in core-binding factor (CBF) acute myeloid leukemia 7/1/2011 6/30/2015 $180,000 N/A American Cancer Society JOHN CUNNINGHAM The genomic basis of therapy-related acute myelogenous leukemia 10/1/2010 9/30/2011 $100,000 N/A Hyundai Hope on Wheels LUCY GODLEY ON01910.Na administered as a 72-hour continuous intravenous infusion every other week in myelodysplastic syndrome patients with excess blasts relapsing after, or refractory to, or intolerant to azacitidine or decitabine 4/28/2011 4/27/2013 $131,775 N/A Onconova Therapeutics, Inc. FOTINI GOUNARI Signaling in thymic selection 9/20/2010 8/31/2011 $390,000 R01 National Institutes of Health MICHAEL THIRMAN A phase 1b/2 open label study to evaluate the safety and efficacy of TRU 016 in combination with bendamustine vs. bendamustine alone in patients with relapsed chronic lymphocytic leukemia 2/10/2011 9/30/2012 $107,170 N/A Emergent Product Development Seattle, LLC UCCCC SCIENTIFIC REPORT 2010 – 2011 JIANJUN CHEN Hematopoiesis and Hematological Malignancies The Hematopoiesis and Hematological Malignancies Program has a funding base of $9,539,829 in annual total costs (current as of July 2011). This sum includes $2,785,376 in NCI funding and $1,545,311 in other NIH funding. Due to space constraints, only selected new awards since January 1, 2010 of $100,000 or greater in annual total costs are listed here. 49 IMMUNOLOGY AND CANCER PROGRAM LEADER Thomas Gajewski, MD, PhD Professor of Pathology and Medicine 50 HE IMMUNOLOGY AND CANCER PROGRAM AIMS TO understand the interface between the host immune system and malignant tumors. The Program, consisting of 22 members (one of whom is a Howard Hughes investigator) from six departments, deciphers all aspects of immune response against tumors to develop immune-based cancer therapeutics. Program members Immunology and Cancer T are bringing new immunology concepts into preclinical models of anti-tumor immunity, translating fundamental discoveries into clinical applications, and testing new hypotheses generated from these studies back in murine models. ■■Fundamental investigations in immunology relevant to cancer; ■■Studies using mouse models of anti-tumor immunity; and ■■Clinical studies of human anti-tumor immunity and novel immunotherapies UCCCC SCIENTIFIC REPORT 2010 – 2011 T H E OV E R A L L G OA L S O F T H E P R O G R A M A R E TO CO N D U C T: 51 UCCCC SCIENTIFIC REPORT 2010 – 2011 Immunology and Cancer PROGRAM MEMBERSHIP† Erin Adams, PhD Assistant Professor of Biochemistry & Molecular Biology Maria-Luisa Alegre, MD, PhD Associate Professor of Medicine Hans Schreiber, MD, PhD Professor of Pathology Anne Sperling, PhD Associate Professor of Medicine Albert Bendelac, MD, PhD Professor of Pathology Ursula Storb, MD Professor of Molecular Genetics & Cell Biology Anita Chong, PhD Professor of Surgery Patrick Wilson, PhD, MS Assistant Professor of Medicine Marcus Clark, MD Professor of Medicine Ping Yu, MD Assistant Professor of Pathology Yang-Xin Fu, MD, PhD Professor of Pathology Jian Zhang, MD Assistant Professor of Medicine Thomas Gajewski, MD, PhD Professor of Pathology and Medicine Tatyana Golovkina, PhD Associate Professor of Microbiology φJose Guevara-Patino, MD, PhD Assistant Professor of Surgery Bana Jabri, MD, PhD Professor of Medicine Justin Kline, MD Assistant Professor of Medicine Vinay Kumar, MD, PhD Professor of Pathology Maciej Lesniak, MD Professor of Surgery Vu Nguyen, MD Assistant Professor of Medicine Glenn Randall, PhD Assistant Professor of Microbiology Peter Savage, PhD Assistant Professor of Pathology † Reflects all Program membership during 2010-2011 φ Individuals who are no longer at the UCCCC 52 Program Highlights† †Due to space constraints, only a small representative sample of Program highlights is presented here. SAP PROTEIN-DEPENDENT NATURAL KILLER T-LIKE CELLS REGULATE CD8+ T CELL DEVELOPMENT (INTERPROGRAMMATIC) abrogate antibody-initiated immunity and decrease resistance to relapse. These findings bear significant clinical impact because they demonstrate that anti-HER2 efficacy depends on the host immune system, but also that antibody-initiated tumor regression can be impaired by certain chemotherapy regimens. (Park et al., Cancer Cell 18:160-70, 2010) THERAPEUTIC EFFECT OF ANTI-HER2/NEU ANTIBODY DEPENDS ON INNATE AND ADAPTIVE IMMUNITY GENE SIGNATURE IN MELANOMA IS ASSOCIATED WITH CLINICAL BENEFIT Yang-Xin Fu, MD, PhD, and colleagues examined the mechanisms of tumor regression induced by anti-HER2/neu antibody therapy in syngeneic wild-type mice. They found that the therapeutic effect of this treatment is dependent on the activation of innate immunity and T cells. Furthermore, an increased influx of both innate and adaptive immune cells into the tumor microenvironment was increased by subsequent antibody-induced immunity, which leads to enhanced tumor regression. Surprisingly, the addition of chemotherapeutic drugs was found to Thomas Gajewski, MD, PhD, and colleagues examined the potential mechanisms of response versus resistance to antitumor immunity through gene expression profiling of melanoma metastases in the context of peptidebased vaccines. They profiled fresh tumor biopsies obtained from patients prior to tumor antigen vaccination and found that T-cell markers and specific chemokines were associated with clinical benefit from immunization against melanoma antigens. These studies suggest that a subset of melanoma patients have metastatic tumors containing an inflammatory infiltrate that may be useful as a UCCCC SCIENTIFIC REPORT 2010 – 2011 Albert Bendelac, MD, PhD, and Barbara Kee, PhD (Hematopoiesis and Hematological Malignancies Program), along with colleagues examined the requirement for ld3 in T cell development by investigating the phenotype and function of CD8 T cells in ld3-/- mice. They found that during thymocyte development, ld3 prevents CD8+ T cells from adopting an innate-like fate characterized by expression of the Eomesodermin transcription factor, expression of a memory surface marker phenotype, and dependence on the SAP signaling pathway. Induction of the innate-like phenotype was dependent on the production of interleukin-4 from an expanded population of NK T-like cells. These observations increase our understanding of how innate-like CD8+ T cells develop and function. (Verykokakis et al., Immunity 33:203-15, 2010) the eradication of aggressive cancers, and that CD4+ T cell cooperation with CD8+ cells is required for T cell activation and during the effector phase in the tumor microenvironment. These results indicate a new role for CD4+ cells and demonstrate the potential of stromal targeting for cancer immunotherapy. (Schietinger et al., J Exp Med 207:2469, 2010) Immunology and Cancer Publications BYSTANDER KILLING OF CANCER REQUIRES COOPERATION OF CD4+ AND CD8+ T CELLS DURING THE EFFECTOR PHASE Hans Schreiber, MD, PhD, and colleagues have tested the efficacy of stromal targeting in a non-transgenic T cell model. Using immunocompetent mice, they tested whether a normal host without prior immunization could eliminate cancer cells through stromal targeting and examined the role of CD4+ T cells alongside CD8+ T cells in this process. They have found that T cell targeting of tumor stroma results in 53 Immunology and Cancer UCCCC SCIENTIFIC REPORT 2010 – 2011 predictive marker for clinical benefit from immunotherapy approaches and guide the development of new therapeutic interventions to overcome tumor resistance. (Gajewski et al., Cancer J 16:399-403, 2010) GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR, INTERLEUKIN-2, AND RITUXIMAB IMPROVE SURVIVAL IN PATIENTS WITH LYMPHOMA (INTRA/ INTERPROGRAMMATIC) Justin Kline, MD, Thomas Gajewski, MD, PhD, and colleagues including Drs. Zimmerman, Van Besien, and Smith (Hematopoiesis and Hematological Malignancies Program) performed a phase II study to determine if granulocyte-macrophage colony-stimulating factor in combination with rituximab and IL-2 could eliminate persistent minimal residual disease and improve eventfree survival in patients with relapsed non-Hodgkin lymphoma or Hodgkin lymphoma following autologous stem cell transplant. The combination therapy was found to be feasible with encouraging event-free and overall survival rates. Further investigation will require a comparative arm to determine if this combination is beneficial. (Poire et al., Leuk Lymphoma 51:1241-50, 2010) INNATE IMMUNE SENSING OF RETROVIRAL INFECTION VIA TOLL-LIKE RECEPTOR 7 OCCURS UPON VIRAL ENTRY Tatyana Golovkina, PhD, and colleagues investigated the sensing mechanisms underlying retrovirusspecific immune response using mice from retrovirus-resistant strains. They found that the ability to enter the host cell was sufficient to trigger antivirus humoral immune response, and that virus sensing is dependent on an endosomal Toll-like receptor 54 7 (TLR7) mechanism independent of type I interferons. These results indicate that viral entry is critical for inducing efficient adaptive immunity and contribute to our understanding of mechanisms involved in developing retroviral resistance. (Kane et al., Immunity 35:135-145, 2011) Grants CYCLIN D3 CONTRIBUTES TO LYMPHOCYTE DEVELOPMENT The development of B cells is regulated by cytokines and expression of the pre-B cell antigen receptor (pre-BCR) on lymphocyte precursors destined to become B cells. Marcus Clark, MD, was awarded an R01 grant from the National Institute of General Medical Sciences to determine the mechanisms that direct this process. In previous studies, Dr. Clark determined that cyclin D3 is required for clonal expansion of pre-B cells. These studies will facilitate an improved understanding of the development of B cells, which can be active participants in antitumor immune responses. Immunology and Cancer Maciej Lesniak, MD, has developed a novel approach for the treatment of malignant brain tumors using neural stem cells (NSC) as carriers of an oncolytic adenovirus that directly targets glioma stem cells. Supported by a U01 award from the National Institutes of Health, Dr. Lesniak is testing the efficacy and safety of virotherapy for malignant glioma to advance this approach and potentially help improve disease outcome. CBL-B INFLUENCES SUSCEPTIBILITY TO ASTHMA AND AUTOIMMUNITY Casitas-B-lineage lymphoma protein-b (Cbl-b), an E3 ubiquitin ligase, plays a role in maintaining a balance between immunity and tolerance. Funded by a National Institutes of Health R01 grant, Jian Zhang, MD, is determining the mechanisms by which Cbl-b contributes to autoimmunity, specifically through regulation of T helper 2 (Th2) cell differentiation and regulatory T cell development. An improved understanding of the mechanisms of Cbl-b action may lead to the development of novel therapeutic approaches for autoimmune diseases, allergic asthma, and cancer. is dependent on type I IFN and lymphotoxin beta receptor (LTβR). Through a National Cancer Institute R01 award, Dr. Fu is further examining the mechanisms by which local radiation stimulates immunity to develop novel, combination modalities for treating cancer. COMBINED RADIATION AND IMMUNOTHERAPY INDUCE TUMOR REGRESSION Glenn Randall, PhD, was awarded an R01 grant from the National Institute of Allergy and Infectious Diseases to investigate the role of various human genes in hepatitis C virus (HCV) infection. Dr. Randall is molecularly characterizing membrane trafficking pathways and the role of host genes in HCV entry into cells. These studies will shed light on stages of the viral life cycle and identify key roles of human genes that may affect the development of liver disease, including cancer, in the HCV-infected population. Established tumors exhibit barriers that limit the eradication of metastases by immune destruction. Yang-Xin Fu, MD, has shown that a large single dose of radiotherapy (RT) targeted against primary tumors can destroy these barriers by increasing cytotoxic T-lymphocyte (CTL) cross-priming and antigen presentation. Furthermore, he demonstrated that RT-induced tumor regression UCCCC SCIENTIFIC REPORT 2010 – 2011 NEURAL STEM CELLS ARE EFFECTIVE CARRIERS OF VIROTHERAPY FOR MALIGNANT GLIOMA HOST GENES INFLUENCE HEPATITIS C VIRUS TRAFFICKING 55 Featured Faculty Profiles† †Due to space constraints, only a small representative sample of Program members is presented here. UCCCC SCIENTIFIC REPORT 2010 – 2011 Immunology and Cancer PATRICK WILSON, PHD, MS Assistant Professor of Medicine Dr. Patrick Wilson’s laboratory is interested in understanding the mechanisms that mediate B cell responses and antibody-mediated immunity to infectious diseases. Dr. Wilson also has a long-standing interest in the control of autoreactive B cells in immune tolerance. Over the years, his laboratory has developed technologies to clone recombinant monoclonal antibodies from discrete populations of B cells. A major focus of the laboratory is using these approaches to isolate antibodies that are protective against infectious agents such as influenza and staphylococci. These antibodies will help identify targets for the rational design of improved vaccines. Furthermore, his laboratory is developing the antibodies themselves as the next class of drugs to treat these infections. Dr. Wilson and his colleagues found that after influenza vaccination, a rapid and robust influenza-specific IgG1 antibody-secreting plasmablast response occurred.1 The response peaked at approximately day 7 and accounted for up to 6% of peripheral blood B cells. By isolating single cells, they demonstrated Patrick Wilson, PhD, MS that numerous high-affinity antibodies could be isolated from humans within a month after vaccination. This technology is now being used worldwide to understand current, ongoing B cell responses during infections or after vaccination. New insights on B cell responses will facilitate the development of novel therapeutics to treat or provide prophylactics against various infectious diseases, and will help identify the targets of human antibodies and appropriate pathogens to target by vaccination. Dr. Wilson’s laboratory used this approach to demonstrate a predominant memory cell origin of the influenza vaccine-induced response but with rapid adaptation to novel vaccines. In a follow-up report, they demonstrated that the approach was widely applicable and could be used after various vaccinations in addition to influenza, such as Pneumovax, anthrax, and hepatitis B.2 Unlike antibodies elicited by annual influenza vaccinations, Dr. Wilson observed that most neutralizing antibodies induced by pandemic H1N1 infection were derived from activated memory B cells specific for epitopes conserved in many influenza strains.3 Consequently, most neutralizing antibodies were broadly reactive against divergent H1N1 and H5N1 influenza strains. This study provides evidence that, given the right immunogen, a pan-influenza vaccine and the potential to eradicate influenza as a human disease may be possible. The antibodies generated offered potent protection and rescued mice from lethal challenge with pandemic H1N1 or antigenically distinct influenza strains, making them excellent therapeutic candidates. Dr. Wilson hopes to apply a similar technology toward the understanding of B cell responses against cancers. Wrammert J, Smith K, Miller J, Langley WA, Kokko K, Larsen C, Zheng NY, Mays I, Garman L, Helms C, James J, Air GM, Capra JD, Ahmed R, Wilson PC. Rapid cloning of high-affinity human monoclonal antibodies against influenza virus. Nature 453:667-671, 2008. 1 Smith K, Garman L, Wrammert J, Zheng NY, Capra JD, Ahmed R, Wilson PC. Rapid generation of fully human monoclonal antibodies specific to a vaccinating antigen. Nat Protoc 4:372-384, 2008. 2 Wrammert J, Koutsonanos D, Li GM, Edupuganti S, Sui J, Morrissey M, McCausland M, Skountzou I, Hornig M, Lipkin WI, Mehta A, Razavi B, Del Rio C, Zheng NY, Lee JH, Huang M, Ali Z, Kaur K, Andrews S, Amara RR, Wang Y, Das SR, O’Donnell CD, Yewdell JW, Subbarao K, Marasco WA, Mulligan MJ, Compans R, Ahmed R, Wilson PC. Broadly cross-reactive antibodies 3 dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection. J Exp Med 208:181-193, 2011. 56 Associate Professor of Medicine Drs. Maria-Luisa Alegre and Anita Chong (Immunology and Cancer Program) have been collaborating for the past 6 years, focusing on the consequences of infections, and the immune signals that they elicit, on immune responses to non-microbial antigens. This focus is relevant for cancer research, as observations of cancer regression in patients experiencing bacterial infections served as some of the first historic reports suggesting a role of the immune system in tumor elimination. More recently, the Alegre and Chong laboratories have reported that LM, but not SA or CpG, could abrogate transplantation tolerance when infection occurred months after cardiac allograft acceptance.3 Rejection was recapitulated with a combination of recombinant IFNβ plus IL-6, demonstrating that reactivation of antigen-specific immune responses is more difficult after animals achieve long-term tolerance. This model is more reminiscent of clinical settings of established cancer, in which tumor-specific T cells may be inactivated or suppressed. Understanding the signals that can restore immune responses in this context may help find avenues to reestablish anti-tumor immunity. A program project to continue these studies, aimed at dissecting pathways that lead to robust and stable antigen-specific tolerance and the mechanisms by which stable tolerance can be abrogated, was recently submitted to the NIH. The project was favorably reviewed and is awaiting council decision. UCCCC SCIENTIFIC REPORT 2010 – 2011 The Alegre and Chong laboratories use mouse models of skin and heart transplantation in which long-term tolerance of fully mismatched allografts is induced by treatment with antibodies to the costimulatory molecule CD154 (CD40L). The team has previously reported that ligation of Tolllike receptor 9 (TLR9), a receptor for unmethylated CpG motifs present in bacteria, prevents the induction of transplantation tolerance, correlating with reduced accumulation of regulatory T cells in the graft. Graft rejection was Maria-Luisa Alegre, MD, PhD dependent on IL-6/IL-17 in CpG-treated animals, suggesting that innate cytokines can shape the differentiation phenotype of graft-reactive T cells. Systemic bacterial infections with Listeria monocytogenes (LM) or Staphylococcus aureus (SA) also prevented anti-CD154-mediated acceptance of skin allografts,1 whereas maximally tolerated titers of Pseudomonas aeruginosa (PA) did not. LM infections prevented graft acceptance through type I Interferon signaling while SA did so in an IL-6-dependent manner. Interestingly, steroid administration reduced IL-6 production in SA-infected mice and prevented graft rejection. These data demonstrate that distinct innate immune signals elicited by different bacteria variously affect the immune response to transplant antigens and point to therapeutic targets to facilitate tolerance induction in transplantation and autoimmunity.2 Immunology and Cancer MARIA-LUISA ALEGRE, MD, PHD Ahmed EB, Wang T, Daniels M, Alegre ML, Chong AS. IL-6 induced by Staphylococcus aureus infection prevents the induction of skin allograft acceptance in mice. Am J Transplant 11:936-946, 2011. 1 Ahmed EB, Daniels M, Alegre ML, Chong AS. Bacterial infections, alloimmunity, and transplantation tolerance. Transplant Rev 25:27-35, 2011. 2 Wang T, Ahmed EB, Chen L, Xu J, Tao J, Wang CR, Alegre ML, Chong AS. Infection with the intracellular bacterium, Listeria monocytogenes, overrides established tolerance in a mouse cardiac allograft model. Am J Transplant 10:1524-1533, 2010. 3 57 UCCCC SCIENTIFIC REPORT 2010 – 2011 Immunology and Cancer YANG-XIN FU, MD, PHD Professor of Pathology Dr. Yang-Xin Fu is a physician scientist with a strong interest in basic immunobiology and tumor immunology. His studies often integrate basic research with disease pathogenesis and treatment. Basic research in Dr. Fu’s laboratory is focused on understanding the biological consequences arising from the interaction between core molecules of the TNF superfamily, lymphotoxin (LT or TNFSF1) and LIGHT (TNFSF14), on lymphocytes and their receptor, LTβR, on stromal cells. This research has contributed substantially to defining the critical role of these molecules in the development and function of primary, secondary, and tertiary lymphoid tissues. The overall goal of Dr. Fu’s laboratory is to understand the role of innate and adaptive immunity in conventional and targeted therapies and to develop new, targeted strategies against local tumor tissues while generating systemic immune responses. An understanding of the role of LIGHT and LT on the LTβR-mediated lymphoid microenvironment has allowed Dr. Fu to pioneer new approaches Yang-Xin Fu, MD, PhD for altering the lymphoid-like microenvironment to enhance infectious or tumor immunity.1 Similarly, Dr. Fu will explore how to target tumors with antibody-based fusion proteins to favor strong immunity. Local radiotherapy (RT) can induce severe DNA damage, causing tumor dormancy. Dr. Fu’s laboratory has revealed an essential role of CD8+ cells in suppressing tumor cell growth and maintaining dormancy.2,3 They have identified an active interaction between tumor and immune cells that is essential for dormancy, opening new avenues for the elimination of dormant cells. His laboratory is further exploring how RT induces danger signals and cytokines to break tolerance. Dr. Fu has also examined the influence of both innate and adaptive immunity in antibody-mediated tumor regression. Current models propose that the therapeutic effect of HER2/neu antibody (Ab) on HER2/neu+ breast cancer is mediated through the interruption of oncogenic signaling on tumor cells and/or the induction of antibody-dependent, cell-mediated cytotoxicity (ADCC). However, relapse often occurs after prolonged treatment. Unexpectedly, Dr. Fu’s laboratory has recently demonstrated that the therapeutic effect of anti-neu Ab is largely dependent on HMGB-1, MyD88, IFN-α/β, and CD8+, and CD4+ T cells.4 They are exploring how innate and adaptive cells interact and developing methods to amplify antibody-mediated immunity. Together, this work demonstrates how the host immune response is critical to the efficacy of traditional cancer therapeutics. Wang Y, Koroleva EP, Kruglov AA, Kuprash DV, Nedospasov SA, Fu YX, Tumanov AV. Lymphotoxin beta receptor signaling in intestinal epithelial cells orchestrates innate immune responses against mucosal bacterial infection. Immunity 32:403-413, 2010. 1 2 Lee Y, Auh SL, Wang Y, Burnette B, Wang Y, Meng Y, Beckett M, Sharma R, Chin R, Tu T, Weichselbaum RR, Fu YX. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood 114:589-595, 2010. Burnette BC, Liang H, Lee Y, Chlewicki L, Khodarev NN, Weichselbaum RR, Fu YX, Auh SL. The efficacy of radiotherapy relies upon induction of type i interferon-dependent innate and adaptive immunity. Cancer Res 71:2488-2496, 2011. 3 Park S, Jiang Z, Mortenson ED, Deng L, Radkevich-Brown O, Yang X, Sattar H, Wang Y, Brown NK, Greene M, Liu Y, Tang J, Wang S, Fu YX. The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity. Cancer Cell 4 18:160-170, 2010. 58 Associate Professor of Microbiology A proper host defense against viral pathogens exists at two levels: the innate immunity response, and adaptive immunity resulting in long-lasting protective immunity. As with all infectious processes, susceptibility to retroviral pathogenesis and tumorigenesis are both controlled by the genetic background of the host. Dr. Tatyana Golovkina is using Mouse Mammary Tumor Virus (MMTV) as well as Murine Leukemia Virus (MuLV) to study different aspects of retrovirus-host interactions, including the anti-virus immune response and the genetics of resistance to retroviral infection and to virally induced tumors. Elucidation of the mechanism of retroviral pathogenesis is of fundamental importance, as it will ultimately lead to increased knowledge about the anti-virus immune response in general and variations in susceptibility to tumor-causing viruses in humans. Mice from non-resistant strains are susceptible to various retroviruses even though they are capable of sensing them. This is due to numerous mechanisms that retroviruses have evolved to counteract immune defenses. Many retroviruses, including MMTV, are transmitted most efficiently through mucosal surfaces rich in microbiota. Dr. Golovkina’s laboratory found that MMTV, when ingested by newborn mice, stimulates a state of unresponsiveness towards viral antigens.4 This process required the intestinal microbiota, as antibiotic-treated mice or germ-free mice did not transmit infectious virus to their offspring. MMTV-bound bacterial lipopolysaccharide triggered Toll-like receptor 4 and subsequent interleukin (IL)-6-dependent induction of the inhibitory cytokine IL-10. Thus, MMTV has evolved to rely on the interaction with the microbiota to induce an immune evasion pathway. Together, these findings reveal the fundamental importance of commensal microbiota in viral infections. UCCCC SCIENTIFIC REPORT 2010 – 2011 By using mice from two inbred strains that control retroviruses via adaptive immune mechanisms and do not develop tumors,1,2 Dr. Golovkina’s laboraTatyana Golovkina, PhD tory found that of all steps in viral replication, the ability to enter the host cell was sufficient to induce anti-virus humoral immune responses.3 Virus sensing occurred in endosomes via a MyD88-Toll-like receptor 7-dependent mechanism and stimulated virus-neutralizing immunity independently of type I interferons. Thus, efficient adaptive immunity to retroviruses is induced in vivo by innate sensing of the early stages of retroviral infection. Immunology and Cancer TATYANA GOLOVKINA, PHD Case LK, Purdy A, Golovkina TV. Molecular and cellular basis of the retrovirus resistance in I/LnJ mice. J Immunol 175:7543-7549, 2005. 1 2 Kane M, Case LK, Golovkina TV. Vital role for CD8+ cells in controlling retroviral infections. J Virol 85:3415-23, 2011. Kane M, Case LK, Wang C, Yurkovetskiy L, Dikiy S, Golovkina TV. Innate immune sensing of retroviral infection via toll-like receptor 7 occurs upon viral entry. Immunity 35:135-145, 2011. 3 Kane M, Case LK, Kopaskie K, Kozlova A, MacDearmid C, Chervonsky A, and Golovkina TV. Successful transmission of a retrovirus depends on the commensal microbiota. Science 334:245-249, 2011. 4 59 UCCCC SCIENTIFIC REPORT 2010 – 2011 Immunology and Cancer BANA JABRI, MD, PHD Professor of Medicine Dr. Bana Jabri’s laboratory is identifying molecular targets that can be exploited to promote or block inflammatory immune responses for the treatment of cancer. Understanding how to modulate inflammatory immune responses in tissues has two implications for cancer therapy: 1) to induce effective T cell immunity against aseptic tolerogenic tissues to allow for the rejection of established cancers; and 2) to avert unwanted, chronic response associated with the development of cancers, as seen in the context of inflammatory bowel disease and celiac disease. Dr. Jabri’s work centers on understanding the innate immune mechanisms that lead to activation of T cells in tissues.1,2 Specifically, she has studied the role of natural killer receptors and IL-15 in T cell-mediated tissue immunity. Dr. Jabri’s laboratory discovered that IL-15 licenses cytotoxic T cells to become potent killer cells and acquire lymphokine killer properties.3 Intriguingly, reports have shown that NKG2D, when engaged in the absence of Bana Jabri, MD, PhD IL-15, is down-regulated and can no longer mediate its anti-tumor effects. Recently, Dr. Jabri has reported in collaboration with her colleagues that NKG2D engagement in the absence of inflammation promotes degradation of the T cell receptor, hence inactivating T cells.4 Dr. Jabri’s laboratory is currently exploring indications that IL-15 may counter these immunosuppressive effects. Furthermore, in collaboration with Dr. Hans Schreiber (Immunology and Cancer Program), she found that IL-15 expression by tumor cells allows rejection of established solid tumors that express low levels of or even lack cognate antigen by cytotoxic T cells (manuscript under review). In addition to enhancing the innate and specific cytolytic properties of T cells, IL-15 can synergize with the vitamin A metabolite, retinoic acid, to activate dendritic cells and promote inflammatory helper type-1 and type-17 responses.5 This provides an explanation for how retinoic acid may have adjuvant effects in cancer therapy, particularly when IL-15 can be induced. Conversely, Dr. Jabri and colleagues are testing molecules that block IL-15 signaling for the treatment of pre-lymphoma in patients with celiac disease.5 Finally, her laboratory is identifying molecules that promote the secretion of IL-10 to prevent chronic inflammation associated with the development of intestinal cancers.6,7 1 Jabri B, Sollid LM. Tissue-mediated control of immunopathology in celiac disease. Nat Rev Immunol 9:858-870, 2009. Abadie V, Sollid LM, Barreiro LB, Jabri B. Integration of genetic and immunological insights into a model of celiac disease pathogenesis. Annu Rev Immunol 29:493-525, 2011. 2 3 Tang F, Chen Z, Ciszewski C, Setty M, Solus J, Tretiakova M, Ebert E, Han J, Lin A, Guandalini S, Groh V, Spies T, Green P, Jabri B. Cytosolic PLA2 is required for CTL-mediated immunopathology of celiac disease via NKG2D and IL-15. J Exp Med 206:707-719, 2009. 4 Hanaoka N, Jabri B, Dai Z, Ciszewski C, Stevens AM, Yee C, Nakakuma H, Spies T, Groh V. NKG2D initiates caspase-mediated CD3zeta degradation and lymphocyte receptor impairments associated with human cancer and autoimmune disease. J Immunol 185:5732-5742, 2010. DePaolo RW, Abadie V, Tang F, Fehlner-Peach H, Hall JA, Wang W, Marietta EV, Kasarda DD, Waldmann TA, Murray JA, Semrad C, Kupfer SS, Belkaid Y, Guandalini S, Jabri B. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature 471:220-224, 2011. 5 6 Depaolo RW, Tang F, Kim I, Han M, Levin N, Ciletti N, Lin A, Anderson D, Schneewind O, Jabri B. Toll-like receptor 6 drives dif- ferentiation of tolerogenic dendritic cells and contributes to LcrV-mediated plague pathogenesis. Cell Host Microbe 4:350-361, 2008. 7 Round JL, Lee SM, Li J, Tran G, Jabri B, Chatila TA, Mazmanian SK. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332:974-977, 2011. 60 Immunology and Cancer HANS SCHREIBER, MD, PHD Professor of Pathology Dr. Schreiber has a long-standing interesting in understanding the nature of the host immune response against cancers. His laboratory was among the first to identify the molecular nature of tumor antigens,1 and he has uncovered a critical role for the tumor stroma in both supporting tumor growth and facilitating tumor resistance to immune destruction.2 Most recently, he has focused on the rules that govern whether adoptively transferred T cells can eliminate established cancers and lead to cure in preclinical models. While most of Dr. Schreiber’s work has focused upon anti-tumor CD8+ T cells, he recently confirmed a therapeutic role for CD4+ T cells in tumor control. Contrary to expectations, CD4+ T cells were not acting only during the priming phase to provide T cell “help,” but rather during the effector phase within the tumor microenvironment. These CD4+ T cells were facilitating destruction of tumor stroma, providing additional support for the notion that destruction of stromal cells is a key component in cancer therapy.3 Hans Schreiber, MD, PhD A key role for cytokines also has been observed with respect to the therapeutic effect of T cells on controlling tumor growth when only the stroma is targeted. Dr. Schreiber’s group has discovered that the cytokines IFN-γ and TNF-α are essential for the ability of T cells to promote bystander control of solid tumors in vivo. This mechanism argues for the generation of polyfunctional T cells producing inflammatory cytokines to maximize immune-mediated tumor control.5 Brooks CL, Schietinger A, Borisova SN, Kufer P, Okon M, Hirama T, Mackenzie CR, Wang LX, Schreiber H, Evans SV. Antibody recognition of a unique tumor-specific glycopeptide antigen. PNAS 107:10056-10061, 2010. 1 UCCCC SCIENTIFIC REPORT 2010 – 2011 Because many tumors can acquire resistance to immune-mediated attack, Dr. Schreiber’s group has recently studied the evolution of resistance over time using a mouse tumor model. His group found that serial passage of a tumor in vivo was associated with loss of susceptibility to the growth-inhibitory effect of IFN-γ. The lack of protective immunity occurred despite retention of tumor antigens, arguing that IFN-γ responsiveness of the tumor cells represents a critical parameter that determines effectiveness of anti-tumor immunity.4 Zhang B, Zhang Y, Bowerman NA, Schietinger A, Fu YX, Kranz DM, Rowley DA, Schreiber H. Equilibrium between host and cancer caused by effector T cells killing tumor stroma. Cancer Res 68:1563-1571, 2008. 2 Schietinger A, Philip M, Liu RB, Schreiber K, Schreiber H. Bystander killing of cancer requires the cooperation of CD4(+) and CD8(+) T cells during the effector phase. J Exp Med 207:2469-2477, 2010. 3 4 Wu TH, Schreiber K, Arina A, Khodarev NN, Efimova EV, Rowley DA, Weichselbaum RR, Schreiber H. Progression of cancer from indolent to aggressive despite antigen retention and increased expression of interferon-gamma inducible genes. Cancer Immun 11:2, 2011. Zhang B, Karrison T, Rowley DA, Schreiber H. IFN-gamma- and TNF-dependent bystander eradication of antigen-loss variants in established mouse cancers. J Clin Invest 118:1398-1404, 2008. 5 61 Selected Publications UCCCC SCIENTIFIC REPORT 2010 – 2011 Immunology and Cancer * : Intraprogrammatic Collaboration # : Interprogrammatic Collaboration ADAMS, ERIN, PHD Kazen AR, Adams EJ. Evolution of the V, D, and J gene segments used in the primate gammadelta T-cell receptor reveals a dichotomy of conservation and diversity. PNAS 108:E332-40, 2011. PMC3141992 Scharf L, Li NS, Hawk AJ, Garzon D, Zhang T, Fox LM, Kazen AR, Shah S, Haddadian EJ, Gumperz JE, Saghatelian A, Faraldo-Gomez JD, Meredith SC, Piccirilli JA, Adams EJ. The 2.5 a structure of CD1c in complex with a mycobacterial lipid reveals an open groove ideally suited for diverse antigen presentation. Immunity 33:853-62, 2010. PMC3010391 Older Aguilar AM, Guethlein LA, Adams EJ, Abi-Rached L, Moesta AK, Parham P. Coevolution of killer cell Ig-like receptors with HLA-C to become the major variable regulators of human NK cells. J Immunol 185:4238-51, 2010. PMC3124317 # Lodolce JP, Kolodziej LE, Rhee L, Kariuki SN, Franek BS, McGreal NM, Logsdon MF, Bartulis SJ, Perera MA, Ellis NA, Adams EJ, Hanauer SB, Jolly M, Niewold TB, Boone DL. African-derived genetic polymorphisms in TNFAIP3 mediate risk for autoimmunity. J Immunol 184:7001-9, 2010. * # Verykokakis M, Boos MD, Bendelac A, Adams EJ, Pereira P, Kee BL. Inhibitor of DNA binding 3 limits development of murine slam-associated adaptor proteindependent “innate” gammadelta T cells. PLoS One 5:e9303, 2010. PMC2824806 ALEGRE, MARIA-LUISA, MD, PHD * Wang T, Ahmed EB, Chen L, Xu J, Tao J, Wang CR, Alegre ML, Chong AS. Infection with the intracellular bacterium, Listeria monocytogenes, overrides established tolerance in a mouse cardiac allograft model. Am J Transplant 10:152433, 2010. * Bhorade SM, Chen H, Molinero L, Liao C, Garrity ER, Vigneswaran WT, Shilling R, Sperling A, Chong A, Alegre ML. Decreased percentage of CD4+FoxP3+ cells in bronchoalveolar lavage from lung transplant recipients correlates with development of bronchiolitis obliterans syndrome. Transplantation 90:540-6, 2010. 62 Sweiss NJ, Salloum R, Gandhi S, Alegre ML, Sawaqed R, Badaracco M, Pursell K, Pitrak D, Baughman RP, Moller DR, Garcia JG, Niewold TB. Significant CD4, CD8, and CD19 lymphopenia in peripheral blood of sarcoidosis patients correlates with severe disease manifestations. PLoS One 5:e9088, 2010. PMC2816716 * Ahmed EB, Wang T, Daniels M, Alegre ML, Chong AS. IL-6 induced by Staphylococcus aureus infection prevents the induction of skin allograft acceptance in mice. Am J Transplant 11:936-46, 2011. PMC3083487 * Ahmed EB, Daniels M, Alegre ML, Chong AS. Bacterial infections, alloimmunity, and transplantation tolerance. Transplant Rev (Orlando) 25:27-35, 2011. PMC2998288 Molinero LL, Miller ML, Evaristo C, Alegre ML. High TCR stimuli prevent induced regulatory T cell differentiation in a NF-kappaB-dependent manner. J Immunol 186:4609-17, 2011. BENDELAC, ALBERT, MD, PHD Constantinides MG, Picard D, Savage AK, Bendelac A. A naive-like population of human CD1d-restricted T cells expressing intermediate levels of promyelocytic leukemia zinc finger. J Immunol 187:30915, 2011. PMC3119760 Thomas SY, Scanlon ST, Griewank KG, Constantinides MG, Savage AK, Barr KA, Meng F, Luster AD, Bendelac A. PLZF induces an intravascular surveillance program mediated by long-lived LFA-1-ICAM-1 interactions. J Exp Med 208:1179-88, 2011. Savage AK, Constantinides MG, Bendelac A. Promyelocytic leukemia zinc finger turns on the effector T cell program without requirement for agonist TCR signaling. J Immunol 186:5801-6, 2011. * # Verykokakis M, Boos MD, Bendelac A, Adams EJ, Pereira P, Kee BL. Inhibitor of DNA binding 3 limits development of murine slam-associated adaptor proteindependent “innate” gammadelta T cells. PLoS One 5:e9303, 2010. PMC2824806 # Verykokakis M, Boos MD, Bendelac A, Kee BL. SAP protein-dependent natural killer T-like cells regulate the development of CD8(+) T cells with innate lymphocyte characteristics. Immunity 33:203-15, 2010. PMC2933745 Wang L, Carr T, Xiong Y, Wildt KF, Zhu J, Feigenbaum L, Bendelac A, Bosselut R. The sequential activity of Gata3 and Thpok is required for the differentiation of CD1d-restricted CD4+ NKT cells. Eur J Immunol 40:2385-90, 2010. Freigang S, Zadorozhny V, McKinney MK, Krebs P, Herro R, Pawlak J, Kain L, Schrantz N, Masuda K, Liu Y, Savage PB, Bendelac A, Cravatt BF, Teyton L. Fatty acid amide hydrolase shapes NKT cell responses by influencing the serum transport of lipid antigen in mice. J Clin Invest 120:1873-84, 2010. PMC2877940 CHONG, ANITA, PHD * Ahmed EB, Wang T, Daniels M, Alegre ML, Chong AS. IL-6 induced by Staphylococcus aureus infection prevents the induction of skin allograft acceptance in mice. Am J Transplant 11:936-46, 2011. PMC3083487 Burns AM, Chong AS. Alloantibodies prevent the induction of transplantation tolerance by enhancing alloreactive T cell priming. J Immunol 186:214-21, 2011. * Ahmed EB, Daniels M, Alegre ML, Chong AS. Bacterial infections, alloimmunity, and transplantation tolerance. Transplant Rev (Orlando) 25:27-35, 2011. 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Active immunotherapy combined with blockade of a coinhibitory pathway achieves regression of large tumor masses in cancer-prone mice. Mol Ther 19:1727-36, 2011. shift for immunotherapy. Pigment Cell Melanoma Res 23:580-1, 2010. Immunology and Cancer Kanodia S, Da Silva DM, Karamanukyan T, Bogaert L, Fu YX, Kast WM. Expression of LIGHT/TNFSF14 combined with vaccination against human papillomavirus Type 16 E7 induces significant tumor regression. Cancer Res 70:3955-64, 2010. PMC2873073 JABRI, BANA, MD, PHD # DePaolo RW, Abadie V, Tang F, FehlnerPeach H, Hall JA, Wang W, Marietta EV, Kasarda DD, Waldmann TA, Murray JA, Semrad C, Kupfer SS, Belkaid Y, Guandalini S, Jabri B. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature 471:220-4, 2011. PMC3076739 Wang Y, Devkota S, Musch MW, Jabri B, Nagler C, Antonopoulos DA, Chervonsky 63 Immunology and Cancer A, Chang EB. 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RANDALL, GLENN, PHD Heaton NS, Perera R, Berger KL, Khadka S, Lacount DJ, Kuhn RJ, Randall G. Dengue virus nonstructural protein 3 redistributes fatty acid synthase to sites of viral replication and increases cellular fatty acid synthesis. PNAS 107:17345-50, 2010. PMC2951450 Berger KL, Kelly SM, Jordan TX, Tartell MA, Randall G. Hepatitis C virus stimulates the phosphatidylinositol 4-kinase III alpha-dependent phosphatidylinositol 4-phosphate production that is essential for its replication. J Virol 85:8870-83, 2011. SAVAGE, PETER, PHD Donkor MK, Sarkar A, Savage PA, Franklin RA, Johnson LK, Jungbluth AA, Allison JP, Li MO. T cell surveillance of oncogene-induced prostate cancer is impeded by T cell-derived TGF-beta1 cytokine. Immunity 35:123-34, 2011. SCHREIBER, HANS, MD, PHD # Schreiber H, Rowley JD, Rowley DA. Targeting mutations predictably. Blood 118:830-1, 2011. Schietinger A, Philip M, Liu RB, Schreiber K, Schreiber H. 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PMC2822025 65 66 UCCCC SCIENTIFIC REPORT 2010 – 2011 Immunology and Cancer Selected Major Grants and Awards INVESTIGATOR TITLE PROJECT START DATE END DATE TOTAL ANNUAL COST CLASS FUNDING AGENCY Medical Scientist National Research Service Award 7/1/2010 6/30/2013 $1,100,000 T32 National Institute of General Medical Sciences MARCUS CLARK Regulation of cyclin D3 in B lymphocyte development 9/1/2010 7/31/2014 $316,451 R01 National Institute of General Medical Sciences YANG-XIN FU Synergy of radiation and immunotherapy: new approaches 7/1/2010 12/31/2014 $353,238 R01 National Cancer Institute YANG-XIN FU TNF family members for lymph angiogenesis and lymph node hypertrophy 5/1/2010 2/28/2015 $313,989 R01 National Cancer Institute YANG-XIN FU The role of negative signal in early infection 6/1/2010 5/31/2012 $231,660 R21 National Institutes of Health THOMAS GAJEWSKI A phase I, open-label, dose-escalation study to determine the safety, tolerability, pharmacokinetics and pharmacodynamics of INCB024360 in patients with advanced malignancies 6/11/2010 6/10/2012 $260,500 N/A Incyte Pharmaceuticals, Inc. BANA JABRI IL-15, NK receptors and adaptive immunity in celiac disease 9/1/2010 8/31/2015 $384,624 R01 National Institutes of Health MACIEJ LESNIAK Neural stem cell-based virotherapy for malignant glioma 7/1/2010 6/30/2015 $1,238,138 U01 National Institute of Neurological Disorders and Stroke VU NGUYEN An open-label, multi-center, three arm randomized, phase 3 study to compare the efficacy and safety of RO5072759 + GC1b, rituximab + chlorambucil or chlorambucil alone in previously untreated CLL patients with comorbidities 10/7/2010 2/28/2012 $123,874 N/A Hoffmann-Laroche VU NGUYEN Preserving tumor immunity following hematopoietic stem cell transplantation 11/1/2010 10/31/2012 $100,000 N/A The V Foundation GLENN RANDALL Hepatitis C virus trafficking in infected hepatocytes 5/1/2010 4/30/2015 $342,700 R01 National Institutes of Health GLENN RANDALL Membrane reorganization in hepatitis C virus infection 1/1/2010 12/31/2013 $215,000 N/A American Cancer Society JERROLD TURNER Mechanisms and consequences of cytokine-induced tight junction barrier regulation 7/15/2010 6/30/2014 $474,305 R01 National Institute of Diabetes & Digestive & Kidney Diseases PATRICK WILSON Human monoclonal antibodies 5/1/2010 4/30/2011 $187,200 U19 National Institutes of Health JIAN ZHANG Cb-I in T cell activation and autoimmunity 7/1/2010 6/30/2014 $386,100 R01 National Institutes of Health UCCCC SCIENTIFIC REPORT 2010 – 2011 MARCUS CLARK Immunology and Cancer The Immunology and Cancer Program has a funding base of $16,876,879 in annual total costs (current as of July 2011). This sum includes $3,288,485 in NCI funding and $10,710,293 in other NIH funding. Due to space constraints, only selected new awards since January 1, 2010 of $100,000 or greater in annual total costs are listed here. 67 PHARMACOGENOMICS AND EXPERIMENTAL THERAPEUTICS PROGRAM LEADERS M. Eileen Dolan, PhD Professor of Medicine 68 Walter Stadler, MD Professor of Medicine HE OVERALL GOAL OF THE PHARMACOGENOMICS AND Experimental Therapeutics Program is to foster interaction between basic and clinical investigators to develop innovative therapies for cancer patients. Program members, consisting of a diverse team of 54 investigators representing nine academic departments, place an emphasis on translational and clinical research as well as lead studies conducted by national clinical trials cooperative groups. The Program participates in all phases of clinical drug development, from preclinical to early phase to cooperative group-led phase III trials, with a strong focus on pharmacogenomics and pharmacology. ■■Pursue a broad program of preclinical, translational, and clinical research in pharmacogenetics and pharmacology; ■■Foster interaction between basic and clinical investigators that will result in innovative and effective therapies; and UCCCC SCIENTIFIC REPORT 2010 – 2011 T H E S C I E N T I F I C A I M S O F T H E P R O G R A M A R E TO : Pharmacogenomics and Experimental Therapeutics T ■■Integrate new drugs into the development of multimodality therapies for patients with advanced solid tumors. 69 UCCCC SCIENTIFIC REPORT 2010 – 2011 Pharmacogenomics and Experimental Therapeutics PROGRAM MEMBERSHIP† Douglas Bishop, PhD Professor of Radiation & Cellular Oncology Edwin Kaplan, MD Professor of Surgery φJoseph Salama, MD Assistant Professor of Radiation & Cellular Oncology Elizabeth Blair, MD Associate Professor of Surgery Theodore Karrison, PhD Associate Professor of Health Studies Daniel Catennaci, MD Instructor of Medicine Hedy Kindler, MD Associate Professor of Medicine Tanguy Seiwert, MD Assistant Professor of Medicine Ezra Cohen, MD Associate Professor of Medicine Mark Lingen, DDS, PhD Associate Professor of Pathology Arieh Shalhav, MD Professor of Surgery Susan Cohn, MD Professor of Pediatrics Marcy List, PhD Associate Director of Administration UCCCC φMark Siegler, MD Professor of Medicine Philip Connell, MD Associate Professor of Radiation & Cellular Oncology φYves Lussier, MD Associate Professor of Medicine Christopher Daugherty, MD Professor of Medicine Michael Maitland, MD, PhD Assistant Professor of Medicine M. Eileen Dolan, PhD Professor of Medicine Bruce Minsky, MD Professor of Radiation & Cellular Oncology Scott Eggener, MD Assistant Professor of Surgery Mark Ferguson, MD Professor of Surgery Alessandro Fichera, MD Associate Professor of Surgery Gini Fleming, MD Professor of Medicine Daniel Haraf, MD, MS Professor of Radiation & Cellular Oncology Rita Nanda, MD Assistant Professor of Medicine M. Kelly Nicholas, MD, PhD Assistant Professor of Neurology Peter H. O’Donnell, MD Instructor of Medicine Terrance Peabody, MD Professor of Surgery Louis Portugal, MD Associate Professor of Surgery Richard Schilsky, MD Professor of Medicine David Song, MD, MBA Professor of Surgery Walter Stadler, MD Professor of Medicine Gary Steinberg, MD Professor of Surgery Kerstin Stenson, MD Professor of Surgery Russell Szmulewitz, MD Assistant Professor of Medicine Ronald Thisted, PhD Professor of Health Studies Victoria Villaflor, MD Assistant Professor of Medicine Everett Vokes, MD Professor of Medicine Ralph Weichselbaum, MD Professor of Radiation & Cellular Oncology John Hart, MD Professor of Pathology φEdwin Posadas, MD Assistant Professor of Medicine Chuan He, PhD Professor of Chemistry Mitchell Posner, MD Professor of Surgery Philip Hoffman, MD Professor of Medicine Mark Ratain, MD Professor of Medicine S. Diane Yamada, MD Professor of Obstetrics & Gynecology R. Stephanie Huang, PhD Assistant Professor of Medicine Kevin Roggin, MD Associate Professor of Surgery Bakhtiar Yamini, MD Assistant Professor of Surgery φFederico Innocenti, MD, PhD Assistant Professor of Medicine Charles Rubin, MD Associate Professor of Pediatrics Chun-Su Yuan, MD, PhD Associate Professor of Anesthesia/ Critical Care H. Rosie Xing, PhD Assistant Professor of Pathology † Reflects all Program membership during 2010-2011 φ Individuals who are no longer at the UCCCC 70 Program Highlights† †Due to space constraints, only a small representative sample of Program highlights is presented here. SNPS ASSOCIATED WITH CHEMOTHERAPEUTIC DRUG SUSCEPTIBILITY ARE ENRICHED IN EXPRESSION QUANTITATIVE TRAIT LOCI (INTRA/ INTERPROGRAMMATIC) GEFITINIB AND CHEMORADIOTHERAPY CONTROL LOCALLY ADVANCED HEAD AND NECK CANCER (INTRA/ INTERPROGRAMMATIC) Everett Vokes, MD, and Ezra Cohen, MD, assessed the efficacy and toxicity of gefitinib in locally advanced head and neck cancer (LA-HNC). Collaborators in this study included Drs. Haraf, Stenson, Blair, Salama, and Lingen along with Drs. Dignam and Olopade (Cancer Prevention and Control Program). Patients with stage III or IV LA-HNC were treated with carboplatin/paclitaxel induction chemotherapy followed by split-course concurrent chemoradiotherapy (CCRT), twice daily radiotherapy, and gefitinib (250 mg SORAFENIB SHOWS EFFICACY IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION (INTRA/ INTERPROGRAMMATIC) Cancer and pulmonary arterial hypertension (PAH) share elements of pathophysiology, which presents an opportunity for the cross-development of anticancer agents. Mark Ratain, MD, Michael Maitland, MD, PhD, and Stephen Archer, MD (Advanced Imaging Program) performed an open-label study of sorafenib, a multi-kinase/angiogenesis inhibitor, in patients with pulmonary arterial hypertension (PAH) for 16 weeks. Patients (n=12) received 200 mg daily sorafenib with weekly clinical safety evaluations and monthly functional testing to guide dose escalations to 400 mg twice daily. A dosing regimen of 200 mg sorafenib twice daily was welltolerated in PAH patients with the most common adverse events being skin reactions and alopecia. (Gomberg-Maitland et al., Clin Pharmacol Ther 87:303-10, 2010) RACIAL DISPARITIES ARE OBSERVED IN CHILDREN WITH NEUROBLASTOMA (INTRAPROGRAMMATIC) Little is known about the racial and ethnic disparities that occur in pediatric patients with neuroblastoma. Susan Cohn, MD, and Tara Henderson, MD, MPH (Cancer Prevention and Control Program), analyzed data collected from 3,539 children enrolled on the Children’s Oncology Group (COG) neuroblastoma protocol to evaluate the relationship between ethnicity, tumor biology, and survival. Results indicated that black and Native American patients have a higher prevalence of high-risk neuroblastoma. In addition, a higher prevalence of late-occurring events among blacks compared with whites was observed, suggesting that this population may be more resistant to chemotherapy. (Henderson et al., J Clin Oncol 29:76-82, 2010) EXPRESSION QUANTITATIVE TRAIT LOCI ARE DISCOVERED IN HUMAN LIVER TISSUE (INTRA/ INTERPROGRAMMATIC) The reproducibility of expression quantitative trait loci (eQTL) studies is largely unknown in primary tissues. Federico Innocenti, MD, PhD, Mark Ratain, MD, and Nancy Cox, PhD (Cancer Prevention and Control Program), performed a three-way replication study of eQTLs in primary human livers and found hundreds of reproducible liver eQTLs, many of which are related directly to complex traits and connected with disease-associated loci. Numerous variables were found to influence reproducibility, including drug exposure, clinical descriptors, and factors associated with tissue ascertainment. The data will facilitate future efforts to identify and functionally characterize genetic contributions to complex traits. (Innocenti et al., PLoS Genet 7:e1002078, 2011) UCCCC SCIENTIFIC REPORT 2010 – 2011 M. Eileen Dolan, PhD, R. Stephanie Huang, PhD, and Nancy Cox, PhD (Cancer Prevention and Control Program), evaluated the genomic regions and functional categories for single nucleotide polymorphisms (SNPs) associated with chemotherapeutic agent-induced cytotoxicity for six anticancer agents. These SNPs were enriched in expression quantitative trait loci (i.e., SNPs associated with baseline gene expression) with even greater enrichment of master regulators (i.e., SNPs associated with baseline gene expression of 10 or more genes). This observation has significant implications for the identification of genetic predictors of drug response and implies regulatory genetic variants are most important for sensitivity to chemotherapeutic agents. (Gamazon et al., PNAS 107:9287-92, 2010) daily), an epidermal growth factor receptor inhibitor for 2 years total. Among the 69 patients enrolled, the complete response rate was 90%, and the 4-year overall survival rate was 74%. However, high EGFR gene copy number may be associated with poor outcome in patients treated with this regimen. (Cohen et al., J Clin Oncol 28:3336-43, 2010) Pharmacogenomics and Experimental Therapeutics Publications FUNCTIONAL EGFR GERMLINE POLYMORPHISMS CONFER RISK FOR EGFR SOMATIC MUTATIONS IN NON-SMALL CELL LUNG CANCER (INTERPROGRAMMATIC) Somatic mutations in the EGFR tyrosine kinase domain are predictive 71 Pharmacogenomics and Experimental Therapeutics UCCCC SCIENTIFIC REPORT 2010 – 2011 biomarkers for clinical response of non-small cell lung cancer (NSCLC) to EGFR inhibitors. Mark Ratain, MD, and Ravi Salgia, MD, PhD, (Molecular Mechanisms of Cancer Program) conducted a case-control study to elucidate genetic susceptibility to these mutations. Functional polymorphisms were examined and found to confer susceptibility to somatic mutations during cancer development, particularly those involving exon 19 microdeletions. These findings have significant clinical implications and may shed light on the pathogenesis of lung malignancies. (Liu et al., Cancer Res 71:2423-7, 2011) Grants RAD51 INHIBITORS MAY INCREASE SENSITIVITY TO CHEMOTHERAPY AND RADIATION THERAPY Elevated levels of homologous recombinational (HR) DNA repair may cause tumor resistance to select chemotherapies and radiotherapy. Funded by an R01 grant from the National Cancer Institute, Philip Connell, MD, is identifying small molecule inhibitors of RAD51, a central protein involved in HR. The overall goal of this study is to generate pharmacologic agents that sensitize human tumors to common oncologic therapies. Given that RAD51 is over-expressed in a wide range of malignancies, this approach could potentially improve treatment efficacy for a large group of cancer patients. GENOME-WIDE INTERROGATIONS AIM TO PREDICT GLUCOCORTICOID SENSITIVITY Glucocorticoids are commonly used for the treatment of cancer and inflammatory diseases including asthma and arthritis. R. Stephanie Huang, PhD, 72 through support from a National Institute of General Medical Sciences K08 award, is making a translational effort to elucidate the underlying cause for inter-individual difference in glucocorticoid sensitivity. Dr. Huang is applying a novel genome-wide model, developed using International HapMap lymphoblastoid cell lines, to identify genetic polymorphisms as predictors of cellular sensitivity to glucocorticoids. The long-term goal is to predict patients “at risk” for adverse events and/or non-response prior to administration of glucocorticoids. PHARMACOGENETICS OF ANTICANCER AGENTS RESEARCH GROUP EXAMINES GENETIC BASIS OF CHEMOTHERAPEUTIC DRUG RESPONSE Pharmacologic response to anticancer agents is variable and historically characterized by severe toxicity and inconsistent efficacy. Mark Ratain, MD, Nancy J. Cox, PhD, and M. Eileen Dolan, PhD, successfully renewed a U01 award from the National Institute of General Medical Sciences and the National Cancer Institute to characterize the genomic basis for this variability through laboratory and translational clinical studies that examine targeted oncology drugs and cytotoxic agents. Candidate genes identified through genome-wide clinical studies and those from HapMap lymphoblastoid cell lines are being examined for functional relationships between drug, gene, and phenotype. Featured Faculty Profiles† †Due to space constraints, only a small representative sample of Program members is presented here. Instructor of Medicine Dr. Daniel Catenacci’s laboratory focuses on RON and MET tyrosine kinase signaling and inhibition strategies in gastroesophageal adenocarcinomas and other aerodigestive malignancies using in vitro cell culture models, in vivo murine models, and human tumor and normal tissue samples. Specifically, he is studying the role of RON and MET receptor tyrosine kinases as biomarkers of prognosis and as novel therapeutic targets for these diseases. Evaluation of the structure and function of RON and MET as well as novel small molecule tyrosine kinase inhibitors and monoclonal antibodies, either as monotherapy or in combination with other biologically targeted agents and/or chemotherapies, is the primary focus of his laboratory. In addition, Dr. Catenacci has observed in vitro that MET inhibition can be overcome by RON cell signaling, given their similar downstream activation pathways. This concept of RONmediated resistance has been supported by a case recently submitted for publication, in a patient with chemo-refractory metastatic gastric cancer who achieved a complete response to MetMAb, a monoclonal antibody inhibiting MET signaling, on a phase I protocol. Laboratory correlatives suggested an autocrine feedback loop given the high tissue expression of HGF (the ligand for MET) and very high serum levels which decreased after dosing with MetMAb. The complete response lasted 2 years. Re-challenge with MetMAb therapy after tumor reoccurrence was not effective. Further studies revealed that RON gene expression and serum levels had become significantly amplified when compared to the original tumor, supporting a RON-mediated resistance mechanism to MET-directed therapy. Further research is ongoing in the laboratory, and future clinical trials are being designed to explore this possibility further. UCCCC SCIENTIFIC REPORT 2010 – 2011 Dr. Catenacci’s recent findings demonstrate that RON is highly over-expressed in malignant gastroesophageal adenocarcinoma, compared to adjacent normal mucosa, with a progressive increase in expression from primary tumor to metastatic lymph node to distant metastases.1 RON is highly oncogenic in Daniel Catenacci, MD cell culture models. Moreover, Dr. Catenacci’s laboratory has observed a novel juxtamembrane mutation in RON in approximately 10% of gastroesophageal tumor tissues. This mutation increases the stability of RON at the membrane by preventing degradation by CBL ubiquitination. They have also observed increased gene copy number in RON to high polysomy in approximately 33% of cases evaluated. RON expression and copy number correlated with a worse overall survival of patients compared to those with low to no expression, while RON and MET co-expression correlated with the worst survival. Pharmacogenomics and Experimental Therapeutics DANIEL CATENACCI, MD Catenacci DV, Cervantes G, Yala S, Nelson EA, El-Hashani E, Kanteti R, El Dinali M, Hasina R, Brägelmann J, Seiwert T, Sanicola M, Henderson L, Grushko TA, Olopade O, Karrison T, Bang YJ, Kim WH, Tretiakova M, Vokes E, Frank DA, Kindler HL, Huet H, Salgia R. RON (MST1R) is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma. Cancer Biol Ther 12:9-46, 2011. 1 †Due to space constraints, only a small representative sample of Program highlights is presented here. 73 Pharmacogenomics and Experimental Therapeutics UCCCC SCIENTIFIC REPORT 2010 – 2011 PHILIP CONNELL, MD Associate Professor of Radiation & Cellular Oncology Dr. Philip Connell’s laboratory is working to identify molecular targets that can be exploited in cancer treatment. His work has centered on DNA repair pathways that are involved in cellular resistance to common cancer treatments. Specifically, he has focused on proteins involved in homologous recombination (HR), a pathway involved in the repair of radiation-induced DNA breaks and chemotherapy-induced DNA cross-links. The central HR protein, RAD51, is highly expressed in many human cancers including breast, bladder, prostate, pancreas, soft tissue sarcoma, upper aerodigestive, and lung. These and other observations suggest that human tumors may develop “addictions” to abnormally high RAD51 levels. Therefore, RAD51 inhibition represents a promising strategy in oncology drug development. Dr. Connell’s laboratory is developing small molecules that inhibit the binding of RAD51 protein to DNA, with the goal of overcoming treatment resistance in tumors. Furthermore, his group is working to develop Philip Connell, MD compounds that stimulate RAD51 protein in normal non-cancerous cells. A RAD51-stimulatory agent could potentially be used to elevate resistance to DNA damaging agents in normal tissues, thereby increasing cell survival and perhaps reducing mutagenesis. This would be an attractive approach for protecting the normal tissues in patients receiving chemotherapy and/or radiotherapy. Dr. Connell previously described RS-1, a RAD51-stimulatory compound identified from a highthroughput chemical screen.1 RS-1 was shown to enhance assembly of RAD51 protein filaments on DNA and to stimulate HR activity in vitro. When introduced into cells in culture, a significant dose-dependent protection in normal human dermal fibroblasts was achieved. More recently, his group identified a novel small molecule, termed RI-1, that interrupts RAD51 binding to DNA and specifically inhibits HR efficiency in human cancer cells. RI-1 significantly sensitizes multiple human cancer cell lines to mitomycin C. As such, RI-1 will likely be the first reported small molecule compound that sensitizes cells by directly and specifically disrupting RAD51. Pharmacologic evaluation and testing in animal tumor models will be necessary to define the full potential of these compounds and related second-generation analogs as drug candidates. Jayathilaka K, Sheridan SD, Bold TD, Bochenska K, Logan HL, Weichselbaum RR, Bishop DK, Connell PP. A chemical compound that stimulates the human homologous recombination protein RAD51. PNAS 105:15848-15853, 2008. 1 74 Professor of Chemistry Dr. Chuan He’s research spans a broad range of chemistry, chemical biology, microbiology, biochemistry, structural biology, and cell biology. His laboratory has pioneered research in developing nucleic acid probes and tools to study the chemistry and mechanism of DNA/RNA repair and modification systems. Chuan He, PhD Dr. He’s group has developed the first high-throughput sequencing method based on a selective chemical labeling strategy to reveal genome-wide distribution of 5-hmC in genomic DNA.1 In addition, Dr. He’s laboratory has presented a detailed mechanistic description of oxidation demethylation.2 Oxidative demethylation is a key mechanism used in histone and nucleic acid demethylation, which impact a broad range of cellular processes. The mechanistic understanding gained from this study may aid future design of new inhibitors for these enzymes. Song CX, Szulwach KE, Fu Y, Dai Q, Yi C, Li X, Li Y, Chen CH, Zhang W, Jian X, Wang J, Zhang L, Looney TJ, Zhang B, Godley LA, Hicks LM, Lahn BT, Jin P, He C. Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine. Nat Biotechnol 29:68-72, 2011. 1 Yi C, Jia G, Hou G, Dai Q, Zhang W, Zheng G, Jian X, Yang CG, Cui Q, He C. Iron-catalysed oxidation intermediates captured in a DNA repair dioxygenase. Nature 468:330-333, 2010. 2 UCCCC SCIENTIFIC REPORT 2010 – 2011 Dr. He has demonstrated the first example of an active site-based disulfide cross-linking strategy to successfully isolate covalently linked protein-DNA/ RNA complexes for structural characterization. This general method allows the stabilization of labile protein-nucleic acid complexes for structural, biochemical, and spectroscopic studies. 5-Hydroxymethylcytosine (5-hmC) is a newly discovered DNA base modification that has been shown to significantly impact cell development and cell progression. Recently, his laboratory invented a new strategy to selectively label 5-hmC in genomic DNA. This method has the potential to significantly broaden the understanding of epigenetics that affect various cellular processes. Overall, Dr. He’s laboratory strives to integrate chemistry with biology to address major research questions in life sciences. Pharmacogenomics and Experimental Therapeutics CHUAN HE, PHD 75 Pharmacogenomics and Experimental Therapeutics UCCCC SCIENTIFIC REPORT 2010 – 2011 R. STEPHANIE HUANG, PHD Assistant Professor of Medicine Dr. Stephanie Huang’s laboratory focuses on translational pharmacogenomic research with a specific emphasis on the pharmacogenomics of anticancer agents. By systematically evaluating the human genomes and their relationships to drug response and toxicity, Dr. Huang’s goal is to develop clinically useful models that predict risks for adverse drug reactions and non-response prior to administration of chemotherapy. She utilizes cell lines and clinical samples to discover and functionally characterize genetic variations, gene, and microRNA (miRNA) expression for their role in chemotherapeutic sensitivity. R. Stephanie Huang, PhD Three major research projects are ongoing in Dr. Huang’s laboratory: 1) identifying genetic variants, in the form of single nucleotide polymorphisms (SNPs) and copy number variations (CNVs), that are predictive of sensitivity to non-cytotoxic chemotherapeutic agents in cell lines and patient samples; 2) interrogating the role of microRNAs in anticancer agent sensitivity through integrative genome-wide analyses of genetic variants, transcriptional expression, and drug sensitivity; and 3) developing clinical, user-friendly models for drug sensitivity screening. Utilizing a genome-wide, cell-based model, Dr. Huang and colleagues discovered a set of SNPs that are associated with platinum sensitivity through regulating transcriptional gene expression in the International HapMap lymphoblastoid cell lines.1 They further validated a subset of these SNPs in predicting chemotherapeutic outcomes after platinum-based induction therapy in head and neck cancer patients. To their knowledge, this was the first published work to have successfully reported the validation of genetic predictors from a cell-based, genome-wide model screening in clinical samples from patients. Through a genome-wide analysis, Dr. Huang and colleagues identified a set of 33 miRNAs whose expression levels differ significantly between samples from those with Caucasian ancestry and those with African ancestry. They further demonstrated the role of genetic variations in these observed miRNA expression differences, and documented that these differentially expressed miRNAs can contribute to gene expression and chemotherapeutic sensitivity differences between Caucasians and Africans. Ziliak D, O’Donnell PH, Im HK, Gamazon ER, Chen P, Delaney S, Shukla S, Das S, Cox NJ, Vokes EE, Cohen EE, Dolan ME, Huang RS. Germline polymorphisms discovered via a cell-based, genome-wide approach predict platinum response in head and neck cancers. Transl Res 157:265-272, 2011. 1 Huang RS, Gamazon ER, Ziliak D, Wen Y, Im HK, Zhang W, Wing C, Duan S, Bleibel WK, Cox NJ, Dolan ME. Population differences in microRNA expression and biological implications. RNA Biol 8:692-701, 2011. 2 76 Instructor of Medicine Dr. Peter O’Donnell’s research focuses on translational pharmacogenomics— achieving individualized patient care by considering each person’s genetic profile when making therapeutic decisions, especially regarding chemotherapy choices. He designed and currently oversees three studies with pharmacogenomic primary aims. In a similar study, Dr. O’Donnell and his collaborators are testing a smaller set of polymorphisms in a clinical study of 60 patients receiving platinum-based therapy for locally advanced and metastatic urothelial cancer of the bladder. Since platinum-based therapy can be quite toxic and result in significant morbidity and mortality for these patients, they hypothesize that validated genetic “platinum susceptibility” biomarkers will allow the identification of patients with urothelial cancer who will most likely benefit from platinum-based chemotherapy. Dr. O’Donnell has recently identified several novel platinum sensitivity variants.1 Lastly, Dr. O’Donnell serves as principal investigator of “The 1200 Patients Project,” a first-of-itskind initiative within the Center for Personalized Therapeutics at The University of Chicago, aimed to explore the feasibility and utility of incorporating broad pharmacogenomic testing into routine clinical practice. In this study, all known germline pharmacogenomic variants previously published will be preemptively tested in consenting patients, including cancer patients, to determine whether pharmacogenomic information can inform prescribing choices by their physicians. UCCCC SCIENTIFIC REPORT 2010 – 2011 The first is a translational study that proposes to enroll 250 adult women with breast cancer who will begin treatment with capecitabine, a commonly used chemotherapeutic agent. Patients will be monitored for manifestation of any of the three most important capecitabine-related toxicities, including diarrhea, hand-foot syndrome, or neutropenia. Dr. O’Donnell and his colleagues will screen for approximately 30 top candidate pharmacogenomic polymorphisms discovered from prior literature and from a recent pre-clinical cell-based analysis conducted in collaboration with Dr. Eileen Dolan. Specifically, patients’ genotypes will be analyzed for association with capecitabine Peter H. O’Donnell, MD toxicity and response, comprising the most comprehensive, prospective analysis of breast cancer/capecitabine pharmacogenomics to date. This study will have a large impact on the field and, most importantly, will potentially improve the care of patients with breast cancer. Pharmacogenomics and Experimental Therapeutics PETER H. O’DONNELL, MD O’Donnell PH, Gamazon E, Zhang W, Stark AL, Kistner-Griffin EO, Huang SR, Dolan EM. Population differences in platinum toxicity as a means to identify novel genetic susceptibility variants. Pharmacogenet Genomics 20:327-337, 2010. 1 77 Pharmacogenomics and Experimental Therapeutics UCCCC SCIENTIFIC REPORT 2010 – 2011 78 TANGUY SEIWERT, MD Assistant Professor of Medicine Dr. Tanguy Seiwert’s laboratory focuses on elucidating treatment-relevant, genetic changes in tumors of the head and neck area as well as esophageal cancers and mesotheliomas. He aims to identify such genetic changes, characterize therapies that specifically target these “driver” aberrations, and translate findings into clinically relevant treatment concepts and trials in collaboration with UCCCC clinicians and researchers, including Drs. Ravi Salgia and Kevin White (Molecular Mechanisms of Cancer Program). Tanguy Seiwert, MD Specifically, Dr. Seiwert is detecting genetic changes in cancers using next generation sequencing technology, array-based approaches, and computational analysis tools. Recently, his team identified aberrations in the PI3K-AKT signaling pathway in head and neck cancer, where mutations and other characteristics render tumors exquisitely sensitive to PI3K inhibitors. In a follow-up study, Dr. Seiwert is conducting a translational clinical trial that focuses on the treatment of these particular tumors with PI3K inhibitors previously evaluated in the laboratory. Furthermore, he is studying how a variety of genetic changes correlate with the efficacy of a large panel of clinically used drugs in cancer cell line models. Dr. Seiwert’s team employs sophisticated computational tools to measure the activity of cancer-relevant pathways and evaluate effects of therapies on these pathways. These studies may enable rapid genetic screening of patients with head and neck cancers to inform more personalized treatment choices. Dr. Seiwert’s team has already characterized the important role of c-MET receptor tyrosine kinase in head and neck cancers in collaboration with Dr. Salgia. As a result, these preclinical discoveries have led to several clinical initiatives aimed at exploiting c-MET inhibition. Associate Professor of Pathology Despite recent advances, improved long-term survival for patients with oral squamous cell carcinoma (OSCC) has remained modest. Several factors contribute to this poor outcome. OSCC is often diagnosed during advanced stages, and as a result of “field cancerization,” the development of multiple primary tumors has a major impact on survival. For patients with early stage disease, second primary tumors are the most common cause of treatment failure and death. Therefore, a comprehensive treatment plan must include early detection and effective chemoprevention strategies. The induction of angiogenesis is one of the first recognizable phenotypic changes observed in both experimental models and in human OSCC. Because of its critical role in cancer, the inhibition of angiogenesis is an attractive target for therapy. Furthermore, mounting evidence indicates that inhibitors of angiogenesis are effective chemopreventive agents against a number of different malignancies. While resistance to cancer therapy is well-appreciated, there are limited data concerning the mechanisms of resistance to chemopreventive agents. This is a critical issue as chemoprevention patients are often treated for prolonged periods of time. Therefore, a need exists to prospectively model mechanisms of chemoprevention-acquired resistance and test hypotheses for monitoring and overcoming resistance. In the 4-NQO model, 12% of the mice develop ZD6474-acquired resistance. Dr. Lingen hypothesizes that ZD6474-acquired resistance in the chemoprevention setting is due to the expression of alternative angiogenesis pathways and the expression of an epithelial to mesenchymal transition (EMT) phenotype. Using the 4-NQO model, Dr. Lingen’s laboratory is seeking to identify biomarkers and alternative angiogenesis pathways that are activated as a result of ZD6474 resistance. These candidates may have potential for use as both diagnostic beacons of resistance and alternative targets for chemopreventive therapy. UCCCC SCIENTIFIC REPORT 2010 – 2011 Using the 4-Nitroquinoline 1-Oxide (4-NQO) mouse model, Dr. Mark Mark Lingen, DDS, PhD Lingen’s laboratory has demonstrated that ABT-510 (a global inhibitor of angiogenesis) and ZD6474 (a dual tyrosine kinase inhibitor (TKI) against EGFR and VEGFR-2) significantly decrease the incidence of dysplasia and OSCC.1,2 These data support the hypothesis that agents with anti-angiogenic activity may hold promise in OSCC chemoprevention. In collaboration with Dr. Ezra Cohen, Dr. Lingen is initiating a doubleblinded, placebo-controlled, randomized phase II trial that will assess the pharmacodynamic and clinical effects of ZD6474 in patients at high risk for developing OSCC. These results will serve as proof-of-principle to implement larger prospective chemoprevention trials of anti-angiogenic or anti-EGFR inhibitors in high-risk patients. Pharmacogenomics and Experimental Therapeutics MARK LINGEN, DDS, PHD Hasina R, Martin LE, Jones C, Jalil A, Lingen MW. ABT-510 is an effective chemopreventive agent in the 4NQO mouse model of oral carcinogenesis. Cancer Prev Res 2:385-393, 2009. 1 Zhou G, Hasina R, Wroblewski K, Mankame TP, Doci CL, Lingen MW. Dual inhibition of VEGFR and EGFR is an effective chemopreventive strategy in the mouse 4NQO model of oral carcinogenesis. Cancer Prev Res 3:1493-1502, 2010. 2 79 Selected Publications UCCCC SCIENTIFIC REPORT 2010 – 2011 Pharmacogenomics and Experimental Therapeutics * : Intraprogrammatic Collaboration # : Interprogrammatic Collaboration BISHOP, DOUGLAS, PHD Qing Y, Yamazoe M, Hirota K, Dejsuphong D, Sakai W, Yamamoto KN, Bishop DK, Wu X, Takeda S. The epistatic relationship between BRCA2 and the other RAD51 mediators in homologous recombination. PLoS Genet 7:e1002148, 2011. PMC3136442 Shah PP, Zheng X, Epshtein A, Carey JN, Bishop DK, Klein HL. Swi2/Snf2-related translocases prevent accumulation of toxic Rad51 complexes during mitotic growth. Mol Cell 39:862-72, 2010. PMC2946244 BLAIR, ELIZABETH, MD * Mouw KW, Haraf DJ, Stenson KM, Cohen EE, Xi X, Witt ME, List M, Blair EA, Vokes EE, Salama JK. Factors associated with long-term speech and swallowing outcomes after chemoradiotherapy for locoregionally advanced head and neck cancer. Arch Otolaryngol Head Neck Surg 136:1226-34, 2010. * Salama JK, Haraf DJ, Stenson KM, Blair EA, Witt ME, Williams R, Kunnavakkam R, Cohen EE, Seiwert T, Vokes EE. A randomized phase II study of 5-fluorouracil, hydroxyurea, and twice-daily radiotherapy compared with bevacizumab plus 5-fluorouracil, hydroxyurea, and twice-daily radiotherapy for intermediatestage and T4N0-1 head and neck cancers. Ann Oncol 22:2304-9, 2011. * Choe KS, Salama JK, Stenson KM, Blair EA, Witt ME, Cohen EE, Haraf DJ, Vokes EE. Adjuvant chemotherapy prior to postoperative concurrent chemoradiotherapy for locoregionally advanced head and neck cancer. Radiother Oncol 97:318-21, 2010. * Villaflor VM, Haraf D, Salama JK, Kocherginsky M, Langerman A, GomezAbuin G, Beniwal P, Blair EA, Stenson KM, Portugal L, Seiwert T, Williams RD, Dekker AJ, Witt ME, Vokes EE, Cohen EE. Phase II trial of pemetrexed-based induction chemotherapy followed by concomitant chemoradiotherapy in previously irradiated patients with squamous cell carcinoma of the head and neck. Ann Oncol 22:2501-7, 2011. * Choe KS, Haraf DJ, Solanki A, Cohen EE, Seiwert TY, Stenson KM, Blair EA, Portugal L, Villaflor VM, Witt ME, Vokes EE, Salama JK. Prior chemoradiotherapy 80 adversely impacts outcomes of recurrent and second primary head and neck cancer treated with concurrent chemotherapy and reirradiation. Cancer, 2011 (Epub ahead of print). * Pederson AW, Haraf DJ, Witt ME, Stenson KM, Vokes EE, Blair EA, Salama JK. Chemoradiotherapy for locoregionally advanced squamous cell carcinoma of the base of tongue. Head Neck 32:1519-27, 2010. Cipriani NA, Blair E, Taxy JB. WHIM syndrome and oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 109:105-8, 2010. * # Cohen EE, Haraf DJ, Kunnavakkam R, Stenson KM, Blair EA, Brockstein B, Lester EP, Salama JK, Dekker A, Williams R, Witt ME, Grushko TA, Dignam JJ, Lingen MW, Olopade OI, Vokes EE. Epidermal growth factor receptor inhibitor gefitinib added to chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol 28:3336-43, 2010. PMC2903330 Rini BI, Schiller JH, Fruehauf JP, Cohen EE, Tarazi JC, Rosbrook B, Bair AH, Ricart AD, Olszanski AJ, Letrent KJ, Kim S, Rixe O. Diastolic blood pressure as a biomarker of axitinib efficacy in solid tumors. Clin Cancer Res 17:3841-9, 2011. Chung CH, Seeley EH, Roder H, Grigorieva J, Tsypin M, Roder J, Burtness BA, Argiris A, Forastiere AA, Gilbert J, Murphy B, Caprioli RM, Carbone DP, Cohen EE. Detection of tumor epidermal growth factor receptor pathway dependence by serum mass spectrometry in cancer patients. Cancer Epidemiol Biomarkers Prev 19:358-65, 2010. PMC2846615 CATENACCI, DANIEL, MD # Rothenberg SM, Mohapatra G, Rivera MN, Winokur D, Greninger P, Nitta M, Sadow PM, Sooriyakumar G, Brannigan BW, Ulman MJ, Perera RM, Wang R, Tam A, Ma XJ, Erlander M, Sgroi DC, Rocco JW, Lingen MW, Cohen EE, Louis DN, Settleman J, Haber DA. A genome-wide screen for microdeletions reveals disruption of polarity complex genes in diverse human cancers. Cancer Res 70:2158-64, 2010. PMC2881662 Stricker T, Catenacci DV, Seiwert TY. Molecular profiling of cancer--the future of personalized cancer medicine: a primer on cancer biology and the tools necessary to bring molecular testing to the clinic. Semin Oncol 38:173-85, 2011. * Kuo WL, Liu J, Mauceri H, Vokes EE, Weichselbaum R, Rosner MR, Cohen EE. Efficacy of the multi-kinase inhibitor enzastaurin is dependent on cellular signaling context. Mol Cancer Ther 9:2814-24, 2010. PMC2953602 * # Catenacci DV, Cervantes G, Yala S, Nelson EA, El-Hashani E, Kanteti R, El Dinali M, Hasina R, Bragelmann J, Seiwert T, Sanicola M, Henderson L, Grushko TA, Olopade O, Karrison T, Bang YJ, Kim WH, Tretiakova M, Vokes E, Frank DA, Kindler HL, Huet H, Salgia R. RON (MST1R) is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma. Cancer Biol Ther 12:9-46, 2011. PMC3149873 * Gangadhar TC, Cohen EE, Wu K, Janisch L, Geary D, Kocherginsky M, House LK, Ramirez J, Undevia SD, Maitland ML, Fleming GF, Ratain MJ. Two drug interaction studies of sirolimus in combination with sorafenib or sunitinib in patients with advanced malignancies. Clin Cancer Res 17:1956-63, 2011. PMC3077032 COHEN, EZRA, MD * # Kurzrock R, Sherman SI, Ball DW, Forastiere AA, Cohen RB, Mehra R, Pfister DG, Cohen EE, Janisch L, Nauling F, Hong DS, Ng CS, Ye L, Gagel RF, Frye J, Muller T, Ratain MJ, Salgia R. Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol 29:2660-6, 2011. * # Cohen EE, Haraf DJ, Kunnavakkam R, Stenson KM, Blair EA, Brockstein B, Lester EP, Salama JK, Dekker A, Williams R, Witt ME, Grushko TA, Dignam JJ, Lingen MW, Olopade OI, Vokes EE. Epidermal growth factor receptor inhibitor gefitinib added to chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol 28:3336-43, 2010. PMC2903330 * Choong NW, Kozloff M, Taber D, Hu HS, Wade J 3rd, Ivy P, Karrison TG, Dekker A, Vokes EE, Cohen EE. Phase II study of sunitinib malate in head and neck squamous cell carcinoma. Invest New Drugs 28:677-83, 2010. COHN, SUSAN, MD Chlenski A, Guerrero LJ, Peddinti R, Spitz JA, Leonhardt PT, Yang Q, Tian Y, Salwen HR, Cohn SL. Anti-angiogenic SPARC peptides inhibit progression of neuroblastoma tumors. Mol Cancer 9:138, 2010. PMC2895596 Bagatell R, London WB, Wagner LM, Voss SD, Stewart CF, Maris JM, Kretschmar C, Cohn SL. Phase II study of irinotecan and temozolomide in children with relapsed or refractory neuroblastoma: a Children’s Oncology Group study. J Clin Oncol 29:208-13, 2011. PMC3058276 # Henderson TO, Bhatia S, Pinto N, London WB, McGrady P, Crotty C, Sun CL, Cohn SL. Racial and ethnic disparities in risk and survival in children with neuroblastoma: a Children’s Oncology Group study. J Clin Oncol 29:76-82, 2011. PMC3055862 Shusterman S, London WB, Gillies SD, Hank JA, Voss SD, Seeger RC, Reynolds CP, Kimball J, Albertini MR, Wagner B, Gan J, Eickhoff J, DeSantes KB, Cohn SL, Hecht T, Gadbaw B, Reisfeld RA, Maris JM, Sondel PM. Antitumor activity of hu14.18-IL2 in patients with relapsed/refractory neuroblastoma: a Children’s Oncology Group (COG) phase II study. J Clin Oncol 28:4969-75, 2010. PMC3020698 Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, Smith M, Anderson B, Villablanca JG, Matthay KK, Shimada H, Grupp SA, Seeger R, Reynolds CP, Buxton A, Reisfeld RA, Gillies SD, Cohn SL, Maris JM, Sondel PM. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotreti- CONNELL, PHILIP, MD * # Shumway D, Corbin K, Salgia R, Hoffman P, Villaflor V, Malik RM, Haraf DJ, Vigneswaren WT, Shaikh AY, Connell PP, Ferguson MK, Salama JK. Pathologic response rates following definitive dose image-guided chemoradiotherapy and resection for locally advanced non-small cell lung cancer. Lung Cancer, 2011 (Epub ahead of print). * # MacDermed DM, Miller LL, Peabody TD, Simon MA, Luu HH, Haydon RC, Montag AG, Undevia SD, Connell PP. Primary tumor necrosis predicts distant control in locally advanced soft-tissue sarcomas after preoperative concurrent chemoradiotherapy. Int J Radiat Oncol Biol Phys 76:1147-53, 2010. PMC2931332 DAUGHERTY, CHRISTOPHER, MD * Bradbury AR, Patrick-Miller L, Egleston B, Sands CB, Li T, Schmidheiser H, Feigon M, Ibe CN, Hlubocky FJ, Hope K, Jackson S, Corbman M, Olopade OI, Daly M, Daugherty CK. Parent opinions regarding the genetic testing of minors for BRCA1/2. J Clin Oncol 28:3498-505, 2010. Zafar SY, Currow DC, Daugherty CK, Abernethy AP. Standards for palliative care delivery in oncology settings. Cancer J 16:436-43, 2010. # Godley LA, Njiaju UO, Green M, Weiner H, Lin S, Odenike O, Rich ES, Artz A, Van Besien K, Daugherty CK, Zhang Y, Le Beau MM, Stock W, Larson RA. Treatment of therapy-related myeloid neoplasms with high-dose cytarabine/ mitoxantrone followed by hematopoietic stem cell transplant. Leuk Lymphoma 51:995-1006, 2010. DOLAN, M. 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Antioxidants potentiate American ginseng-induced killing of colorectal cancer cells. Cancer Lett 289:62-70, 2010. PMC2824022 Du GJ, Dai Q, Williams S, Wang CZ, Yuan CS. Synthesis of protopanaxadiol derivatives and evaluation of their anticancer activities. Anticancer Drugs 22:35-45, 2011. PMC2992804 Qi LW, Wang CZ, Yuan CS. American ginseng: potential structure-function relationship in cancer chemoprevention. Biochem Pharmacol 80:947-54, 2010. Selected Major Grants and Awards PROJECT START DATE END DATE EZRA COHEN A phase 1b trial of LY2584702 in combination with erlotinib or everolimus in patients with solid tumors 3/24/2010 3/23/2012 EZRA COHEN Randomized phase II trial of everolimus versus placebo as adjuvant therapy in patietns with locally advanced squamous cell cancer of the head and neck 3/1/2010 EZRA COHEN Phase II study of cetuximab and lenalidomide in recurrent/metastatic squamous cell carcinoma of the head and neck EZRA COHEN INVESTIGATOR TITLE TOTAL ANNUAL COST FUNDING AGENCY $479,400 N/A Lilly, Eli & Company 12/31/2015 $204,883 N/A Novartis Pharmaceuticals Corporation 1/22/2010 1/21/2012 $157,500 N/A Celgene Corporation Selection of chemoradiotherapy based on response to induction chemotherapy — a randomized phase 2 study in locally advanced squamous cell carcinoma of the head and neck 4/1/2010 12/31/2015 $125,000 N/A Novartis Pharmaceuticals Corporation SUSAN COHN Racial and ethnic disparities in survival in children with neuroblastoma 7/1/2011 6/30/2013 $100,000 N/A Alex's Lemonade Stand Foundation for Childhood Cancer PHILIP P. CONNELL RAD51 inhibitors for chemotherapy and radiation therapy 3/16/2010 1/31/2015 $434,469 R01 National Cancer Institute CHUAN HE Chemistry and mechanism of direct DNA repair proteins 8/5/2010 7/31/2014 $295,699 R01 National Institutes of Health CHUAN HE Selective recognition of heavy elements by protein-based reagents 5/15/2010 5/14/2013 $165,000 N/A Department of Energy STEPHANIE R. HUANG Genome-wide interrogation of genetic signatures for glucocorticoid sensitivity 3/1/2010 2/28/2015 $100,666 K08 National Institutes of Health MICHAEL MAITLAND A phase 1 study evaluating the safety and pharmacokinetics of ABT-348 as monotherapy, in combination with carboplatin/gemcitabine or in combination with docetaxel in subjects with advanced solid tumors 2/12/2010 2/11/2012 $526,027 N/A Abbott Laboratories MICHAEL MAITLAND A randomized, open-label, dose escalation study of bevacizumab with ambulatory blood pressure monitoring in previously untreated patients with advanced non-squamous non-small cell lung cancer 3/9/2010 3/1/2013 $129,980 N/A Genentech, Inc. EDWIN POSADAS A phase II, open-label, single-arm study evaluating the safety, efficacy and pharmacokinetics of KX2-391 in patients with bone-metastatic, castration-resistant prostate cancer who have not received prior chemotherapy 1/12/2010 1/31/2011 $102,575 N/A Kinex Pharmaceuticals LLC MARK RATAIN PAAR-Pharmacogenomics of Anticancer Agents Research Group 7/16/2010 6/30/2015 $2,000,000 U01 National Institute of General Medical Sciences MARK RATAIN Clinical therapeutics 7/1/2010 6/30/2015 $245,220 T32 National Institutes of Health MARK RATAIN Building a genomic prescribing system 7/1/2011 6/30/2014 $100,000 N/A American Society of Clinical Oncology RUSSELL SZMULEWITZ An open-label study of sipuleucel-T in men with metastatic castrate resistant prostate cancer 3/10/2010 3/9/2012 $134,767 N/A Dendreon Corporation RUSSELL SZMULEWITZ A phase I, open-label study of the safety and pharmacokinteics of escalalting doses of DSTP30865 in patients with metastatic castration resistant prostate cancer 2/9/2011 6/30/2014 $118,618 N/A Genentech, Inc. UCCCC SCIENTIFIC REPORT 2010 – 2011 CLASS Pharmacogenomics and Experimental Therapeutics The Pharmacogenomics and Experimental Therapeutics Program has a funding base of $15,051,170 in annual total costs (current as of July 2011). This sum includes $5,720,234 in NCI funding and $3,396,687 in other NIH funding. Due to space constraints, only selected new awards since January 1, 2010 of $100,000 or greater in annual total costs are listed here. 93 ADVANCED IMAGING PROGRAM LEADERS Gregory Karczmar, PhD Professor of Radiology 94 Heber MacMahon, MB, ChB Professor of Radiology HE A DVA N CE D extraordinary forefront of I M AG I N G advances the that imaging P RO G R A M place revolution the that IS UCCCC is M A K I N G at the transforming cancer care. Imaging resources at the UCCCC are broad and include X-ray, ultrasound, magnetic resonance, molecular Advanced Imaging T imaging, physiological modeling, and quantitative image analysis. The Program consists of 29 members from five departments who conduct both pre-clinical and clinical imaging studies using animal models of disease, cells, tissues, and patients. These members develop strong collaborations with cancer biologists and oncologists to translate new imaging technologies to the clinical arena. Research in the Advanced Imaging Program is focused on several image-guided therapy, and image analysis; 2) development of targeted contrast agents; 3) early diagnosis of cancer; 4) applications of imaging to guide pre-clinical and clinical drug development; and 5) use of imaging to study cancer initiation and progression. TO AC H I E V E T H E S E G OA L S , R E S E A R C H E R S I N T H E A DVA N C E D I M AG I N G P R O G R A M A R E A P P LY I N G I M AG I N G M E T H O D S TO : UCCCC SCIENTIFIC REPORT 2010 – 2011 interlinked areas: 1) development of new technology for imaging, ■■Increase the understanding of cancer initiation and progression; ■■Provide non-invasively measured parameters that correlate with biomarkers; ■■Improve early detection and risk assessment of cancer by developing new approaches to imaging and image analysis; ■■Detect response to therapy in clinical trials and develop image-guided therapies; and ■■Evaluate cancer risk and guide risk-management. 95 UCCCC SCIENTIFIC REPORT 2010 – 2011 Advanced Imaging PROGRAM MEMBERSHIP† Hiroyuki Abe, MD Assistant Professor of Radiology Patrick La Riviere, PhD Associate Professor of Radiology Hania Al-Hallaq, PhD Assistant Professor of Radiation & Cellular Oncology Stanley Liauw, MD Assistant Professor of Radiation & Cellular Oncology Daniel Appelbaum, MD Associate Professor of Radiology Heber MacMahon, MB, ChB Professor of Radiology Stephen Archer, MD Professor of Medicine Charles Metz, PhD Professor of Radiology Samuel Armato, PhD Associate Professor of Radiology δGillian Newstead, MB, ChB Professor of Radiology Issam Awad, MD Professor of Surgery Robert Nishikawa, PhD Associate Professor of Radiology Bulent Aydogan, PhD Associate Professor of Radiation & Cellular Oncology Aytekin Oto, MD Professor of Radiology Richard Baron, MD Professor of Radiology Xiaochun Pan, PhD Professor of Radiology Chin-Tu Chen, PhD Associate Professor of Radiology Charles Pelizzari, PhD Associate Professor of Radiation & Cellular Oncology Abraham Dachman, MD Professor of Radiology Brian Roman, PhD Assistant Professor of Radiology Maryellen Giger, PhD Professor of Radiology Charlene Sennett, MD Associate Professor of Radiology Howard Halpern, MD, PhD Professor of Radiation & Cellular Oncology Kenji Suzuki, PhD Assistant Professor of Radiology Yulei Jiang, PhD Associate Professor of Radiology Michael Vannier, MD Professor of Radiology Chien-Min Kao, PhD Associate Professor of Radiology Gregory Karczmar, PhD Professor of Radiology Anthony Kossiakoff, PhD Professor of Biochemistry and Molecular Biology † Reflects all Program membership during 2010-2011 δ Emeritus 96 Program Highlights† †Due to space constraints, only a small representative sample of Program highlights is presented here. DIFFUSION-WEIGHTED AND DYNAMIC CONTRASTENHANCED MR IMAGING DIFFERENTIATE PROSTATE CANCER (INTRA/ INTERPROGRAMMATIC) DCE-MR IMAGING AIDS IN CLASSIFICATION OF BREAST LESIONS (INTRAPROGRAMMATIC) Dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging enables the differentiation of lesions from normal tissue. Maryellen Giger, PhD, and Gillian Newstead, MB, ChB, assessed the performance of DCE-MR in the differentiation of invasive and metastatic breast lesions in a retrospective study using a breast MR imaging database. Significant differences in the area under the receiver operating characteristic curve (AUCs) indicate that DCE-MR imaging has the potential to aid in the classification of noninvasive and invasive lesions, and also discriminate between metastatic and non-metastatic lesions. (Bhooshan et al., Radiology 254:680-90, 2010) VEGF SPATIALLY CORRELATES WITH PO2 IMAGES IN TUMORS (INTRA/ INTERPROGRAMMATIC) Tumor microenvironments with spatially heterogeneous oxygenation (pO2), can determine the response to radiation therapy and may allow early prediction of therapeutic effect. Howard Halpern, MD, PhD, and Charles Pelizzari, PhD, along with Ralph Weichselbaum, MD (Pharmacogenomics and Experimental Therapeutics Program), designed a stereotactic delivery system with a bone biopsy needle to co-localize the biopsy location in the tumor with UCCCC SCIENTIFIC REPORT 2010 – 2011 Central gland carcinoma, which accounts for 30% of all prostate cancers, can potentially be treated by image-guided biopsy procedures and focal therapy if detected and localized accurately. Aytekin Oto, MD, Yulei Jiang, PhD, and Greg Karczmar, PhD, in collaboration with Walter Stadler, MD, and Arieh Shalhav, MD (Pharmacogenomics and Experimental Therapeutics Program), compared the diffusion and perfusion parameters of prostatic lesions to determine their role in differentiating central gland carcinoma from benign hyperplasia in a retrospective study of 49 patients who underwent preoperative magnetic resonance imaging with an endorectal detector. The apparent diffusion coefficient (ADC) differed significantly between central gland carcinoma, stromal hyperplasia foci, and glandular hyperplasia foci. These results indicate that the combination of diffusion-weighted and dynamic contrast-enhanced MR imaging has potential to improve the differentiation of central gland carcinoma from benign prostatic hyperplasia. (Oto et al., Radiology 257:715-23, 2010) agents. Bulent Aydogan, PhD, and Charles Pelizzari, PhD, along with Steven Chmura, MD, PhD (Molecular Mechanisms of Cancer Program), investigated the feasibility of using a 2-deoxy-d-glucose (2-DG) labeled gold nanoparticle (AuNP-2-DG) as a functionally targeted CT contrast agent for obtaining high-resolution metabolic and anatomic tumor information in a single CT scan. In vitro cellular uptake assays showed significant contrast enhancement in multiple CT slices in cells incubated with AuNP-2-DG. These experiments justify further studies to test the use of AuNP-2-DG as a functional CT contrast agent in radiation therapy settings. (Li et al., Phys Med Biol 55:4389-97, 2010) Advanced Imaging Publications AUNP-2-DG FUNCTIONS AS A CONTRAST AGENT FOR CT (INTRA/ INTERPROGRAMMATIC) When an appropriate X-ray contrast agent is used, computed tomography (CT) imaging can provide anatomic and functional information. This technique, called functional CT, is not widely used in patient care because of the lack of ideal contrast 97 Advanced Imaging the location of electron paramagnetic resonance image voxels. Using this system, biopsies stereotactically located in EPR images of pO2 showed that VEGF levels correlated with local pO2 in mouse tumors in vivo. These measurements will eventually allow individualized delivery of cancer therapeutics. (Elas et al., Mol Imaging Biol 13:1107-1113, 2011) UCCCC SCIENTIFIC REPORT 2010 – 2011 NORMAL BREAST PARENCHYMAL ENHANCEMENT CHARACTERISTICS IN DCEMRI VARY BY TISSUE DENSITY (INTRAPROGRAMMATIC) Drs. Gillian Newstead, Gregory Karczmar, and Maryellen Giger characterized the kinetic and morphological presentation of the normal breast using DCE-MR imaging in a large cohort of asymptomatic women. The goal was to develop improved predictors of cancer risk and minimize false-positive results caused by normal tissue enhancement. Women under the age of 45 with increased breast density exhibited an increased parenchymal enhancement pattern (PEP) and a higher proportion of nodular PEP. This study provides baseline qualitative and quantitative measurements of normal breast tissue enhancement. (Jansen et al., Eur Radiol 21:1374-82, 2011) Grants NEW CAD SYSTEM TO IMPROVE PROSTATE CANCER DETECTION The lack of standardized analysis tools limits accurate, reproducible cancer detection and widespread use of MR imaging techniques for imaging prostate cancer. Aytekin Oto, MD, received funding from the Department of Defense to develop a computer-aided diagnosis (CAD) system for detection of prostate 98 cancer using multiparametric 1.5-T MR images. Development of this innovative CAD system will allow more accurate localization of prostate cancer and allow the determination of its aggressiveness based on non-invasively obtained MR imaging - derived parameters. Currently, a noninvasive method to estimate the histologic aggressiveness of prostate cancer does not exist. IMAGE-GUIDED X-RAY IRRADIATOR SUPPORTS BIOMEDICAL RESEARCH Charles Pelizzari, PhD, was awarded an S10 shared instrumentation grant from the National Center for Research Resources to purchase the Precision X-ray X RAD225Cx Image Guided Biological Irradiator System to support modern, high-precision image-guided experimental X-ray irradiation of animals and cells. The Advanced Imaging device allows investigators to use low-dose imaging in radiographic or cone-beam CT scanning mode to show the position of the animal prior to experimental dose. Similar to patient treatment, this enables irradiation of the targeted region of anatomy and not elsewhere. MRI AIDS IN UNDERSTANDING THE NATURAL HISTORY OF PRE-INVASIVE BREAST CANCER CBCT DEVELOPMENTS TO ENHANCE PROSTATIC ADAPTIVE RADIOTHERAPY Image-guided radiotherapy (IGRT) is a standard practice for clinical prostate treatment. Adaptive radiotherapy is a recently developed form of IGRT based on diagnostic CT images and adjusted according to images acquired by cone-beam CT (CBCT) before and during treatment. However, the quality of UCCCC SCIENTIFIC REPORT 2010 – 2011 Funded by an R01 grant from the National Cancer Institute, Gregory Karczmar, PhD, and Suzanne Conzen, MD (Molecular Mechanisms of Cancer Program), are examining the biology of mammary intra-epithelial neoplasia (MIN), an early neoplasia similar to ductal carcinoma in situ (DCIS) in humans, using quantitative serial MR imaging combined with X-ray fluorescence microscopy and histology. These efforts aim to identify optimal MR imaging parameters for detecting various stages of mammary cancer and MR imaging-detectable biological markers that differentiate malignant from benign disease. The transdisciplinary approach involving imaging and tumor biology will improve the understanding of pre-invasive breast cancer, facilitate the evaluation of therapies targeting early cancers, and identify MR imaging markers for cancer risk. CBCT images limits its utilization. Through support from a Department of Defense grant, Xiaochuan Pan, PhD, is enhancing the image quality of CBCT by developing advanced CBCT reconstruction algorithms. Improved image quality will lead to more effective tumor control with fewer complications to surrounding tissues. 99 Featured Faculty Profiles† †Due to space constraints, only a small representative sample of Program members is presented here. Advanced Imaging HIROYUKI ABE, MD Assistant Professor of Radiology The clinical research team in the Department of Radiology, Section of Breast Imaging, is working to improve the diagnostic process for breast cancer patients. The team utilizes advanced MR imaging techniques along with computerized imaging analysis. Major research efforts are aimed at developing a clinical decision support (CDS) system for breast cancer on MR imaging. This CDS system aids physicians’ decision-making by presenting similar images to those in question. Clinical similarity was determined subjectively by expert radiologists and by computer image processing algorithms designed to match the experts’ perceptual characteristics. The goal is to develop a fully functional CDS system via a hybrid approach that leverages both our radiologists’ expertise and state-of-the-art computer techniques. The team has already reported an observer performance study showing improved radiologists’ performance in differentiating between malignant and benign breast lesions on MR imaging with use of the computerized system.1 UCCCC SCIENTIFIC REPORT 2010 – 2011 Hiroyuki Abe, MD A second area of focus is the development of a computerized technique for breast cancer staging that takes into account axillary lymph node status, an important factor in determining treatment. The technique is based on morphologic criteria established by the team in a previous clinical study. In a feasibility study, the ability of the computerized scheme to identify the same axillary lymph nodes on different modalities such as ultrasound and MR imaging was reported.2 The results revealed that combined multimodality data provide a more robust noninvasive method of lymph node staging. The team is also working to improve the assessment of surgically excised specimens. A key factor in successful breast conservation therapy is complete tumor resection, leaving no residual tumor cells in the breast. In standard practice, excised breast tissue is radiographed to assess whether the tumor has been completely excised with sufficient margins. Using a high-field (9.4T) MR imaging system, preliminary results suggest that MR images of specimens may provide superior visualization, allowing for more accurate assessment of the tumor edge and surgical margins. 1 Shimauchi A, Giger ML, Bhooshan N, Lan L, Pesce LL, Lee JK, Abe H, Newstead GM. Evaluation of clinical breast MR imaging performed with prototype computer-aided diagnosis breast MR imaging workstation: reader study. Radiology 258:696-704, 2011. 2 Meinel LA, Abe H, Bergtholdt M, Ecanow J, Schmidt R, Newstead G. Multi-modality morphological correlation of axillary lymph nodes. Int J Comput Assist Radiol Surg 5:343-350, 2010. 100 Associate Professor of Radiation & Cellular Oncology Imaging is accepted as a central component in our fight against cancer. Nonetheless, clinically applicable tumor-specific functional imaging, especially for the purpose of radiation oncology, is currently very limited. To meet this challenge, Dr. Bulent Aydogan and his colleagues are developing a novel functionally targeted CT contrast agent using gold nanoparticles that will provide high-resolution images without the use of additional radioactive agents. Dr. Aydogan successfully developed, in collaboration with Argonne National Laboratories, a novel functional CT contrast agent using gold nanoparticles labeled with 2-deoxyglucose (AuNP-DG). They demonstrated preferential uptake and functional targeting of cancer cells in preliminary in vitro experiments. Their goal is to demonstrate the feasibility of this novel CT contrast agent in preclinical imaging. The successful completion of this project will advance the development of a new set of capabilities in cancer detection by providing unmatched high-resolution anatomical and functional images in a single CT scan. Such a contrast agent would be valuable in the early detection, accurate localization, and monitoring of therapeutic response of human cancers. UCCCC SCIENTIFIC REPORT 2010 – 2011 Gold, because of its high atomic number, significantly attenuates X-rays and is capable of producing high contrast in a CT scan. The attachment of organic molecules, such as deoxyglucose, to the surface of the gold nanoparticles can potentially enhance their preferential uptake by cancer cells. Deoxyglucose increases specificity for highly glycolytic cells, and a high rate of glycolysis is a marker for cancer. Consequently, cancer cells will have a higher concentration of gold particles labeled with deoxyglucose, and therefore, show higher contrast with respect to the surrounding normal tissue in a CT image. A CT Bulent Aydogan, PhD scan taken under this condition will provide both anatomical and physiological information of the subject under investigation, hence the term, functional CT (fCT). This approach offers potential advantages over positron emission tomography (PET) scans, such as eliminating the need for radioactive tracers and offering the superior spatial resolution of CT scans, which is essential for tumor definition and targeting as well as early detection of cancer. Advanced Imaging BULENT AYDOGAN, PHD 101 Advanced Imaging UCCCC SCIENTIFIC REPORT 2010 – 2011 102 GREGORY KARCZMAR, PHD Professor of Radiology Work in the Florsheim Magnetic Resonance Imaging/Spectroscopy (MRIS) laboratory focuses on the development and validation of quantitative MR imaging methods and the use of those methods for early diagnosis and noninvasive evaluation of response to therapy. In addition, quantitative MRI is used in the pre-clinical setting to study initiation and progression of early mammary, prostate, and GI cancers. The laboratory is also involved in the development of new approaches to MR imaging-guided therapy. Several advances in the development and application of quantitative functional MR imaging have been made recently. The laboratory has developed a new approach to calculating local contrast agent arterial input function.1 The arterial input function is inferred from the dynamics of contrast agent in local reference tissues (e.g., muscle) with wellknown pharmacokinetic properties, and combined with measurements of contrast media washout in an artery. This approach allows correction of perfuGregory Karczmar, PhD sion measurements to remove variability due to contrast media dose, injection speed, cardiac output, and other systemic factors. As a result, error in measurements of perfusion and capillary permeability are greatly reduced, resulting in increased sensitivity to tumor vasculature and changes in vascular function during therapy. Quantitative MR imaging methods were used to evaluate DCE-MRI data from suspicious breast lesions acquired with high temporal and spatial resolution.2 This pilot study demonstrated the feasibility of quantitative analysis of early contrast kinetics at high temporal resolution and points to the potential for such analysis to improve the characterization of DCIS. 1 Fan X, Haney CR, Mustafi D, Yang C, Zamora M, Markiewicz EJ, Karczmar GS. Use of a reference tissue and blood vessel to measure the arterial input function in DCEMRI. Magn Reson Med 64:1821-1826, 2010. 2 Jansen SA, Fan X, Medved M, Abe H, Shimauchi A, Yang C, Zamora M, Foxley S, Olopade OI, Karczmar GS, Newstead GM. Characterizing early contrast uptake of ductal carcinoma in situ with high temporal resolution dynamic contrast-enhanced MRI of the breast: a pilot study. Phys Med Biol 55:N473-485, 2010. Professor of Radiology A need exists for a more efficient and cost-effective diagnosis and management algorithm for prostate cancer patients. Currently, MR imaging is the best tool for prostate imaging, but its utilization has limitations. Dr. Aytekin Oto’s primary research focuses on MR imaging of prostate cancer with specific aims to 1) develop and optimize prostate MR imaging protocols; 2) improve MR image interpretation by establishing better MR imaging and histopathological correlation and developing computer-aided diagnosis software to assist radiologists in the interpretation of prostate MR imaging images; and 3) develop and improve MR imaging-guided focal therapy methods for prostate cancer, such as laser or high-frequency ultrasound tumor ablation. Dr. Oto’s work has shown that novel MR imaging techniques, such as diffusion-weighted imaging (DWI) and DCE imaging, can improve the diagnosis of central gland cancer which comprises 30% of all prostate cancers.1 His research has also demonstrated that apparent diffusion coefficient values (ADC) calculated by DWI correlate with the Gleason Score and, therefore, the biologic aggressiveness of prostate cancer. Assessment of prostate cancer aggressiveness can aid in the stratification of patients and identification of appropriate treatments. In addition, Dr. Oto has successfully led a clinical trial to perform focal therapy for prostate cancer in nine patients, an emerging treatment using MR imaging-guided laser ablation. He has introduced routine use of MR-guided prostate biopsies. In collaboration with Philips Healthcare, he is also developing high-frequency ultrasound ablation of prostate tissues. UCCCC SCIENTIFIC REPORT 2010 – 2011 During the last 4 years, the Radiology Department has established a busy prostate MR imaging practice at The University of Chicago Medical Center with excellent collaboration among colleagues in urology (Drs. Arieh Shalhav and Scott Eggener), medical oncology (Dr. Walter Stadler), pathology, radiaAytekin Oto, MD tion oncology (Dr. Stanley Liauw) and medical physicists (Drs. Maryellen Geiger, Gregory Karczmar, and Yulei Jiang) in the department. Through these collaborations, the department has received several grants for prostate MR imaging, including those from the UCCCC, industry (Philips Healthcare, Invivo Corporation, Visualase Corporation), foundations (American Cancer Society Illinois Division, Admetech Foundation, Partnership for a Cure Foundation), and a federal institution (Department of Defense). Advanced Imaging AYTEKIN OTO, MD Oto A, Kayhan A, Jiang Y, Tretiakova M, Yang C, Antic T, Dahi F, Shalhav AL, Karczmar G, Stadler WM. Prostate cancer: differentiation of central gland cancer from benign prostatic hyperplasia by using diffusion-weighted and dynamic contrast-enhanced MR imaging. Radiology 257:715-723, 2010. 1 103 UCCCC SCIENTIFIC REPORT 2010 – 2011 Advanced Imaging KENJI SUZUKI, PHD Assistant Professor of Radiology Dr. Kenji Suzuki’s laboratory conducts interdisciplinary research in cancer diagnosis and medical physics, with a primary focus on CAD of lesions in the abdomen and thorax as well as the development of machine-learning and pattern-recognition techniques for cancer diagnosis. The long-term goal of his research is to develop a computer system capable of diagnosing disease from medical images, similar to how radiologists assist non-expert doctors with diagnoses. Dr. Suzuki believes that the development of sophisticated techniques, their theoretical backups, and an understanding of radiologists’ decision-making process and of the human visual system are essential to achieving this goal. The Suzuki laboratory is making efforts to “weave” the clinical and technological sciences into a new paradigm that will contribute to both medicine and medical physics. Specific aims of Dr. Suzuki’s research are to develop 1) CAD systems for early detection and accurate diagnosis of lesions in medical images; 2) computerKenji Suzuki, PhD aided systems for quantifying the characteristics of lesions in medical images; 3) enhanced medical imaging for improving the conspicuity of lesions; and 4) machine-learning and pattern-recognition techniques for detection, diagnosis, quantification, assessment, and enhancement of lesions in medical images to reduce cancer mortality. The Suzuki laboratory, in collaboration with Dr. Abraham Dachman, has developed a CAD system for early detection of polyps (i.e., precursor of colorectal cancer) in CT colonography. Using a new machine-learning technique developed for false-positive (FP) reduction, the number of FP detections was reduced by 63% without loss of any true positives. Thus, the FP rate of the CAD system was improved from 3.1 to 1.1 FPs per patient while maintaining the original sensitivity of 96%.1 By incorporating a new machine-learning model and nonlinear dimension reduction, the training time of the machine-learning-based FP reduction technique was reduced from 38 hours to 1.2 minutes (by a factor of 1900) while the original performance was maintained.2,3 This significant improvement in efficiency facilitates the development of CAD schemes based on the FP reduction technique. In an evaluation of clinical cases from a large multicenter clinical trial, the CAD system detected 58% of the polyps “missed” by radiologists in CT colonography.4 Thus, the CAD system has the potential to save 58% of false-negative cases in CT colonography and potentially reduce colorectal cancer mortality. Suzuki K, Yoshida H, Nappi J, Armato SG, 3rd, Dachman AH. Mixture of expert 3D massive-training ANNs for reduction of multiple types of false positives in CAD for detection of polyps in CT colonography. Med Phys 35:694-703, 2008. 1 2 Suzuki K, Zhang J, Xu J. Massive-training artificial neural network coupled with Laplacian-eigenfunction-based dimensionality reduction for computer-aided detection of polyps in CT colonography. IEEE Trans Med Imaging 29:1907-1917, 2010. 3 Xu J, and Suzuki K. Massive-training support vector regression and Gaussian process for false-positive reduction in computer-aided detection of polyps in CT colonography. Med Phys 38:1888-1902, 2011. 4 Suzuki K, Rockey DC, Dachman AH. CT colonography: Advanced computer-aided detection scheme utilizing MTANNs for detec- tion of “missed” polyps in a multicenter clinical trial. Med Phys 30:2-21, 2010. 104 Professor of Radiology For over 25 years, Dr. Maryellen Giger’s laboratory has been conducting research in computer-aided diagnosis and quantitative image analysis. Multimodality breast images are acquired and interpreted in the diagnostic work-up of potential breast cancer cases and in subsequent treatment planning. Dr. Giger’s research focuses on finding new ways to use computers to help radiologists more effectively and efficiently extract information from medical images such as mammograms, ultrasound images, and MR images. Her laboratory develops new methods for manipulating and mining digital breast image data to yield image-based biomarkers and tumor signatures. Output from such methods can help characterize tumors, distinguish between cancerous tumors and benign lesions, assess breast cancer risk, and serve as prognostic and predictive surrogate biomarkers. In the future, Dr. Giger’s vision is to develop a comprehensive predictive framework for determining novel image-based tumor signatures. This framework would aid in the diagnosis of breast cancers and facilitate the design of patient-specific, tailored breast cancer treatments, including initial treatment recommendations and therapy response assessments. Tumor signatures will be multiscale and multimodality, including attributes of the tumor and its surroundings as well as systemic contributions. Specifically, they will include computer-extracted macro- and microimaging characteristics (imaging phenotypes), histological classification, molecular classification (expression), genomics, and clinical presentations. Such a framework will mimic an augmented electronic tumor board in which contributions from and correlations among clinical, imaging, pathology, and genomic data will be supplemented by a web-based computer expert system. In addition, feedback from the relationship between the predictive framework and survival status will aid in directing future treatment options. UCCCC SCIENTIFIC REPORT 2010 – 2011 In a collaborative effort between medical physicists and breast radiologists, Dr. Giger and her colleagues analyzed breast MR images [132 benign, 71 Maryellen Giger, PhD ductal carcinoma in situ (DCIS), and 150 invasive ductal carcinoma (IDC) lesions] in the development of image-based prognostic biomarkers.1 Lesion segmentation and extraction of morphologic and kinetic features were automatically performed by a laboratory-developed computer workstation. The computer differentiated between DCIS, IDC lesions, and benign lesions, and also accurately distinguished between IDC lesions associated with positive lymph nodes (LNs) and those associated with negative LNs. From this study, Dr. Giger and her colleagues demonstrated that computer-aided diagnosis methods for breast DCE-MR imaging can be extended from the task of discriminating between malignant and benign lesions to the prognostic tasks of distinguishing between noninvasive and invasive lesions and between metastatic and nonmetastatic lesions, yielding MR imaging-based prognostic markers. Advanced Imaging MARYELLEN GIGER, PHD 1 Bhooshan N, Giger ML, Jansen SA, Li H, Lan L, Newstead GM. Cancerous breast lesions on dynamic contrast-enhanced MR images: computerized characterization for image-based prognostic markers. Radiology 254:680-690, 2010. 105 Selected Publications UCCCC SCIENTIFIC REPORT 2010 – 2011 Advanced Imaging * : Intraprogrammatic Collaboration # : Interprogrammatic Collaboration ABE, HIROYUKI, MD Shiraishi J, Appelbaum D, Pu Y, Engelmann R, Li Q, Doi K. Clinical utility of temporal subtraction images in successive whole-body bone scans: evaluation in a prospective clinical study. J Digit Imaging 24:680-7, 2011. * # Medved M, Newstead GM, Abe H, Olopade OI, Shimauchi A, Zamora MA, Karczmar GS. Clinical implementation of a multislice high spectral and spatial resolution-based MRI sequence to achieve unilateral full-breast coverage. Magn Reson Imaging 28:16-21, 2010. PMC2789876 Huang YE, Chen CF, Huang YJ, Konda SD, Appelbaum DE, Pu Y. Interobserver variability among measurements of the maximum and mean standardized uptake values on (18)F-FDG PET/CT and measurements of tumor size on diagnostic CT in patients with pulmonary tumors. Acta Radiol 51:782-8, 2010. * # Shimauchi A, Jansen SA, Abe H, Jaskowiak N, Schmidt RA, Newstead GM. Breast cancers not detected at MRI: review of false-negative lesions. AJR Am J Roentgenol 194:1674-9, 2010. Ilkhchoui Y, Appelbaum DE, Pu Y. FDGPET/CT findings of a metastatic pituitary tumor. Cancer Imaging 10:114-6, 2010. Nakayama R, Abe H, Shiraishi J, Doi K. Evaluation of objective similarity measures for selecting similar images of mammographic lesions. J Digit Imaging 24:75-85, 2011. PMC3046795 # Gomberg-Maitland M, Maitland ML, Barst RJ, Sugeng L, Coslet S, Perrino TJ, Bond L, Lacouture ME, Archer SL, Ratain MJ. A dosing/cross-development study of the multikinase inhibitor sorafenib in patients with pulmonary arterial hypertension. Clin Pharmacol Ther 87:303-10, 2010. * Abe H, Schmidt RA, Shah RN, Shimauchi A, Kulkarni K, Sennett CA, Newstead GM. MR-directed (“Second-Look”) ultrasound examination for breast lesions detected initially on MRI: MR and sonographic findings. AJR Am J Roentgenol 194:370-7, 2010. * Shimauchi A, Giger ML, Bhooshan N, Lan L, Pesce LL, Lee JK, Abe H, Newstead GM. Evaluation of clinical breast MR imaging performed with prototype computer-aided diagnosis breast MR imaging workstation: reader study. Radiology 258:696-704, 2011. * # Jansen SA, Fan X, Medved M, Abe H, Shimauchi A, Yang C, Zamora M, Foxley S, Olopade OI, Karczmar GS, Newstead GM. Characterizing early contrast uptake of ductal carcinoma in situ with high temporal resolution dynamic contrastenhanced MRI of the breast: a pilot study. Phys Med Biol 55:N473-85, 2010. APPELBAUM, DANIEL, MD Huang YE, Pu YL, Huang YJ, Chen CF, Pu QH, Konda SD, Appelbaum DE. The utility of the nonattenuation corrected 18F-FDG PET images in the characteriza 106 tion of solitary pulmonary lesions. Nucl Med Commun 31:945-51, 2010. Shiraishi J, Abe H, Ichikawa K, Schmidt RA, Doi K. Observer study for evaluating potential utility of a super-high-resolution LCD in the detection of clustered microcalcifications on digital mammograms. J Digit Imaging 23:161-9, 2010. PMC3043779 ARCHER, STEPHEN, MD ARMATO, SAMUEL, PHD Corson N, Sensakovic WF, Straus C, Starkey A, Armato SG 3rd. Characterization of mesothelioma and tissues present in contrast-enhanced thoracic CT scans. Med Phys 38:942-7, 2011. PMC3041808 # Sensakovic WF, Armato SG 3rd, Straus C, Roberts RY, Caligiuri P, Starkey A, Kindler HL. Computerized segmentation and measurement of malignant pleural mesothelioma. Med Phys 38:238-44, 2011. PMC3021556 # Sensakovic WF, Armato SG 3rd, Starkey A, Kindler HL, Vigneswaran WT. Quantitative measurement of lung reexpansion in malignant pleural mesothelioma patients undergoing pleurectomy/ decortication. Acad Radiol 18:294-8, 2011. 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Region of interest imaging for a general trajectory with the rebinned BPF algorithm. Tsinghua Sci Technol 15:68-73, 2010. PMC2898485 Cho S, Sidky EY, Bian J, Pan X. Dualenergy technique at low tube voltages for small animal imaging. Tsinghua Sci Technol 15:79-86, 2010. PMC2892926 Sidky EY, Anastasio MA, Pan X. Image reconstruction exploiting object sparsity in boundary-enhanced X-ray phase-contrast tomography. Opt Express 18:10404-22, 2010. PMC2987648 Xia D, Cho S, Pan X. Backprojectionfiltration reconstruction without invoking a spatially varying weighting factor. Med Phys 37:1201-9, 2010. PMC2837731 110 Cho S, Xia D, Pellizzari CA, Pan X. A BPF-FBP tandem algorithm for image reconstruction in reverse helical conebeam CT. Med Phys 37:32-9, 2010. PMC2801731 PELIZZARI, CHARLES, PHD * Haney CR, Pelizzari CA, Foxley S, Zamora MA, Mustafi D, Tretiakova M, Li S, Fan X, Karczmar GS. HiSStology: high spectral and spatial resolution magnetic resonance imaging detection of vasculature validated by histology and micro-computed tomography. Mol Imaging 10:187-96, 2011. PMC3079458 * Pederson AW, Fricano J, Correa D, Pelizzari CA, Liauw SL. Late toxicity after intensity-modulated radiation therapy for localized prostate cancer: An exploration of dose-volume histogram parameters to limit genitourinary and gastrointestinal toxicity. Int J Radiat Oncol Biol Phys, 2010 (Epub ahead of print). * # Elas M, Hleihel D, Barth ED, Haney CR, Ahn KH, Pelizzari CA, Epel B, Weichselbaum RR, Halpern HJ. Where it’s at really matters: In situ in vivo vascular endothelial growth factor spatially correlates with electron paramagnetic resonance pO(2) images in tumors of living mice. Mol Imaging Biol 13:1107-13, 2011. * Bian J, Siewerdsen JH, Han X, Sidky EY, Prince JL, Pelizzari CA, Pan X. Evaluation of sparse-view reconstruction from flatpanel-detector cone-beam CT. Phys Med Biol 55:6575-99, 2010. * Kalakota K, Rakhno E, Pelizzari CA, Jani AB, Liauw SL. Late rectal toxicity after prostate brachytherapy: influence of supplemental external beam radiation on dose-volume histogram analysis. Brachytherapy 9:131-6, 2010. * # Li J, Chaudhary A, Chmura SJ, Pelizzari C, Rajh T, Wietholt C, Kurtoglu M, Aydogan B. A novel functional CT contrast agent for molecular imaging of cancer. Phys Med Biol 55:4389-97, 2010. # MacDermed DM, Khodarev NN, Pitroda SP, Edwards DC, Pelizzari CA, Huang L, Kufe DW, Weichselbaum RR. MUC1-associated proliferation signature predicts outcomes in lung adenocarcinoma patients. BMC Med Genomics 3:16, 2010. PMC2876055 * # Aydogan B, Li J, Rajh T, Chaudhary A, Chmura SJ, Pelizzari C, Wietholt C, Kurtoglu M, Redmond P. AuNP-DG: deoxyglucose-labeled gold nanoparticles as X-ray computed tomography contrast agents for cancer imaging. Mol Imaging Biol 12:463-7, 2010. ROMAN, BRIAN, PHD Leoni L, Roman BB. MR imaging of pancreatic islets: tracking isolation, transplantation and function. Curr Pharm Des 16:1582-94, 2010. SENNETT, CHARLENE, MD * Yuan Y, Giger ML, Li H, Bhooshan N, Sennett CA. Multimodality computer-aided breast cancer diagnosis with FFDM and DCE-MRI. Acad Radiol 17:1158-67, 2010. * Abe H, Schmidt RA, Shah RN, Shimauchi A, Kulkarni K, Sennett CA, Newstead GM. MR-directed (“Second-Look”) ultrasound examination for breast lesions detected initially on MRI: MR and sonographic findings. AJR Am J Roentgenol 194:370-7, 2010. SUZUKI, KENJI, PHD Suzuki K, Kohlbrenner R, Epstein ML, Obajuluwa AM, Xu J, Hori M. Computeraided measurement of liver volumes in CT by means of geodesic active contour segmentation coupled with level-set algorithms. Med Phys 37:2159-66, 2010. PMC2874039 * Lostumbo A, Wanamaker C, Tsai J, Suzuki K, Dachman AH. Comparison of 2D and 3D views for evaluation of flat lesions in CT colonography. Acad Radiol 17:39-47, 2010. Suzuki K, Zhang J, Xu J. Massive-training artificial neural network coupled with Laplacian-eigenfunction-based dimensionality reduction for computer-aided detection of polyps in CT colonography. IEEE Trans Med Imaging 29:1907-17, 2010. Xu JW, Suzuki K. Massive-training support vector regression and Gaussian process for false-positive reduction in computer-aided detection of polyps in CT colonography. Med Phys 38:1888-902, 2011. PMC3069995 * Chen S, Suzuki K, MacMahon H. Development and evaluation of a computer-aided diagnostic scheme for lung nodule detection in chest radiographs by means of two-stage nodule enhancement with support vector classification. Med Phys 38:1844-58, 2011. PMC3069992 Selected Major Grants and Awards INVESTIGATOR TITLE PROJECT START DATE END DATE TOTAL ANNUAL COST CLASS FUNDING AGENCY O2 sensing in the human and rabbit ductus arteriosus 7/1/2011 4/30/2016 $390,000 R01 National Heart, Lung, and Blood Institute SAMUEL ARMATO An image storage and retrieval system for biomedical imaging research 5/1/2011 4/30/2012 $357,000 S10 National Institutes of Health MARYELLEN GIGER Research Training in Medical Physics 9/1/2010 8/31/2015 $266,942 T32 National Institutes of Health MARYELLEN GIGER Somo versus ABUS ROC reader observer study 4/15/2010 1/2/2012 $200,000 N/A U-Systems, Inc. GREGORY KARCZMAR MRI of early non-invasive rodent mammary cancers 3/1/2011 12/31/2015 $337,038 R01 National Cancer Institute GREGORY KARCZMAR Development and clinical evaluation of MR-guided focused ultrasound for tattooing tumors to guide radiotherapy as well as other therapies 8/1/2010 7/31/2011 $100,000 N/A Focused Ultrasound Surgery Foundation PATRICK LA RIVIERE High-resolution large field of view ultrasound breast imager 6/1/2011 5/31/2013 $248,984 N/A Department of Defense PATRICK LA RIVIERE X-ray fluorescence tomography with emission tomography apertures 9/1/2010 8/31/2012 $101,767 R21 National Institute of Biological Imaging and Bioengineering AYTEKIN OTO Computer-aided diagnosis of prostate cancer with multi-parametric MR imaging 8/1/2010 8/31/2012 $351,000 N/A Department of Defense XIAOCHUAN PAN Targeted imaging in helical cone-beam CT 2/7/2011 1/31/2015 $410,720 R01 National Institute of Biological Imaging and Bioengineering CHARLES PELIZZARI Image-guided X-ray irradiator for biomedical research 8/14/2010 8/13/2011 $423,555 S10 National Institutes of Health UCCCC SCIENTIFIC REPORT 2010 – 2011 STEPHEN ARCHER Advanced Imaging The Advanced Imaging Program has a funding base of $10,308,792 in annual total costs (current as of July 2011). This sum includes $1,576,690 in NCI funding and $5,324,646 in other NIH funding. Due to space constraints, only selected new awards since January 1, 2010 of $100,000 or greater in annual total costs are listed here. 111 CANCER PREVENTION AND CONTROL PROGRAM LEADERS Habibul Ahsan, MBBS, MMedSc Professor of Health Studies 112 Brian Chiu, PhD Associate Professor of Health Studies Andrea King, PhD Professor of Psychiatry HE CANCER PREVENTION AND CONTROL PROGRAM IS determining the genetic, psychological, behavioral, and socio-environmental basis of cancer, and interactions among these variables. The Program consists of 41 members from 11 departments and two University Divisions (Biological Sciences, Social Sciences) who focus their research on high-risk individuals defined by these factors as well as health outcomes, survivorship, Cancer Prevention and Control T and economics. Members emphasize cancer control and molecular epidemiology research and aim to translate and disseminate their efforts to the community. The Program is committed to outreach efforts in South Side Chicago neighborhoods to enhance participation and utilization of University of Chicago research, education, outcomes, and their modifiable determinants in the community. THE SCIENTIFIC AIMS OF THE CANCER PREVENTION A N D CO N T R O L P R O G R A M A R E TO : ■■Identify novel genomic, nutritional, and environmental determinants and their interactions in cancer risk and prevention; UCCCC SCIENTIFIC REPORT 2010 – 2011 and clinical services to reduce cancer disparities, other health ■■Identify the biological and behavioral basis for tobacco and alcohol use, and apply this knowledge to develop prevention and cessation-related treatment strategies; ■■Examine biological and behavioral factors related to screening, early detection, and prevention of cancer; ■■Investigate the biobehavioral, psychosocial, and environmental determinants of cancer-related health outcomes, including survivorship; and ■■Examine cost-effectiveness and economic factors related to cancer diagnosis, treatment, and survivorship. 113 Cancer Prevention and Control PROGRAM MEMBERSHIP† Habibul Ahsan, MBBS, MMedSc Professor of Health Studies Tara Henderson, MD, MPH Assistant Professor of Pediatrics Blase Polite, MD, MPH Assistant Professor of Medicine Kenneth Alexander, MD, PhD Professor of Pediatrics Susan Hong, MD, MPH Assistant Professor of Medicine φAnirban Basu, PhD Assistant Professor of Medicine Dezheng Huo, MD, PhD Assistant Professor of Health Studies Iris Romero, MD Assistant Professor of Obstetrics/Gynecology Marc Bissonnette, MD Associate Professor of Medicine Eugene Chang, MD Professor of Medicine UCCCC SCIENTIFIC REPORT 2010 – 2011 Brian Chiu, PhD Associate Professor of Health Studies Nora Jaskowiak, MD Assistant Professor of Surgery φLisa Sanchez-Johnsen, PhD Assistant Professor of Psychiatry Karen E. Kim, MD, MS Associate Professor of Medicine Marion Verp, MD Associate Professor of Obstetrics/Gynecology Andrea King, PhD Professor of Psychiatry Rena Conti, PhD Instructor of Pediatrics Sonia Kupfer, MD Assistant Professor of Medicine Nancy Cox, PhD Professor of Medicine Diane Lauderdale, PhD Associate Professor of Health Studies William Dale, MD, PhD Associate Professor of Medicine Soma Das, PhD Associate Professor of Human Genetics Harriet de Wit, PhD Professor of Psychiatry Anna Di Rienzo, PhD Professor of Human Genetics James Dignam, PhD Associate Professor of Health Studies David Grdina, PhD, MBA Professor of Radiation & Cellular Oncology Paul Vezina, PhD Professor of Psychiatry Irving Waxman, MD Professor of Medicine Yan Chun Li, PhD Associate Professor of Medicine Stacy Tessler Lindau, MD, MAPP Associate Professor of Obstetrics/Gynecology Christopher Masi, MD, PhD Assistant Professor of Medicine Martha McClintock, PhD Professor of Psychology Daniel McGehee, PhD Associate Professor of Anesthesia/ Critical Care David Meltzer, MD, PhD Associate Professor of Medicine William Green, PhD Professor of Neurobiology φEneida Mendonca, MD, PhD Associate Professor of Pediatrics Yasmin Hasan, MD Instructor of Radiation & Cellular Oncology Olufunmilayo Olopade, MBBS Professor of Medicine Joshua Hemmerich, PhD Assistant Professor of Medicine David Rubin, MD Associate Professor of Medicine Brandon Pierce, PhD Assistant Professor of Health Studies † Reflects all Program membership during 2010-2011 φ Individuals who are no longer at the UCCCC 114 Program Highlights† †Due to space constraints, only a small representative sample of Program highlights is presented here. NEURAL SUBSTRATES UNDERLIE ALCOHOL-INDUCED SMOKING CHEMOTHERAPEUTIC DRUG SUSCEPTIBILITYASSOCIATED SNPS ARE ENRICHED IN EXPRESSION QUANTITATIVE TRAIT LOCI (INTERPROGRAMMATIC) EGFR DOWNREGULATES TUMOR SUPPRESSORS IN WESTERN DIET-PROMOTED COLONIC TUMOR (INTRA/ INTERPROGRAMMTIC) Previous studies indicate that the promotion of colonic tumorigenesis requires epidermal growth factor receptor (EGFR) signaling. Marc Bissonnette, MD, Sonia Kupfer, MD, Alessandro Fichera, MD (Pharmacogenomics and Experimental Therapeutics Program), and Kathleen Goss, PhD (Molecular Mechanisms of Cancer Program), investigated the effects of EGFR on two micro RNAs (miRNAs), miR-143 and miR-145. EGFR signals suppressed the expression of both miRNAs in murine colonic tumors and down-regulated their putative and established targets involved in cell cycle regulation. The findings uncover the tumor suppressor role of miR-143 and miR-145 in the presence of a Western diet. Approaches that prevent the down-regulation of these miRNAs may serve as potential strategies to prevent colon cancer. (Zhu et al., Mol Cancer Res 9:960-75, 2011) RACIAL AND ETHNIC DISPARITIES INFLUENCE RISK AND SURVIVAL IN CHILDREN WITH NEUROBLASTOMA (INTERPROGRAMMATIC) Tara Henderson, MD, MPH, and Susan Cohn, MD (Pharmacogenomics and Experimental Therapeutics Program), evaluated the racial and ethnic differences in risk factors and survival in 3,539 pediatric patients with neuroblastoma enrolled in the Children’s Oncology Group (COG). Black and Native American patients had a higher prevalence of high-risk disease and 5-year event free survival (EFS) compared with whites. The data suggest that this population may be more resistant to chemotherapy UCCCC SCIENTIFIC REPORT 2010 – 2011 A strong link exists between cigarette smoking and alcohol use. Andrea King, PhD, in a double-blinded, placebo-controlled, crossover study, used functional magnetic resonance imaging to examine the response to smoking cues in heavy drinking, nondaily social smokers after consuming an intoxicating dose of alcohol or placebo. The consumption of a moderately intoxicating oral dose of alcohol increased the desire to smoke and amplified ventral striatum reactivity in response to smoking compared with control cues. Alcohol also dampened orbitofrontal activity across both cue types, whereas dorsolateral prefrontal and anterior cingulate cortex activation to smoking cues was not affected by alcohol. These results provide a potential neurobiological mechanism to explain the co-abuse of these two commonly consumed cancer-causing agents. (King et al., Neuropsychopharmacology 35:692-701, 2010) for six different anticancer agents. Chemotherapeutic drug susceptibility-associated SNPs were more likely to be eQTLs and associated with the transcriptional expression level of multiple genes as potential master regulators. These findings highlight the importance of genetic variations in affecting transcript abundance in elucidating the genetic determinants of chemotherapeutic drug susceptibility. (Gamazon et al., PNAS 107:9287-92, 2010) Cancer Prevention and Control Publications Pharmacogenomics has employed both candidate gene studies and genome-wide association studies (GWAS) to identify loci associated with drug response and/or toxicity. Nancy Cox, PhD, along with M. Eileen Dolan, PhD, and R. Stephanie Huang, PhD (Pharmacogenomics and Experimental Therapeutics Program), evaluated the genomic regions and functional categories of drug susceptibility-associated single nucleotide polymorphisms (SNPs) 115 Cancer Prevention and Control UCCCC SCIENTIFIC REPORT 2010 – 2011 and encourage additional studies to delineate the genetic basis for these disparities. (Henderson et al., J Clin Oncol 29:76-82, 2011) A STRONG CONCORDANCE IN HORMONE RECEPTOR STATUS EXISTS BETWEEN PRIMARY AND SECOND BREAST CANCERS (INTRAPROGRAMMATIC) Women with breast cancer are more susceptible to developing a second breast cancer than women in the general population are to developing a primary breast cancer. Dezheng Huo, MD, PhD, and Olufunmilayo Olopade, MBBS, investigated the histological and biological relationship between primary first and second breast cancers by analyzing 30,617 patients from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) registries. Strong associations were found between hormone receptor status, tumor grade, and histological type between bilateral breast cancers. These findings suggest that tumors arise from a common milieu and have important implications in the prevention and management of second breast cancers. (Huo et al., Cancer 117:907-15, 2011) THE HNF1A REGION IS A NOVEL PANCREATIC CANCER SUSCEPTIBILITY LOCUS SNPs that are associated with human phenotypes are more likely to associate with pancreatic cancer risk than SNPs with no known effects. Brandon Pierce, PhD, and Habibul Ahsan, MBBS, MMedSc, examined 1,087 SNPs with known implications for human phenotypes for association with pancreatic cancer risk. The method increased the statistical power of the GWA study, reduced the number of tests conducted, and focused on SNPs with increased probabilities of disease risk association. HNF1A, a region that harbors variants influencing several human traits, was identified as a pancreatic cancer-risk locus. This novel GWA approach may be useful for identifying susceptibility loci for other cancer types. (Pierce et al., Cancer Res 71:4352-8, 2011) Grants STUDY TO IDENTIFY GENETIC RISK FOR BREAST CANCER IN THE AFRICAN DIASPORA Women in the African diaspora suffer from a disproportionate burden of pre-menopausal breast cancer in comparison to other races. Olufunmilayo Olopade, MBBS, was awarded an R01 grant from the National Cancer Institute to perform a GWA study in indigenous African women to identify alleles associated with breast cancer risk. Results from this study have the potential to identify risk alleles that may have implications for early detection, prognosis, and treatment of breast cancer in all women. 116 Cancer Prevention and Control Measuring the impact of comorbidities on quality of life (QOL) is an important factor in treatment selection and evaluation. As a recipient of a National Cancer Institute R21 award, William Dale, MD, PhD, is testing the generalizability of a prediction model he developed for estimating QOL in men with prostate cancer and various comorbidities. Extension of the prediction model will establish better QOL measurement for cost-effectiveness analysis for men at risk for prostate cancer, and may be applicable in a broader context across cancer sites and other prevalent noncancer comorbidities. RESEARCHERS SEARCH FOR RARE VARIANTS RESPONSIBLE FOR COMPLEX HUMAN PHENOTYPES Nancy Cox, PhD, along with colleagues, was awarded a U01 grant from the National Human Genome Research Institute to develop a program for the analysis of sequence data from the 1000 Genomes Project. The program aims to identify rare variants that affect complex human traits, determine what proportion of the heritability for complex traits is attributable to these variants, and predict which genes are most likely to harbor these variants. PROGRAM AIMS TO DEVELOP AN ONCOLOGY WORKFORCE FOR THE 21ST CENTURY The University of Chicago, under the leadership of Olufunmilayo Olopade, MBBS, received the National Cancer Institute Paul Calabresi Career Development Award for Clinical Oncology (K12) to create an interdisciplinary training program in patient-oriented research for clinicians and basic scientists. The highly mentored, didactic program provides clinical research training, enabling participants to conduct high-quality and highimpact hypothesis-driven bench to bedside research to make fundamental contributions toward the goal of personalized cancer treatment. EGFR-VDR SIGNALS IN DIET PROMOTE INFLAMMATION AND CANCER Diet is thought to play a major role in the development of sporadic colon cancer. Marc Bissonnette, MD, has shown that tumor promotion by Western-style, high-fat diets requires the suppression of vitamin D action by epidermal growth factor receptor (EGFR) signaling. Through support from a National Cancer Institute R21 grant, Dr. Bissonnette is uncovering the EGFR and vitamin D cellular and molecular pathways that interact to modulate dietary inflammation and colonic tumor risk. These studies will identify potential new targets for chemoprevention. UCCCC SCIENTIFIC REPORT 2010 – 2011 PREDICTION MODEL AIDS IN QOL ASSESSMENT FOR PATIENTS WITH PROSTATE CANCER 117 Featured Faculty Profiles† †Due to space constraints, only a small representative sample of Program members is presented here. Cancer Prevention and Control TARA HENDERSON, MD, MPH Assistant Professor of Pediatrics Survival after a diagnosis of childhood cancer has improved from less than 20% in the 1960s to over 80% today. As a result, there are over 325,000 childhood cancer survivors in the U.S. Despite these high cure rates, many survivors are at elevated risk for morbidity as a result of their prior cancer and its treatment. These risks include the development of second malignant neoplasms (SMN) and damage to vital organs, which can lead to premature mortality. Clinicians and researchers must carefully identify those survivors at risk for SMN and late effects to develop surveillance recommendations aimed at early detection and treatment. UCCCC SCIENTIFIC REPORT 2010 – 2011 Tara Henderson, MD, MPH Dr. Tara Henderson’s research program in childhood cancer survivorship aims to: 1) identify and describe SMN in childhood cancer survivors, including treatment-, familial-, and lifestyle-related risk factors associated with their development; 2) develop recommendations for the surveillance and early detection of SMN; 3) identify barriers and facilitators to survivors receiving appropriate riskbased healthcare including surveillance of SMN; and 4) develop intervention studies aimed at improving SMN surveillance in childhood cancer survivors. Dr. Henderson and her colleagues have recently identified 45 cases of gastrointestinal SMN in the Childhood Cancer Survivor Study, a cohort of over 14,000 childhood cancer survivors diagnosed between 1970 and 1986. This risk is almost 5-fold higher than the general population. Risk of the development of these tumors was associated with prior diagnosis of Hodgkin lymphoma or Wilms tumor, as well as exposure to abdominal radiation, platinum chemotherapy, and highdose procarbazine. In addition, Dr. Henderson and her collaborators performed large studies of subspecialists and primary care physicians to determine their attitudes regarding this population and their knowledge of late effects and available surveillance guidelines.1 Pediatric oncologists described being uncomfortable with older survivors, and many were unaware of the available screening guidelines, such as those for women at high risk for breast cancer. Dr. Henderson recently completed a study of 1500 U.S. family physicians, which was reported at the 2011 American Society of Clinical Oncology meeting. Similarly, the study found that while these physicians are willing to care for survivors, most are not aware of the available surveillance guidelines for these patients. 1 Henderson TO, Hlubocky FJ, Wroblewski KE, Diller L, Daugherty CK. Physician preferences and knowledge gaps regarding the care of childhood cancer survivors: a mailed survey of pediatric oncologists. J Clin Oncol 28:878-883, 2010. 118 Assistant Professor of Health Studies Dr. Dezheng Huo focuses his research on the genetic and molecular epidemiology of breast cancer with an emphasis on health disparity and global health. He has published extensively on cancer epidemiology and utilizes a population approach to understand the molecular subtypes of breast cancer. The breadth of his research interest is reflected in his multiple research projects, including a validation and fine-mapping study of breast cancer susceptibility loci in women of African ancestry; a two-country case-control study of breast cancer subtypes; reproductive and lifestyle factors that influence breast cancer in African populations; a genome-wide association study of breast cancer in women of African ancestry; a molecular epidemiological study of microRNAs as biomarkers for breast cancer; a systemic study of treatment utilization and health disparity using national databases; and a study of hormone receptor concordance among primary breast cancers. Dr. Huo also conducts research on prostate cancer. For example, he and his colleagues have analyzed data from the National Health Interview Survey to examine PSA screening rates as a function of age, life expectancy, and other factors. Excessive PSA screening was documented in elderly men with limited life expectancies, which may lead to unnecessary anxiety, diagnoses, treatment, and healthcare expenditures without meaningful clinical benefit.3 UCCCC SCIENTIFIC REPORT 2010 – 2011 Recently, Dr. Huo’s group used the Surveillance Epidemiology and End Dezheng Huo, MD, PhD Results (SEER) database to examine the hormone receptor status of 30,617 patients diagnosed with bilateral breast cancers between 1990 and 2007. A strong agreement was found between estrogen receptor status and having two bilateral tumors even in cases separated by 10 years or longer, suggesting that two tumors arise in a common milieu, and tumor subtypes are predetermined in the early stage of breast carcinogenesis.1 Using sequencing technique, Dr. Huo and colleagues showed that germline mutations of the MERIT40 gene are not responsible for the elevated risk of breast cancer associated with this genomic locus, suggesting regulatory variation might be important for common diseases like breast cancer.2 Cancer Prevention and Control DEZHENG HUO, MD, PHD 1 Huo D, Melkonian S, Rathouz P, Khramtsov A, Olopade OI. Concordance in histological and biological parameters between first and second primary breast cancers. Cancer 117:907-915, 2011. 2 Zheng Y, Zhang J, Niu Q, Olopade OI, Huo D. Germline mutational analysis of the C19orf62 gene in African-American women with breast cancer. Breast Cancer Res Treat 127:871-877, 2011. Drazer MW, Huo D, Schonberg MA, Razmaria A, Eggener SE. Population-based patterns and predictors of PSA screening among older men in the United States. J Clin Oncol 29:1736-1743, 2011. 3 119 UCCCC SCIENTIFIC REPORT 2010 – 2011 Cancer Prevention and Control BRANDON PIERCE, PHD Assistant Professor of Health Studies Dr. Pierce is an epidemiologist working in the context of large cohort and case-control studies of cancer. His research focuses on the interrelated roles of genetic, molecular, and environmental factors in cancer risk and prognosis with an emphasis on breast, prostate, and pancreatic cancer. Dr. Pierce’s laboratory uses high-dimensional genomic data, such as genome-wide genotype data and DNA methylation data, to identify cancer risk and prognostic factors and also to elucidate cancer-related biological mechanisms. He is interested in developing and employing innovative methods for identifying cancerassociated genes and gene-environment interactions, and in using genetic data for causal inference in the epidemiological setting. The environmental factors of interest to Dr. Pierce include arsenic and diabetes mellitus. Dr. Pierce’s various research projects are focused on 1) using novel methods to identify cancer susceptibility genes from genome-wide association data; 2) identifying cancer-related methylation features in multiethnic studies Brandon Pierce, PhD of human prostate tissue; 3) developing and implementing “Mendelian randomization” methods to assess the causality of cancer risk factors in epidemiological studies; and 4) assessing the effect of arsenic, a known carcinogen, on genomic features such as telomeres. In recent work, Dr. Pierce used a “pleiotropy scan” approach to identify HNF1A as a pancreatic cancer susceptibility gene.1 A large genome-wide association study of pancreatic cancer was restricted to genetic variants that have been reported to associate with human phenotypes in prior genome-wide association studies. This approach provided enhanced power to detect associations, resulting in the identification of a novel pancreatic cancer susceptibility factor. In another recent study, Dr. Pierce and colleagues discovered that susceptibility to arsenic toxicity varies substantially by the type of diet consumed.2 Using data from a large longitudinal study of arsenic exposure in Bangladesh, they identified three distinct types of diets and found that among individuals with high intakes of gourds and root vegetables, there was a substantially lower risk for developing arsenical skin lesions and a weaker effect of arsenic on skin lesion risk. Such information will have implications for future efforts to prevent arsenic toxicity in Bangladesh. 1 Pierce BL and Ahsan H. Genome-wide “pleiotropy scan” identifies HNF1A region as a novel pancreatic cancer susceptibility locus. Cancer Res 71:4352-4358, 2011. 2 Pierce BL, Argos M, Chen Y, et al. Arsenic exposure, dietary patterns, and skin lesion risk in Bangladesh: A prospective study. Am J Epidemiol 173:345-354, 2011. 120 Cancer Prevention and Control SONIA KUPFER, MD Assistant Professor of Medicine Dr. Sonia Kupfer is a physician scientist in the Section of Gastroenterology with a translational research laboratory as well as a clinical practice. She is in the first year of her NIH K08 career development grant, and her broad area of interest is in colorectal cancer prevention with a specific focus on highrisk populations. Colorectal cancer is one of the three most common causes of cancer and cancer deaths, with African Americans having the highest colorectal cancer incidence and mortality of all U.S. populations. Fortunately, with high-quality screening and removal of pre-cancerous polyps, colorectal cancer is a preventable cancer. One focus of Dr. Kupfer’s clinical practice is in testing and treating individuals with hereditary colorectal cancer syndromes, such as Lynch syndrome and familial adenomatous polyposis (FAP). While genetic testing is available for these patients to help identify those at risk, genetic and environmental factors that put the general population at risk for colorectal cancer are incompletely understood and form the basis of her research program. Sonia Kupfer, MD In a recent study, Dr. Kupfer and her colleagues reported the results of a genome-wide study of genetic variants in colorectal cancer patients.1 They sought to replicate 22 single nucleotide polymorphism associations in a large African American case-control series and found heterogeneity in the results. These findings, which are informing our ongoing fine-mapping studies, suggest that different markers may be associated in a non-European population. A second recent study of vitamin D receptor (VDR) gene polymorphism associations did not show significant associations between VDR genetic variants and colorectal cancer. Preliminary evidence for a possible geneenvironment interaction was found, but requires validation in a larger sample. UCCCC SCIENTIFIC REPORT 2010 – 2011 Dr. Kupfer’s goal is to identify genetic susceptibility factors for colorectal cancer using complementary approaches including genome-wide, candidate gene, and gene expression studies. A large, racially diverse case-control series has been assembled in collaboration with the University of North Carolina and the University of Illinois at Chicago. The first aim is to fine-map colorectal cancer genetic variants discovered using genome-wide association studies. Dr. Kupfer and her collaborators are utilizing next-generation sequencing to identify novel and functional variants in these regions. Her second aim is to investigate genetic and environmental factors in vitamin D metabolism in relation to colorectal cancer. Vitamin D is a protective factor against colorectal cancer and is an excellent candidate for chemoprevention. The third aim of Dr. Kupfer’s laboratory is to perform expression quantitative loci mapping in the healthy and diseased human gastrointestinal tract. 1 Kupfer SS, Anderson JR, Hooker S, Skol A, Kittles RA, Keku TO, Sandler RS, Ellis NA. Genetic heterogeneity in colorectal cancer associations between African and European americans. Gastroenterology 139:1677-1685, 2010. 121 Cancer Prevention and Control STACY TESSLER LINDAU, MD, MAPP Associate Professor of Obstetrics/Gynecology Dr. Stacy Lindau is a population- and clinic-based researcher with expertise in female aging and sexuality at the interface of cancer and other complex illnesses. She has helped pioneer the biosocial survey research field, incorporating cutting-edge, minimally invasive methods for obtaining biological and physiological data in population-based research. She created and directs the National Institute on Aging (NIA)-funded Chicago Core on Biomeasures in Population-Based Aging Research at the Center on Demography and Economics of Aging, a complementary clinical core at The University of Chicago Institute for Translational Medicine, and the Program in Integrative Sexual Medicine (PRISM) for Women and Girls with Cancer. In addition, Dr. Lindau’s laboratory focuses on urban health. She directs the South Side Health and Vitality Studies of the Urban Health Initiative, which focus on how technology assets can be optimized to promote health in low-income urban communities. UCCCC SCIENTIFIC REPORT 2010 – 2011 Stacy Tessler Lindau, MD, MAPP PRISM provides comprehensive clinical care for women seeking treatment and prevention for sexual problems and to recover sexual function following cancer treatment. Since its inception in October 2008, the clinic has seen 117 unique patients, 75 of whom have cancer. Its multidisciplinary design includes collaborations with gynecology oncology, radiation oncology, certified sex therapy, pelvic physical therapy, dermatology and other relevant specialties. A needs assessment carried out by Dr. Lindau and colleagues demonstrated that nearly half of the 261 gynecologic and breast cancer patients surveyed reported sexual concerns, yet only 7% had recently sought medical care for these concerns.1 PRISM’s prospective, longitudinal patient registry tracks the prevalence, evolution, and treatment outcomes in PRISM patients. The registry serves as a foundation for multisite collaboration to accelerate research and improve sexual outcomes for females with cancer. Fifty-six patients have been enrolled. An abstract documenting this unique registry was presented in June 2011 at the Cancer Survivors and Sexual Health Symposium, held by the International Society for Sexual Medicine, in Washington, DC.2 To create an infrastructure to support multisite research, interdisciplinary teams from the UCCCC and Memorial Sloan-Kettering Cancer Center jointly developed the mission for a national conference to convene active clinicians and researchers in the field of cancer and female sexuality. In November 2010, 43 researchers from 20 institutions across 14 states attended the 1st National Conference on Cancer and Female Sexuality in Chicago, IL. Scientific working groups were established to help promote research in this field. An abstract documenting this work was also recently presented at the Cancer Survivors and Sexual Health Symposium in Washington, DC. 1 Hill EK, Sandbo S, Abramsohn E, Makelarski J, Wroblewski K, Wenrich ER, McCoy S, Temkin SM, Yamada SD, Lindau ST. Assessing gynecologic and breast cancer survivors’ sexual health care needs. Cancer 117:2643-2651, 2010. 2 Abramsohn EM, Makelarski J, Baron SL, Florendo J, Githens K, Sandbo S, Sobecki J, Yamada SD, Lindau ST. Foundation for a multi-site registry to accelerate research and improve sexual outcomes for females with cancer. Presented at: Cancer Survivorship and Sexual Health Symposium, Washington DC, 2011. 122 Cancer Prevention and Control DANIEL MCGEHEE, PHD Associate Professor of Anesthesia/Critical Care Dr. Daniel McGehee’s laboratory is investigating the cellular mechanisms underlying nicotine addiction – one of the most common causes of cancer in this country. His work has centered on studying the impact of nicotinic receptor activation on the output of the midbrain dopamine system, which is a central component of the brain’s reward circuitry. Dr. McGehee’s research has shown that in addition to the direct excitation of dopamine neurons that occurs via nicotinic receptor activation, these receptors also activate changes in synaptic drive to these cells. One critically important synaptic change is long-term potentiation (LTP) of the excitatory inputs to midbrain dopamine neurons. Increased dopamine activity is necessary for the rewarding effects of nicotine, and both of these effects are blocked when animals are treated with drugs that inhibit LTP induction. Therefore, his laboratory has focused on understanding the mechanisms that link nicotine exposure to LTP of the excitatory inputs to midbrain dopamine neurons. Daniel McGehee, PhD The co-abuse of ethanol and tobacco products increases the prevalence of abuse of both these drugs. Current investigations are testing the interaction of ethanol with nicotinic receptors in brain reward and motor control circuitry. The results indicate remarkable modifications in nicotinic receptor function that are mediated by changes in the adenylyl cyclase/cAMP/protein kinase A system. The interactions of these two drugs at nicotinic receptors may contribute to the behavioral consequences of co-abuse of nicotine and ethanol. UCCCC SCIENTIFIC REPORT 2010 – 2011 Recently, the McGehee laboratory used an in vitro exposure paradigm to study the effect of nicotine on excitatory synaptic strength. Brief exposure of nicotine to brain slices from drug-naive adult rats followed by a period of recovery resulted in an NMDA glutamate receptor (NMDAR)-dependent increase in the strength of excitatory inputs to midbrain dopamine neurons.1 The induction of synaptic potentiation required direct excitation via nicotinic receptors on dopamine neurons, as well as an enhancement of NMDAR function via D5 dopamine receptors, also on DA neurons. Nicotine-induced increase of presynaptic glutamate release also contributed to the induction of synaptic plasticity. These results identified important receptor systems involved in nicotine-induced long-term changes in excitatory synaptic input to midbrain dopamine neurons. The data also revealed remarkable similarity in the mechanisms underlying synaptic plasticity induced by nicotine and cocaine in the VTA. 1 Mao D, Gallagher K, McGehee DS. Nicotine potentiation of excitatory inputs to ventral tegmental area dopamine neurons. J Neurosci 31:6710-6720, 2011. 123 Cancer Prevention and Control ANDREA KING, PHD Professor of Psychiatry Dr. Andrea King’s research projects include integrated human laboratory and clinical trials research methodology to bear a psychobiological perspective on addiction. The primary goal of her research is to examine the mechanisms of vulnerability to substance use disorders and to identify efficacious behavioral and pharmacological interventions for treatment of addiction, particularly alcohol and nicotine dependence. Dr. King is also involved in research to identify and ultimately reduce health disparities for these disorders among racial/ethnic minorities and women. Human laboratory methodologies have been used to determine acute subjective, objective, and performance effects of alcohol in high- and low-risk drinkers and to examine how alcohol affects smoking urges and behaviors. Clinical and prospective studies in the laboratory are used to study innovative pharmacological and behavioral interventions for alcohol and tobacco use disorders and track changes in substance use patterns over time. UCCCC SCIENTIFIC REPORT 2010 – 2011 Andrea King, PhD Recent work in Dr. King’s laboratory has shown that heavy social “binge” drinkers are more sensitive to positive-like hedonic and motivational effects of alcohol than light drinkers, and that this response pattern is predictive of future alcohol problems.1 These results challenge conventional theories that vulnerability to alcohol use disorders is the result of a low-level response to alcohol. Dr. King’s group has been the first to conduct large-scale rigorous laboratory tests with intensive follow-up scale to shift the paradigm to newer models of addiction propensity.2 They have also identified potentially important protective mechanisms garnering some individuals at low risk for future alcohol problems. Additionally, other recent work in the King laboratory has examined behavioral and neurobiological mechanisms underlying alcohol’s elicitation of smoking urge and behavior. Recent research in the laboratory using functional magnetic resonance imaging (fMRI) has shown that the brain region related to addiction processes (ventral striatum) is activated by alcohol during viewing of salient smoking vs. non-smoking images.3 Current investigations are under way to examine interventions and longer-term course of alcohol and smoking behaviors. 1 King AC, de Wit H, McNamara PJ, Cao D. Rewarding, stimulant and sedative alcohol responses and relationship to future binge drinking. Arch Gen Psychiatry 68:389-399, 2011. 2 King AC, Roche DJO, Rueger SY. Subjective responses to alcohol: A paradigm shift may be brewing. Alcohol Clin Exp Res 35:17261728, 2011. 3 King AC, McNamara PJ, Angstadt M, Phan KL. Neural substrates of alcohol-induced smoking urge in heavy drinking nondaily smokers. Neuropsychopharmacology 35:692-701, 2010. 124 Associate Professor of Medicine Dr. Karen Kim’s research interests are focused on understanding the impact of culturally appropriate and linguistically specific primary and secondary cancer prevention among minority populations with a specific focus on colorectal and hepatitis B-induced liver cancer. Her primary interest is to understand the role of collaborative community partnerships in improving population-level health outcomes by creating sustainable environmental changes in minority community sectors in which health-related behaviors occur. Specifically, Dr. Kim’s research team utilizes a multi-sector approach as a mechanism for information sharing, coordination, and bidirectional evaluation of processes of care models to enhance cancer screening and prevention. Recently, Dr. Kim’s group has been the recipient of a Centers for Disease Control and Prevention conference grant to host a Midwest Viral Hepatitis Conference to address these barriers. Dr. Kim’s research should serve as a framework for healthcare policies that will enhance access and reduce cancer disparities among underserved populations. UCCCC SCIENTIFIC REPORT 2010 – 2011 In collaboration with the non-profit organization, Asian Health Coalition, Dr. Kim developed the Hepatitis Education and Prevention Program as a multi-tiered dissemination model, integrating bilingual community health workers, academic institutions, and public health systems to study the impact Karen E. Kim, MD, MS of interventions on hepatitis B-related outcomes and to serve as a platform for policy and advocacy for underserved Asian Americans. This work has resulted in three interesting observations: 1) the absence of bilingual health systems for monolingual Asians is a significant barrier to care; 2) stigma associated with hepatitis B, especially among Asian immigrants, inhibits adequate integration into care; and 3) the paucity of knowledge about hepatitis B risk stratification among the health system significantly contributes to the early morbidity and mortality from the disease among Asian Americans. Cancer Prevention and Control KAREN E. KIM, MD, MS 125 Selected Publications UCCCC SCIENTIFIC REPORT 2010 – 2011 Cancer Prevention and Control * : Intraprogrammatic Collaboration # : Interprogrammatic Collaboration AHSAN, HABIBUL, MBBS, MMEDSC * Pierce BL, Ahsan H, Vanderweele TJ. Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants. Int J Epidemiol 40:740-52, 2011. PMC3147064 * Argos M, Kalra T, Rathouz PJ, Chen Y, Pierce B, Parvez F, Islam T, Ahmed A, Rakibuz-Zaman M, Hasan R, Sarwar G, Slavkovich V, van Geen A, Graziano J, Ahsan H. Arsenic exposure from drinking water, and all-cause and chronic-disease mortalities in Bangladesh (HEALS): a prospective cohort study. Lancet 376:252-8, 2010. * Pierce BL, Ahsan H. Genetic susceptibility to type 2 diabetes is associated with reduced prostate cancer risk. Hum Hered 69:193-201, 2010. PMC2866577 * Argos M, Kalra T, Pierce BL, Chen Y, Parvez F, Islam T, Ahmed A, Hasan R, Hasan K, Sarwar G, Levy D, Slavkovich V, Graziano JH, Rathouz PJ, Ahsan H. A prospective study of arsenic exposure from drinking water and incidence of skin lesions in Bangladesh. Am J Epidemiol 174:185-94, 2011. * Pierce BL, Ahsan H. Genome-wide “pleiotropy scan” identifies HNF1A region as a novel pancreatic cancer susceptibility locus. Cancer Res 71:4352-8, 2011. PMC3129443 * Pierce BL, Austin MA, Ahsan H. Association study of type 2 diabetes genetic susceptibility variants and risk of pancreatic cancer: an analysis of PanScan-I data. Cancer Causes Control 22:877-83, 2011. * Pierce BL, Argos M, Chen Y, Melkonian S, Parvez F, Islam T, Ahmed A, Hasan R, Rathouz PJ, Ahsan H. Arsenic exposure, dietary patterns, and skin lesion risk in bangladesh: a prospective study. Am J Epidemiol 173:345-54, 2011. PMC3105269 * Melkonian S, Argos M, Pierce BL, Chen Y, Islam T, Ahmed A, Syed EH, Parvez F, Graziano J, Rathouz PJ, Ahsan H. A prospective study of the synergistic effects of arsenic exposure and smoking, sun exposure, fertilizer use, and pesticide 126 use on risk of premalignant skin lesions in Bangladeshi men. Am J Epidemiol 173:183-91, 2011. PMC3011951 BASU, ANIRBAN, PHD * Basu A, Dale W, Elstein A, Meltzer D. A time tradeoff method for eliciting partner’s quality of life due to patient’s health states in prostate cancer. Med Decis Making 30:355-65, 2010. * Meltzer D, Basu A, Conti R. The economics of comparative effectiveness studies: societal and private perspectives and their implications for prioritizing public investments in comparative effectiveness research. Pharmacoeconomics 28:843-53, 2010. * Shah LM, King AC, Basu A, Krishnan JA, Borden WB, Meltzer D, Arora V. Effect of clinician advice and patient preparedness to quit on subsequent quit attempts in hospitalized smokers. J Hosp Med 5:26-32, 2010. Arora VM, Fish M, Basu A, Olson J, Plein C, Suresh K, Sachs G, Meltzer DO. Relationship between quality of care of hospitalized vulnerable elders and postdischarge mortality. J Am Geriatr Soc 58:1642-8, 2010. PMC2946097 gene expression in human colon cancer. PLoS One 6:e16221, 2011. PMC3024403 * # Zhu H, Dougherty U, Robinson V, Mustafi R, Pekow J, Kupfer S, Li YC, Hart J, Goss K, Fichera A, Joseph L, Bissonnette M. EGFR signals downregulate tumor suppressors miR-143 and miR-145 in Western diet-promoted murine colon cancer: Role of G1 regulators. Mol Cancer Res 9:960-75, 2011. Chen CC, Pekow J, Llado V, Kanneganti M, Lau CW, Mizoguchi A, MinoKenudson M, Bissonnette M, Mizoguchi E. Chitinase 3-like-1 expression in colonic epithelial cells as a potentially novel marker for colitis-associated neoplasia. Am J Pathol 179:1494-503, 2011. PMC3157229 Wang HL, Hart J, Fan L, Mustafi R, Bissonnette M. Upregulation of glycogen synthase kinase 3beta in human colorectal adenocarcinomas correlates with accumulation of CTNNB1. Clin Colorectal Cancer 10:30-6, 2011. BISSONNETTE, MARC, MD * Zheng W, Wong KE, Zhang Z, Dougherty U, Mustafi R, Kong J, Deb DK, Zheng H, Bissonnette M, Li YC. Inactivation of the vitamin D receptor in APC(min/+) mice reveals a critical role for the vitamin D receptor in intestinal tumor growth. Int J Cancer 130:10-9, 2012. # Holgren C, Dougherty U, Edwin F, Cerasi D, Taylor I, Fichera A, Joseph L, Bissonnette M, Khare S. Sprouty-2 controls c-Met expression and metastatic potential of colon cancer cells: sprouty/cMet upregulation in human colonic adenocarcinomas. Oncogene 29:5241-53, 2010. PMC2945447 * # Pekow JR, Dougherty U, Mustafi R, Zhu H, Kocherginsky M, Rubin DT, Hanauer SB, Hart J, Chang EB, Fichera A, Joseph LJ, Bissonnette M. miR-143 and miR-145 are downregulated in ulcerative colitis: Putative regulators of inflammation and protooncogenes. Inflamm Bowel Dis, 2011 (Epub ahead of print). # Mustafi D, Fan X, Dougherty U, Bissonnette M, Karczmar GS, Oto A, Hart J, Markiewicz E, Zamora M. High-resolution magnetic resonance colonography and dynamic contrast-enhanced magnetic resonance imaging in a murine model of colitis. Magn Reson Med 63:922-9, 2010. PMC3086519 CHANG, EUGENE, MD * Hu S, Dong TS, Dalal SR, Wu F, Bissonnette M, Kwon JH, Chang EB. The microbe-derived short chain fatty acid butyrate targets miRNA-dependent p21 # Hu S, Wang Y, Lichtenstein L, Tao Y, Musch MW, Jabri B, Antonopoulos D, Claud EC, Chang EB. Regional differences in colonic mucosa-associated microbiota determine the physiological expression of host heat shock proteins. Am J Physiol Gastrointest Liver Physiol 299:G1266-75, 2010. PMC3006241 * # Pekow JR, Dougherty U, Mustafi R, Zhu H, Kocherginsky M, Rubin DT, Hanauer SB, Hart J, Chang EB, Fichera A, Joseph LJ, Bissonnette M. miR-143 and and their implications for prioritizing public investments in comparative effectiveness research. Pharmacoeconomics 28:843-53, 2010. * Hu S, Dong TS, Dalal SR, Wu F, Bissonnette M, Kwon JH, Chang EB. The microbe-derived short chain fatty acid butyrate targets miRNA-dependent p21 gene expression in human colon cancer. PLoS One 6:e16221, 2011. PMC3024403 Conti R, Veenstra DL, Armstrong K, Lesko LJ, Grosse SD. Personalized medicine and genomics: challenges and opportunities in assessing effectiveness, cost-effectiveness, and future research priorities. Med Decis Making 30:328-40, 2010. Iwashita Y, Sakiyama T, Musch MW, Ropeleski MJ, Tsubouchi H, Chang EB. Polyamines mediate glutamine-dependent induction of the intestinal epithelial heat shock response. Am J Physiol Gastrointest Liver Physiol 301:G181-7, 2011. PMC3129932 COX, NANCY, PHD Leung FW, Aljebreen AM, Brocchi E, Chang EB, Liao WC, Mizukami T, Schapiro M, Triantafyllou K. Sedationrisk-free colonoscopy for minimizing the burden of colorectal cancer screening. World J Gastrointest Endosc 2:81-9, 2010. PMC2998881 Grulich AE, Vajdic CM, Falster MO, Kane E, Smedby KE, Bracci PM, de Sanjose S, Becker N, Turner J, MartinezMaza O, Melbye M, Engels EA, Vineis P, Costantini AS, Holly EA, Spinelli JJ, La Vecchia C, Zheng T, Chiu BC, Franceschi S, Cocco P, Maynadie M, Foretova L, Staines A, Brennan P, Davis S, Severson RK, Cerhan JR, Breen EC, Birmann B, Cozen W. Birth order and risk of nonhodgkin lymphoma--true association or bias? Am J Epidemiol 172:621-30, 2010. PMC2950815 # Chiu BC, Kwon S, Evens AM, Surawicz T, Smith SM, Weisenburger DD. Dietary intake of fruit and vegetables and risk of non-Hodgkin lymphoma. Cancer Causes Control 22:1183-95, 2011. Evens AM, Jovanovic BD, Su YC, Raisch DW, Ganger D, Belknap SM, Dai MS, Chiu BC, Fintel B, Cheng Y, Chuang SS, Lee MY, Chen TY, Lin SF, Kuo CY. Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: meta-analysis and examination of FDA safety reports. Ann Oncol 22:117080, 2011. PMC3082161 CONTI, RENA, PHD * Meltzer D, Basu A, Conti R. The economics of comparative effectiveness studies: societal and private perspectives # Wheeler HE, Gorsic LK, Welsh M, Stark AL, Gamazon ER, Cox NJ, Dolan ME. Genome-wide local ancestry approach identifies genes and variants associated with chemotherapeutic susceptibility in African Americans. PLoS One 6:e21920, 2011. PMC3130766 # Innocenti F, Cooper GM, Stanaway IB, Gamazon ER, Smith JD, Mirkov S, Ramirez J, Liu W, Lin YS, Moloney C, Aldred SF, Trinklein ND, Schuetz E, Nickerson DA, Thummel KE, Rieder MJ, Rettie AE, Ratain MJ, Cox NJ, Brown CD. Identification, replication, and functional fine-mapping of expression quantitative trait loci in primary human liver tissue. PLoS Genet 7:e1002078, 2011. PMC3102751 Innocenti F, Cox NJ, Dolan ME. The use of genomic information to optimize cancer chemotherapy. Semin Oncol 38:186-95, 2011. PMC3076508 Gamazon ER, Nicolae DL, Cox NJ. A study of CNVs as trait-associated polymorphisms and as expression quantitative trait loci. PLoS Genet 7:e1001292, 2011. PMC3033384 # Gamazon ER, Zhang W, Konkashbaev A, Duan S, Kistner EO, Nicolae DL, Dolan ME, Cox NJ. SCAN: SNP and copy number annotation. Bioinformatics 26:259-62, 2010. PMC2852202 # Gamazon ER, Huang RS, Cox NJ, Dolan ME. Chemotherapeutic drug susceptibility associated SNPs are enriched in expression quantitative trait loci. PNAS 107:9287-92, 2010. PMC2889115 DALE, WILLIAM, MD, PHD * Dale W, Bilir SP, Hemmerich J, Basu A, Elstein A, Meltzer D. The prevalence, correlates, and impact of logically inconsistent preferences in utility assessments for joint health states in prostate cancer. Med Care 49:59-66, 2011. # Sajid S, Mohile SG, Szmulewitz R, Posadas E, Dale W. Individualized decision-making for older men with prostate cancer: balancing cancer control with treatment consequences across the clinical spectrum. Semin Oncol 38:309-25, 2011. Mohile SG, Fan L, Reeve E, Jean-Pierre P, Mustian K, Peppone L, Janelsins M, Morrow G, Hall W, Dale W. Association of cancer with geriatric syndromes in older Medicare beneficiaries. J Clin Oncol 29:1458-64, 2011. PMC3082984 Dale W. What is the best model for estimating joint health states utilities? Comparing the linear index model to the proportional decrement model. Med Decis Making 30:531-3, 2010. * # Bylow K, Hemmerich J, Mohile SG, Stadler WM, Sajid S, Dale W. Obese frailty, physical performance deficits, and falls in older men with biochemical recurrence of prostate cancer on androgen deprivation therapy: a case-control study. Urology 77:934-40, 2011. PMC3074039 UCCCC SCIENTIFIC REPORT 2010 – 2011 CHIU, BRIAN, PHD # Gamazon ER, Im HK, O’Donnell PH, Ziliak D, Stark AL, Cox NJ, Dolan ME, Huang RS. Comprehensive evaluation of the contribution of X chromosome genes to platinum sensitivity. Mol Cancer Ther 10:472-80, 2011. PMC3079551 # Nicolae DL, Gamazon E, Zhang W, Duan S, Dolan ME, Cox NJ. Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS. PLoS Genet 6:e1000888, 2010. PMC2848547 Cancer Prevention and Control miR-145 are downregulated in ulcerative colitis: Putative regulators of inflammation and protooncogenes. Inflamm Bowel Dis, 2011 (Epub ahead of print). * Basu A, Dale W, Elstein A, Meltzer D. A time tradeoff method for eliciting partner’s quality of life due to patient’s health states in prostate cancer. Med Decis Making 30:355-65, 2010. # Mohile SG, Lacy M, Rodin M, Bylow K, Dale W, Meager MR, Stadler WM. Cognitive effects of androgen deprivation therapy in an older cohort of men with prostate cancer. Crit Rev Oncol Hematol 75:152-9, 2010. PMC3028591 DAS, SOMA, PHD * # Glubb DM, Cerri E, Giese A, Zhang W, Mirza O, Thompson EE, Chen P, Das S, Jassem J, Rzyman W, Lingen MW, Salgia R, Hirsch FR, Dziadziuszko R, Ballmer-Hofer K, Innocenti F. Novel functional germline variants in the VEGF 127 Cancer Prevention and Control UCCCC SCIENTIFIC REPORT 2010 – 2011 receptor 2 gene and their effect on gene expression and microvessel density in lung cancer. Clin Cancer Res 17:5257-5267, 2011. PMC3156871 cocorticoid treatment and cis-regulatory polymorphisms contribute to cellular response phenotypes. PLoS Genet 7:e1002162, 2011. PMC3131293 * # Ziliak D, O’Donnell PH, Im HK, Gamazon ER, Chen P, Delaney S, Shukla S, Das S, Cox NJ, Vokes EE, Cohen EE, Dolan ME, Huang RS. Germline polymorphisms discovered via a cell-based, genome-wide approach predict platinum response in head and neck cancers. Transl Res 157:265-72, 2011. PMC3079878 * Sun C, Southard C, Olopade OI, Di Rienzo A. Differential allelic expression of c.1568C > A at UGT2B15 is due to variation in a novel cis-regulatory element in the 3’UTR. Gene 481:24-8, 2011. PMC3105206 * # Huang RS, Johnatty SE, Gamazon ER, Im HK, Ziliak D, Duan S, Zhang W, Kistner EO, Chen P, Beesley J, Mi S, O’Donnell PH, Fraiman YS, Das S, Cox NJ, Lu Y, Macgregor S, Goode EL, Vierkant RA, Fridley BL, Hogdall E, Kjaer SK, Jensen A, Moysich KB, Grasela M, Odunsi K, Brown R, Paul J, Lambrechts D, Despierre E, Vergote I, Gross J, Karlan BY, Defazio A, Chenevix-Trench G, Dolan ME. Platinum sensitivity-related germline polymorphism discovered via a cell-based approach and analysis of its association with outcome in ovarian cancer patients. Clin Cancer Res 17:5490-5500, 2011. PMC3160494 DE WIT, HARRIET, PHD Wignall ND, de Wit H. Effects of nicotine on attention and inhibitory control in healthy nonsmokers. Exp Clin Psychopharmacol 19:183-91, 2011. Wardle MC, Munafo MR, de Wit H. Effect of social stress during acute nicotine abstinence. Psychopharmacology 218:3948, 2011. PMC3094594 Mahler SV, de Wit H. Cue-reactors: individual differences in cue-induced craving after food or smoking abstinence. PLoS One 5:e15475, 2010. PMC2978100 Childs E, de Wit H. Effects of acute psychosocial stress on cigarette craving and smoking. Nicotine Tob Res 12:449-53, 2010. PMC2847070 Bedi G, Preston KL, Epstein DH, Heishman SJ, Marrone GF, Shaham Y, de Wit H. Incubation of cue-induced cigarette craving during abstinence in human smokers. Biol Psychiatry 69:708-11, 2011. PMC3027849 DI RIENZO, ANNA, PHD Maranville JC, Luca F, Richards AL, Wen X, Witonsky DB, Baxter S, Stephens M, Di Rienzo A. Interactions between glu- 128 * Sun C, Huo D, Southard C, Nemesure B, Hennis A, Cristina Leske M, Wu SY, Witonsky DB, Olopade OI, Di Rienzo A. A signature of balancing selection in the region upstream to the human UGT2B4 gene and implications for breast cancer risk. Hum Genet 130:767-75, 2011. # Sucheston L, Witonsky DB, Hastings D, Yildiz O, Clark VJ, Di Rienzo A, Onel K. Natural selection and functional genetic variation in the p53 pathway. Hum Mol Genet 20:1502-8, 2011. PMC3063984 * Sun C, Southard C, Huo D, Hernandez RD, Witonsky DB, Olopade OI, Di Rienzo A. SNP discovery, expression and cis-regulatory variation in the UGT2B genes. Pharmacogenomics J, 2011 (Epub ahead of print). * Sun C, Olopade OI, Di Rienzo A. rs2981582 is associated with FGFR2 expression in normal breast. Cancer Genet Cytogenet 197:193-4, 2010. PMC2831800 * Sun C, Southard C, Witonsky DB, Olopade OI, Di Rienzo A. Allelic imbalance (AI) identifies novel tissuespecific cis-regulatory variation for human UGT2B15. Hum Mutat 31:99-107, 2010. PMC2922057 DIGNAM, JAMES, PHD * # Cohen EE, Haraf DJ, Kunnavakkam R, Stenson KM, Blair EA, Brockstein B, Lester EP, Salama JK, Dekker A, Williams R, Witt ME, Grushko TA, Dignam JJ, Lingen MW, Olopade OI, Vokes EE. Epidermal growth factor receptor inhibitor gefitinib added to chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol 28:3336-43, 2010. PMC2903330 Zamboni BA, Yothers G, Choi M, Fuller CD, Dignam JJ, Raich PC, Thomas CR Jr, O’Connell MJ, Wolmark N, Wang SJ. Conditional survival and the choice of conditioning set for patients with colon cancer: an analysis of NSABP trials C-03 through C-07. J Clin Oncol 28:2544-8, 2010. PMC2881729 Huang L, Johnson KA, Mariotto AB, Dignam JJ, Feuer EJ. Population-based survival-cure analysis of ER-negative breast cancer. Breast Cancer Res Treat 123:257-64, 2010. Dookeran KA, Dignam JJ, Ferrer K, Sekosan M, McCaskill-Stevens W, Gehlert S. p53 as a marker of prognosis in AfricanAmerican women with breast cancer. Ann Surg Oncol 17:1398-405, 2010. * # Mell LK, Dignam JJ, Salama JK, Cohen EE, Polite BN, Dandekar V, Bhate AD, Witt ME, Haraf DJ, Mittal BB, Vokes EE, Weichselbaum RR. Predictors of competing mortality in advanced head and neck cancer. J Clin Oncol 28:15-20, 2010. Wapnir IL, Dignam JJ, Fisher B, Mamounas EP, Anderson SJ, Julian TB, Land SR, Margolese RG, Swain SM, Costantino JP, Wolmark N. Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS. J Natl Cancer Inst 103:478-88, 2011. PMC3107729 Chung CH, Dignam JJ, Hammond ME, Klimowicz AC, Petrillo SK, Magliocco A, Jordan R, Trotti A, Spencer S, Cooper JS, Le QT, Ang KK. Glioma-associated oncogene family zinc finger 1 expression and metastasis in patients with head and neck squamous cell carcinoma treated with radiation therapy (RTOG 9003). J Clin Oncol 29:1326-34, 2011. PMC3084000 Bae K, Bruner DW, Baek S, Movsas B, Corn BW, Dignam JJ. Patterns of missing mini mental status exam (MMSE) in radiation therapy oncology group (RTOG) brain cancer trials. J Neurooncol, 2011 (Epub ahead of print). GRDINA, DAVID, PHD, MBA Fu P, Murley JS, Grdina DJ, Birukova AA, Birukov KG. Induction of cellular antioxidant defense by amifostine improves ventilator-induced lung injury. Crit Care Med, 2011 (Epub ahead of print). Murley JS, Kataoka Y, Miller RC, Li JJ, Woloschak G, Grdina DJ. SOD2-mediated effects induced by WR1065 and low-dose ionizing radiation on micronucleus formation in RKO human colon carcinoma cells. Radiat Res 175:57-65, 2011. HENDERSON, TARA, MD, MPH GREEN, WILLIAM, PHD Henderson TO, Friedman DL, Meadows AT. Childhood cancer survivors: transition to adult-focused risk-based care. Pediatrics 126:129-36, 2010. Alexander JK, Sagher D, Krivoshein AV, Criado M, Jefford G, Green WN. Ric-3 promotes alpha7 nicotinic receptor assembly and trafficking through the ER subcompartment of dendrites. J Neurosci 30:10112-26, 2010. PMC2945888 Alexander JK, Govind AP, Drisdel RC, Blanton MP, Vallejo Y, Lam TT, Green WN. Palmitoylation of nicotinic acetylcholine receptors. J Mol Neurosci 40:12-20, 2010. HASAN, YASMIN, MD Hasan Y, Kim L, Wloch J, Chi Y, Liang J, Martinez A, Yan D, Vicini F. Comparison of planned versus actual dose delivered for external beam accelerated partial breast irradiation using cone-beam CT and deformable registration. Int J Radiat Oncol Biol Phys 80:1473-6, 2011. Hasan Y, Schoenherr D, Martinez AA, Wilson GD, Marples B. Prostate-specific natural health products (dietary supplements) radiosensitize normal prostate cells. Int J Radiat Oncol Biol Phys 76:896-904, 2010. HEMMERICH, JOSHUA, PHD * # Bylow K, Hemmerich J, Mohile SG, Stadler WM, Sajid S, Dale W. Obese frailty, physical performance deficits, and falls in older men with biochemical recurrence of prostate cancer on androgen deprivation therapy: a case-control study. Urology 77:934-40, 2011. PMC3074039 * Dale W, Bilir SP, Hemmerich J, Basu A, Elstein A, Meltzer D. The prevalence, correlates, and impact of logically inconsistent preferences in utility assessments for joint health states in prostate cancer. Med Care 49:59-66, 2011. Smith SM, Ford JS, Rakowski W, Moskowitz CS, Diller L, Hudson MM, Mertens AC, Stanton AL, Henderson TO, Leisenring WM, Robison LL, Oeffinger KC. Inconsistent mammography perceptions and practices among women at risk of breast cancer following a pediatric malignancy: a report from the Childhood Cancer Survivor Study. Cancer Causes Control 21:1585-95, 2010. PMC2941535 Frazier AL, Shamberger RC, Henderson TO, Diller L. Decision analysis to compare treatment strategies for Stage I/ favorable histology Wilms tumor. Pediatr Blood Cancer 54:879-84, 2010. Henderson TO, Hlubocky FJ, Wroblewski KE, Diller L, Daugherty CK. Physician preferences and knowledge gaps regarding the care of childhood cancer survivors: a mailed survey of pediatric oncologists. J Clin Oncol 28:878-83, 2010. PMC3040043 # Henderson TO, Bhatia S, Pinto N, London WB, McGrady P, Crotty C, Sun CL, Cohn SL. Racial and ethnic disparities in risk and survival in children with neuroblastoma: a Children’s Oncology Group study. J Clin Oncol 29:76-82, 2011. PMC3055862 Nathan PC, Ness KK, Mahoney MC, Li Z, Hudson MM, Ford JS, Landier W, Stovall M, Armstrong GT, Henderson TO, Robison LL, Oeffinger KC. Screening and surveillance for second malignant neoplasms in adult survivors of childhood cancer: a report from the childhood cancer survivor study. Ann Intern Med 153:44251, 2010. PMC3084018 HUO, DEZHENG, MD, PHD * Sun C, Huo D, Nemesure B, Hennis A, Cristina Leske M, Wu SY, Niu Q, Olopade OI, Rienzo AD. Lack of association between common UGT2B nonsynonymous SNPs and breast cancer in populations of African ancestry. Int J Cancer, 2011 (Epub ahead of print). Huo D, Melkonian S, Rathouz PJ, Khramtsov A, Olopade OI. Concordance in histological and biological parameters between first and second primary breast cancers. Cancer 117:907-15, 2011. PMC3022996 * Sun C, Huo D, Southard C, Nemesure B, Hennis A, Cristina Leske M, Wu SY, Witonsky DB, Olopade OI, Di Rienzo A. A signature of balancing selection in the region upstream to the human UGT2B4 gene and implications for breast cancer risk. Hum Genet, 2011 (Epub ahead of print). # Drazer MW, Huo D, Schonberg MA, Razmaria A, Eggener SE. Population-based patterns and predictors of prostate-specific antigen screening among older men in the United States. J Clin Oncol 29:1736-43, 2011. * Zheng Y, Zhang J, Niu Q, Olopade OI, Huo D. Germline mutational analysis of the C19orf62 gene in African-American women with breast cancer. Breast Cancer Res Treat 127:871-7, 2011. * Xu J, Huo D, Chen Y, Nwachukwu C, Collins C, Rowell J, Slamon DJ, Olopade OI. CpG island methylation affects accessibility of the proximal BRCA1 promoter to transcription factors. Breast Cancer Res Treat 120:593-601, 2010. * Ogundiran TO, Huo D, Adenipekun A, Campbell O, Oyesegun R, Akang E, Adebamowo C, Olopade OI. Case-control study of body size and breast cancer risk in Nigerian women. Am J Epidemiol 172:682-90, 2010. PMC2950817 * Huo D, Olopade OI. Interpretation of genome-wide association study results. Oncology (Williston Park) 24:643, 646, 2010. UCCCC SCIENTIFIC REPORT 2010 – 2011 Hasselle MD, Rose BS, Kochanski JD, Nath SK, Bafana R, Yashar CM, Hasan Y, Roeske JC, Mundt AJ, Mell LK. Clinical outcomes of intensity-modulated pelvic radiation therapy for carcinoma of the cervix. Int J Radiat Oncol Biol Phys 80:1436-45, 2011. McCullough L, Ng A, Najita J, Janov A, Henderson T, Mauch P, Diller L. Breastfeeding in survivors of Hodgkin lymphoma treated with chest radiotherapy. Cancer 116:4866-71, 2010. Cancer Prevention and Control Dziegielewski J, Goetz W, Murley JS, Grdina DJ, Morgan WF, Baulch JE. Amifostine metabolite WR-1065 disrupts homologous recombination in mammalian cells. Radiat Res 173:175-83, 2010. PMC2831807 JASKOWIAK, NORA, MD # Shimauchi A, Jansen SA, Abe H, Jaskowiak N, Schmidt RA, Newstead GM. Breast cancers not detected at MRI: review of false-negative lesions. AJR Am J Roentgenol 194:1674-9, 2010. Williams RT, Yao K, Stewart AK, Winchester DJ, Turk M, Gorchow A, Jaskowiak N, Winchester DP. Needle versus excisional biopsy for noninvasive and invasive breast cancer: Report from the National Cancer Data Base, 20032008. Ann Surg Oncol, 2011 (Epub ahead of print). 129 Cancer Prevention and Control KIM, KAREN E., MD, MS Vela MB, Kim KE, Tang H, Chin MH. Improving underrepresented minority medical student recruitment with health disparities curriculum. J Gen Intern Med 25 Suppl 2:S82-5, 2010. PMC2847120 KING, ANDREA, PHD King A, McNamara P, Angstadt M, Phan KL. Neural substrates of alcohol-induced smoking urge in heavy drinking nondaily smokers. Neuropsychopharmacology 35:692-701, 2010. PMC2868310 Roche DJ, Childs E, Epstein AM, King AC. Acute HPA axis response to naltrexone differs in female vs. male smokers. Psychoneuroendocrinology 35:596-606, 2010. PMC2843791 UCCCC SCIENTIFIC REPORT 2010 – 2011 Sanchez-Johnsen LA, Carpentier MR, King AC. Race and sex associations to weight concerns among urban African American and Caucasian smokers. Addict Behav 36:14-7, 2011. Roche DJ, King AC. Alcohol impairment of saccadic and smooth pursuit eye movements: impact of risk factors for alcohol dependence. Psychopharmacology (Berl) 212:33-44, 2010. * Shah LM, King AC, Basu A, Krishnan JA, Borden WB, Meltzer D, Arora V. Effect of clinician advice and patient preparedness to quit on subsequent quit attempts in hospitalized smokers. J Hosp Med 5:26-32, 2010. King AC, Cao D, Southard CC, Matthews A. Racial differences in eligibility and enrollment in a smoking cessation clinical trial. Health Psychol 30:40-8, 2011. PMC3057492 King AC, de Wit H, McNamara PJ, Cao D. Rewarding, stimulant, and sedative alcohol responses and relationship to future binge drinking. Arch Gen Psychiatry 68:389-99, 2011. KUPFER, SONIA, MD # DePaolo RW, Abadie V, Tang F, FehlnerPeach H, Hall JA, Wang W, Marietta EV, Kasarda DD, Waldmann TA, Murray JA, Semrad C, Kupfer SS, Belkaid Y, Guandalini S, Jabri B. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature 471:220-4, 2011. PMC3076739 * Khan O, Blanco A, Conrad P, Gulden C, Moss TZ, Olopade OI, Kupfer SS, Terdiman J. Performance of Lynch syndrome predictive models in a multicenter US referral population. Am J Gastroenterol 106:1822-7, 2011. 130 Kupfer SS, Anderson JR, Hooker S, Skol A, Kittles RA, Keku TO, Sandler RS, Ellis NA. Genetic heterogeneity in colorectal cancer associations between African and European americans. Gastroenterology 139:1677-85, 1685.e1-8, 2010. LI, YAN CHUN, PHD Zhang Y, Kong J, Deb DK, Chang A, Li YC. 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LINDAU, STACY TESSLER, MD, MAPP Lindau ST, Surawska H, Paice J, Baron SR. Communication about sexuality and intimacy in couples affected by lung cancer and their clinical-care providers. Psychooncology 20:179-85, 2011. Lindau ST, Gavrilova N. Sex, health, and years of sexually active life gained due to good health: evidence from two US population based cross sectional surveys of ageing. BMJ 340:c810, 2010. PMC2835854 # Hill EK, Sandbo S, Abramsohn E, Makelarski J, Wroblewski K, Wenrich ER, McCoy S, Temkin SM, Yamada SD, Lindau ST. Assessing gynecologic and breast cancer survivors’ sexual health care needs. Cancer 117:2643-51, 2011. Schneider J, Makelarski JA, Van Haitsma M, Lipton RB, Abramsohn E, Lauderdale DS, Lindau ST. Differential access to digital communication technology: association with health and health survey recruitment within an African-American underserviced urban population. J Urban Health 88:47992, 2011. PMC3126929 Lindau ST, Makelarski JA, Chin MH, Desautels S, Johnson D, Johnson WE Jr, Miller D, Peters S, Robinson C, Schneider J, Thicklin F, Watson NP, Wolfe M, Whitaker E. Building community-engaged health research and discovery infrastructure on the South Side of Chicago: science in service to community priorities. Prev Med 52:200-7, 2011. PMC3062697 # Hill EK, Sandbo S, Abramsohn E, Makelarski J, Wroblewski K, Wenrich ER, McCoy S, Temkin SM, Yamada SD, Lindau ST. Assessing gynecologic and breast cancer survivors’ sexual health care needs. Cancer, 117:2643-51, 2011. MASI, CHRISTOPHER, MD, PHD Masi CM, Hawkley LC, Cacioppo JT. Serum 2-methoxyestradiol, an estrogen metabolite, is positively associated with serum HDL-C in a population-based sample. Lipids, 2011 (Epub ahead of print). Patel S, Hawkley LC, Cacioppo JT, Masi CM. Dietary fiber and serum 16alpha-hydroxyestrone, an estrogen metabolite associated with lower systolic blood pressure. Nutrition 27:778-81, 2011. PMC3116971 MCCLINTOCK, MARTHA, PHD * # Gehlert S, Murray A, Sohmer D, McClintock M, Conzen S, Olopade O. The importance of transdisciplinary collaborations for understanding and resolving health disparities. Soc Work Public Health 25:408-22, 2010. Vilhauer RP, McClintock MK, Matthews AK. Online support groups for women with metastatic breast cancer: a feasibility pilot study. J Psychosoc Oncol 28:560-86, 2010. MCGEHEE, DANIEL, PHD * Chang B, Daniele CA, Gallagher K, Madonia M, Mitchum RD, Barrett L, Vezina P, McGehee DS. Nicotinic excitation of serotonergic projections from dorsal raphe to the nucleus accumbens. J Neurophysiol 106:801-8, 2011. PMC3154831 Mao D, Gallagher K, McGehee DS. Nicotine potentiation of excitatory inputs to ventral tegmental area dopamine neurons. J Neurosci 31:6710-20, 2011. PMC3118498 MELTZER, DAVID, MD, PHD Meltzer D. Cost-effectiveness analysis in oncology. Clin Adv Hematol Oncol 8:589-90, 2010. * Dale W, Bilir SP, Hemmerich J, Basu A, Elstein A, Meltzer D. 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MENDONCA, ENEIDA, MD, PHD # Surati M, Robinson M, Nandi S, Faoro L, Demchuk C, Rolle CE, Kanteti R, Ferguson BD, Hasina R, Gangadhar TC, Salama AK, Arif Q, Kirchner C, Mendonca E, Campbell N, Limvorasak S, Villaflor V, Hensing TA, Krausz T, Vokes EE, Husain AN, Ferguson MK, Karrison TG, Salgia R. Proteomic characterization of non-small cell lung cancer in a comprehensive translational thoracic oncology database. J Clin Bioinforma 1:1-11, 2011. * Ogundiran TO, Huo D, Adenipekun A, Campbell O, Oyesegun R, Akang E, Adebamowo C, Olopade OI. Case-control study of body size and breast cancer risk in Nigerian women. Am J Epidemiol 172:682-90, 2010. PMC2950817 * # Cohen EE, Haraf DJ, Kunnavakkam R, Stenson KM, Blair EA, Brockstein B, Lester EP, Salama JK, Dekker A, Williams R, Witt ME, Grushko TA, Dignam JJ, Lingen MW, Olopade OI, Vokes EE. Epidermal growth factor receptor inhibitor gefitinib added to chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol 28:3336-43, 2010. PMC2903330 * Sun C, Huo D, Southard C, Nemesure B, Hennis A, Cristina Leske M, Wu SY, Witonsky DB, Olopade OI, Di Rienzo A. A signature of balancing selection in the region upstream to the human UGT2B4 gene and implications for breast cancer risk. Hum Genet 130:767-75, 2011. * Zheng Y, Zhang J, Niu Q, Olopade OI, Huo D. Germline mutational analysis of the C19orf62 gene in African-American women with breast cancer. Breast Cancer Res Treat 127:871-7, 2011. * Sun C, Huo D, Nemesure B, Hennis A, Cristina Leske M, Wu SY, Niu Q, Olopade OI, Rienzo AD. Lack of association between common UGT2B nonsynonymous SNPs and breast cancer in populations of African ancestry. Int J Cancer 2011 (Epub ahead of print). # Best T, Li D, Skol AD, Kirchhoff T, Jackson SA, Yasui Y, Bhatia S, Strong LC, Domchek SM, Nathanson KL, Olopade OI, Huang RS, Mack TM, Conti DV, Offit K, Cozen W, Robison LL, Onel K. Variants at 6q21 implicate PRDM1 in the etiology of therapy-induced second malignancies after Hodgkin’s lymphoma. Nat Med 17:941-3, 2011. * Campbell MJ, Tonlaar NY, Garwood ER, Huo D, Moore DH, Khramtsov AI, Au A, Baehner F, Chen Y, Malaka DO, Lin A, Adeyanju OO, Li S, Gong C, McGrath M, Olopade OI, Esserman LJ. Proliferating macrophages associated with high grade, hormone receptor negative breast cancer and poor clinical outcome. Breast Cancer Res Treat 128:703-11, 2011. El Dinali M, Hasina R, Bragelmann J, Seiwert T, Sanicola M, Henderson L, Grushko TA, Olopade O, Karrison T, Bang YJ, Kim WH, Tretiakova M, Vokes E, Frank DA, Kindler HL, Huet H, Salgia R. RON (MST1R) is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma. Cancer Biol Ther 12:9-46, 2011. PMC3149873 PIERCE, BRANDON, PHD * Pierce BL, Austin MA, Ahsan H. Association study of type 2 diabetes genetic susceptibility variants and risk of pancreatic cancer: an analysis of PanScan-I data. Cancer Causes Control 22:877-83, 2011. * Argos M, Kalra T, Pierce BL, Chen Y, Parvez F, Islam T, Ahmed A, Hasan R, Hasan K, Sarwar G, Levy D, Slavkovich V, Graziano JH, Rathouz PJ, Ahsan H. A prospective study of arsenic exposure from drinking water and incidence of skin lesions in Bangladesh. Am J Epidemiol 174:185-94, 2011. * Pierce BL, Ahsan H. Genome-wide “pleiotropy scan” identifies HNF1A region as a novel pancreatic cancer susceptibility locus. Cancer Res 71:4352-8, 2011. PMC3129443 * Pierce BL, Argos M, Chen Y, Melkonian S, Parvez F, Islam T, Ahmed A, Hasan R, Rathouz PJ, Ahsan H. Arsenic exposure, dietary patterns, and skin lesion risk in bangladesh: a prospective study. Am J Epidemiol 173:345-54, 2011. PMC3105269 * Melkonian S, Argos M, Pierce BL, Chen Y, Islam T, Ahmed A, Syed EH, Parvez F, Graziano J, Rathouz PJ, Ahsan H. A prospective study of the synergistic effects of arsenic exposure and smoking, sun exposure, fertilizer use, and pesticide use on risk of premalignant skin lesions in Bangladeshi men. Am J Epidemiol 173:183-91, 2011. PMC3011951 UCCCC SCIENTIFIC REPORT 2010 – 2011 * Shah LM, King AC, Basu A, Krishnan JA, Borden WB, Meltzer D, Arora V. Effect of clinician advice and patient preparedness to quit on subsequent quit attempts in hospitalized smokers. J Hosp Med 5:26-32, 2010. OLOPADE, OLUFUNMILAYO, MBBS Cancer Prevention and Control Meltzer DO, Hoomans T, Chung JW, Basu A. Minimal modeling approaches to value of information analysis for health research. Med Decis Making 31:E1-22, 2011. * Argos M, Kalra T, Rathouz PJ, Chen Y, Pierce B, Parvez F, Islam T, Ahmed A, Rakibuz-Zaman M, Hasan R, Sarwar G, Slavkovich V, van Geen A, Graziano J, Ahsan H. Arsenic exposure from drinking water, and all-cause and chronic-disease mortalities in Bangladesh (HEALS): a prospective cohort study. Lancet 376:252-8, 2010. # Catenacci DV, Cervantes G, Yala S, Nelson EA, El-Hashani E, Kanteti R, 131 Cancer Prevention and Control UCCCC SCIENTIFIC REPORT 2010 – 2011 * Pierce BL, Ahsan H, Vanderweele TJ. Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants. Int J Epidemiol 40:740-52, 2011. PMC3147064 * Pierce BL, Ahsan H. Genetic susceptibility to type 2 diabetes is associated with reduced prostate cancer risk. Hum Hered 69:193-201, 2010. PMC2866577 POLITE, BLASE, MD, MPH # Sharma MR, Wroblewski, MPH K, Polite BN, Knost JA, Wallace JA, Modi S, Sleckman BG, Taber D, Vokes EE, Stadler WM, Kindler HL. Dasatinib in previously treated metastatic colorectal cancer: a phase II trial of the University of Chicago Phase II Consortium. Invest New Drugs, 2011 (Epub ahead of print). Moy B, Polite BN, Halpern MT, Stranne SK, Winer EP, Wollins DS, Newman LA. 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Clin Colorectal Cancer 9:290-6, 2010. # Mell LK, Jeong JH, Nichols MA, Polite BN, Weichselbaum RR, Chmura SJ. Predictors of competing mortality in early breast cancer. Cancer 116:5365-73, 2010. * # Mell LK, Dignam JJ, Salama JK, Cohen EE, Polite BN, Dandekar V, Bhate 132 AD, Witt ME, Haraf DJ, Mittal BB, Vokes EE, Weichselbaum RR. Predictors of competing mortality in advanced head and neck cancer. J Clin Oncol 28:15-20, 2010. scope (with videos). Gastrointest Endosc 72:1052-6, 2010. ROMERO, IRIS, MD Konda VJ, Chennat JS, Hart J, Waxman I. Confocal laser endomicroscopy: potential in the management of Barrett’s esophagus. Dis Esophagus 23:E21-31, 2010. # Chen L, Park SM, Tumanov AV, Hau A, Sawada K, Feig C, Turner JR, Fu YX, Romero IL, Lengyel E, Peter ME. CD95 promotes tumour growth. Nature 465:492-6, 2010. PMC2879093 Chennat J, Waxman I. Initial performance profile of a new 6F self-expanding metal stent for palliation of malignant hilar biliary obstruction. Gastrointest Endosc 72:632-6, 2010. # Zillhardt M, Park SM, Romero IL, Sawada K, Montag A, Krausz T, Yamada SD, Peter ME, Lengyel E. Foretinib (GSK1363089), an orally available multikinase inhibitor of c-Met and VEGFR-2, blocks proliferation, induces anoikis, and impairs ovarian cancer metastasis. Clin Cancer Res 17:4042-51, 2011. Kahi CJ, Anderson JC, Waxman I, Kessler WR, Imperiale TF, Li X, Rex DK. High-definition chromocolonoscopy vs. high-definition white light colonoscopy for average-risk colorectal cancer screening. Am J Gastroenterol 105:1301-7, 2010. RUBIN, DAVID, MD * # Pekow JR, Dougherty U, Mustafi R, Zhu H, Kocherginsky M, Rubin DT, Hanauer SB, Hart J, Chang EB, Fichera A, Joseph LJ, Bissonnette M. miR-143 and miR-145 are downregulated in ulcerative colitis: Putative regulators of inflammation and protooncogenes. Inflamm Bowel Dis, 2011 (Epub ahead of print). * # Pekow JR, Hetzel JT, Rothe JA, Hanauer SB, Turner JR, Hart J, Noffsinger A, Huo D, Rubin DT. 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Selected Major Grants and Awards INVESTIGATOR TITLE PROJECT START DATE END DATE TOTAL ANNUAL COST CLASS 9/30/2010 7/31/2015 $2,000,000 R01 National Cancer Institute FUNDING AGENCY Chemoprevention of arsenic-induced skin cancer HABIBUL AHSAN A genome-wide investigation of autozygosity and breast cancer risk 7/1/2010 7/31/2012 $156,000 N/A Department of Defense MARC BISSONNETTE EGFR-VDR signals in diet promoted inflammation and cancer 3/1/2010 2/29/2012 $197,473 R21 National Cancer Institute EUGENE CHANG IBD and mucosal inflammation, immunology, and microbiology of the GI tract 2/25/2011 11/30/2015 $1,100,000 P30 National Institutes of Health EUGENE CHANG The role of enteric microbiota in mediating the bioavailability and actions of daikenchuto 1/1/2011 12/31/2011 $268,689 N/A TSUMURA USA INC. NANCY COX Rare variants and complex human phenotypes 7/1/2010 3/31/2012 $448,329 U01 National Institutes of Health NANCY COX Using the transcriptome for SNP and gene annotation 9/17/2010 7/31/2012 $321,012 R01 National Institute on Mental Health WILLIAM DALE Utility-assessment for co-morbidities in prostate cancer 7/2/2010 7/1/2011 $168,861 R21 National Cancer Institute WILLIAM DALE John A. Hartford Foundation's Center of Excellence National Program Award 7/1/2011 6/30/2012 $120,000 N/A American Federation for Aging Research WILLIAM GREEN The neuronal alpha-bungarotoxin binding site 8/1/2010 7/31/2011 $342,309 R01 National Institute of Neurological Disorders and Stroke SONIA KUPFER Genetic association studies in African American colorectal cancer patients 9/17/2010 8/31/2015 $164,376 K08 National Cancer Institute DAVID MELTZER UC/UIC Comparative Effectiveness Research Institutional Career Development Award 9/30/2010 9/29/2013 $811,907 KM1 National Cancer Institute OLUFUNMILAYO OLOPADE Developing a global oncology workforce for the 21st century 8/12/2010 7/31/2015 $571,564 K12 National Institutes of Health OLUFUNMILAYO OLOPADE Genome-wide association study of breast cancer in the African Diaspora 8/1/2010 7/31/2013 $419,055 R01 National Cancer Institute OLUFUNMILAYO OLOPADE Developing an infrastructure to conduct clinical breast cancer trials in resource poor nations such as Nigeria 10/1/2010 9/30/2011 $223,000 N/A Breast Cancer Research Foundation OLUFUNMILAYO OLOPADE Targeting the Fanconi anemia-BRCA1 pathway to breast cancer 10/1/2010 9/30/2011 $223,000 N/A Breast Cancer Research Foundation UCCCC SCIENTIFIC REPORT 2010 – 2011 HABIBUL AHSAN Cancer Prevention and Control The Cancer Prevention and Control Program has a funding base of $17,748,186 in annual total costs (current as of July 2011). This sum includes $6,541,103 in NCI funding and $8,113,974 in other NIH funding. Due to space constraints, only selected new awards since January 1, 2010 of $100,000 or greater in annual total costs are listed here. 133 CLINICAL TRIALS 134 HE UCCCC HAS SUSTAINED A VIGOROUS CLINICAL research program for many years, and has long been recognized for its strength in basic and clinical research. Most recently, these activities have been expanded to population research including epidemiology and prevention trials. The tight and dynamic linkages connecting our basic scientists with our enhanced team of translational and clinical researchers have led to major contributions in early phase clinical trials and drug development. The integration of population researchers is taking these trials to the population and community level. Clinical Trials T UCCCC therapeutic clinical trials are conceived and conducted by multidisciplinary teams, which comprise a group of clinical investigators representing Medical Oncology, Radiation Oncology, Radiology, Pathology, Biostatistics, and appropriate surgical specialties. All of our research programs conduct clinical research. These clinical efforts focus on studies of new drugs with clinical and translational endpoints, sequencing of multidisciplinary treatment, transplantation, organ preservation, and treatment intensification as strategies to increase cure rates and response. There is a strong focus on pharmacogenomics and the development of personalized therapeutics. Within the past few years, there has been a remarkable increase in tangible benchmarks, such as multi-investigator, multi-disciplinary grants, as well as investigator-initiated clinical trials. UCCCC SCIENTIFIC REPORT 2010 – 2011 The clinical trials activity of the UCCCC is managed through the Cancer Clinical Trials Office (CCTO). The CCTO provides oversight and quality control for these studies through the provision of policies and procedures, by centralizing regulatory and reporting functions, supervision of staff, auditing, and tracking of these activities with a centralized database. The overall objective of the CCTO is to provide the infrastructure to support successful cancer clinical research across departments within the University, as well as through national coop- The tight and dynamic linkages connecting erative groups. CCTO services and areas of operation can be divided into our basic scientists with our enhanced team four distinct but somewhat overlapof translational and clinical researchers have ping areas: (1) regulatory affairs; (2) affiliate institution coordination and led to major contributions in early phase oversight; (3) protocol tracking and management; and (4) quality control. clinical trials and drug development. Our drug development program is unique in the Chicago metropolitan area and is among the largest in the United States. Patients travel from throughout the world to be evaluated for enrollment in phase I and phase II trials of novel anticancer agents. Annually, close to 2000 patients are enrolled on clinical trials, with 800-1000 entered on therapeutic trials. Clinical trials span the gamut from preclinical development to investigator-initiated phase I clinical trials to phase II trials in the regional phase II network to phase III studies within CALGB. Many trials also incorporate correlative laboratory studies which include genotyping studies, population pharmacology and pharmacogenetics, and measurement of biomarker endpoints. In 2010, clinical trials enrollment included 900 patients to 179 therapeutic protocols; 485 patients were treated on 94 phase II protocols, and 190 patients were treated on 27 phase I studies. 135 Clinical Trials In 2010, regulatory managers in the CCTO opened 116 new protocols (95 therapeutic) and were responsible for ongoing regulatory activities of an additional 325 studies already open to enrollment, as well as the regulatory activities (e.g., IRB continuing renewals, amendments, safety reports) for over 350 studies closed to enrollment but not terminated with the IRB. These trials represent over 50 principal investigators from multiple departments (Medicine, Radiology, Radiation and Cellular Oncology, Surgery, Pediatrics, and Obstetrics and Gynecology). NUMBER OF THERAPEUTIC PROTOCOLS (N=315*) and patient accrual (N=900) by sponsor in 2010 TOTAL NO. TRIALS NO. INVESTIGATOR INITIATED NO. OF PTS ENROLLED (INCLUDING AFFILIATES) INSTITUTIONAL 44 (14%) 26 216 (24%) NCI 42 (13%) 9 315 (35%) COOPERATIVE GROUP 125 (40%) 2 131 (15%) INDUSTRY 104 (33%) 4 238 (26%) 315 41 (13%) 900 STUDY SPONSOR UCCCC SCIENTIFIC REPORT 2010 – 2011 TOTAL 136 *Note that of the 315 trials open to accrual in 2010, approximately 13% were investigator-initiated. In addition, close to 60% of our accrual to therapeutic protocols is to NCI and institutional studies. The UCCCC and CCTO have been instrumental in the success of several major grants and contracts including the Phase I Clinical Trials of Anticancer Agents; the Phase II Contract (N01), Early Therapeutics Development with Phase II Emphasis; the CALGB grant, The Chicago Prostate Cancer Association (CPCa): A Cooperative Effort for Conducting Prostate Cancer Focused Clinical Trials; and the SPORE in Prostate Cancer (in collaboration with the Lurie Comprehensive Cancer Center at Northwestern University). Through association with our Phase II N01, we were instrumental in receiving an award for a metastatic pancreatic cancer trial funded under the American Recovery and Reinvestment Act of 2009 (ARRA, Public Law 111-5). The Phase II program is one of our larger programs and continues to enroll approximately 200 patients annually. In our N01 Competing Renewal awarded in 2011, we will be further expanding the network to include the Lurie Comprehensive Cancer Center and Indiana University. The CCTO supports clinical trials activity associated with all UCCCC research programs. RESOURCES AND SERVICES Shared Resources Shared Resources The UCCCC supports 13 core facilities, which serve as centralized centers of expertise and provide researchers access to a comprehensive set of cutting-edge technical resources. These facilities are funded in large part by the UCCCC and include the Biostatistics Core Facility, Cancer Clinical Trials Office, Epidemiology and Research Recruitment Core, Frank W. Fitch Monoclonal Antibody Facility, Flow Cytometry Facility, Genomics Core Facility, Human Integrated Microscopy Facility, Magnetic Resonance Imaging and Spectroscopy Facility, Pharmacology Core Facility, Scientific Image Reconstruction and Analysis Facility, and Transgenic Mouse and Embryonic Stem Cell Facility. Biostatistics Core Facility The Biostatistics Core Facility provides collaborative statistical support to investigators for the design, conduct, and analysis of clinical trials, observational, and population-based studies, and basic science research projects. The Facility assists in experimental design, analyses of data, manuscript and grant preparation, review of clinical protocols, and training investigators in fundamental statistical concepts, study design, and clinical trials methodology. Director: Ronald Thisted, PhD. Website: http://health.bsd.uchicago.edu/Biostatistics-Laboratory. UCCCC SCIENTIFIC REPORT 2010 – 2011 Immunologic Monitoring Core, Human Tissue Resource Center, Cancer Clinical Trials Office (CCTO) The CCTO provides oversight and quality control for clinical trials activity at the UCCCC by centralizing regulatory and reporting functions. The overall objective of the CCTO is to provide the infrastructure to support successful clinical research across departments. The CCTO facilitates regulatory management, coordination and oversight of affiliate institutions enrolling patients on trials at the UCCCC, protocol tracking and management, and quality control. Director: Marcy List, PhD. Website: http://cancer.uchicago.edu. Frank W. Fitch Monoclonal Antibody Facility The Frank W. Fitch Monoclonal Antibody Facility provides standard and custom services for comprehensive hybridoma and protein production. Services include novel monoclonal antibody production, protein purification and conjugation, subcloning of hybridoma cell lines, cell storage, and an extensive antibody/hybridoma bank. Director: Anne Sperling, PhD. Website: http://fitchantibodies.bsd.uchicago.edu. 137 Shared Resources Flow Cytometry Facility The Flow Cytometry Facility provides access to state-of-the-art technology and quantitative analytical approaches to measure molecular and cellular function. The Facility is designed to meet the wide-spread needs for specialized cytologic analysis by providing instrumentation for cell sorting and bench-top analysis of subcellular components using multiparametric fluorescence detection technology. Director: Anne Sperling, PhD. Website: http://ucflow.uchicago.edu. Genomics Core Facility UCCCC SCIENTIFIC REPORT 2010 – 2011 The Genomics Core Facility provides state-of-the-art microarray, DNA sequencing, and genotyping platforms with specialized databases for storing, managing, and manipulating both clinical information and diverse types of genetic and genomic data. The Facility offers sophisticated hardware, bioinformatic software applications, and database solutions. Services include next-generation sequencing, high-throughput gene expression and genotyping arrays, DNA preparation and sequencing, protein array profiling, customized RNA/DNA extraction and quantification, and genomic and bioinformatic analyses. Director: Pieter Faber, PhD. Websites: http://fgf.bsd. uchicago.edu, http://cancer-seqbase.uchicago.edu, https://ibi.uchicago.edu. Human Immunologic Monitoring (HIM) Facility The HIM Facility is a specialized laboratory that performs analyses of immunologic endpoints and other pharmacodynamic parameters for cancer-based clinical trials. The Facility assists with project development, evaluates immune response parameters in response to immunotherapeutic interventions, monitors biologic effects of pharmacologic agents using lymphocytes or other hematopoietic cell subsets as a surrogate tissue, and interfaces with the current Good Manufacturing Practice (cGMP) Facility to prepare clinical-grade products, such as cancer vaccines, for administration to patients. Director: Thomas Gajewski, MD, PhD. Website: http://him.bsd.uchicago.edu. Human Tissue Resource Center (HTRC) The HTRC provides investigators with a centralized infrastructure to optimize the efficiency and costs related to research involving human biospecimens. The HTRC comprises three integrated components including the Biospecimen Bank (BSB), Laser Capture Microdissection (LCM), Pathology Image Analysis (PIA), and Immunohistochemistry (IHC). HTRC staff assists with the procurement, processing, distribution, and analysis of human biospecimens. Services include centralized tissue banking, pathological verification of tissue samples, tissue microarray fabrication, laser capture microdissection, histological services, and quantitative image analyses. Director: Mark Lingen, DDS, PhD. Website: http://pathcore.bsd.uchicago.edu. Integrated Microscopy Facility The Integrated Microscopy Facility is a supervised, user-based core that provides imaging capabilities to investigators through microscopy instrumentation, data analysis and storage, and expert training and assistance. The Facility provides high-quality optics and equipment that most labs do not possess, including confocal and state-of-the-art two-photon spectral and STED superresolution spectral microscopes. Available techniques provided by the Facility include classic color histological stain imaging, contrast generation in unstained cells, and fluorescence technologies that allow for applications ranging from localization of multiple targets to readouts of biochemical or physiologic parameters in either fixed or living preparations. Director: Benjamin Glick, PhD. Website: http://digital.uchicago.edu. 138 The MRIS Facility provides magnetic resonance imaging for studies of both animal models of cancer and clinical research involving human subjects. The Facility delivers very high-resolution anatomic images, images of hemodynamic parameters such as perfusion rate and capillary permeability, and images of tumor oxygenation. The scanners can also provide metabolic measurements with MR spectroscopy and MR spectroscopic imaging. Additional services include molecular imaging, functional MR imaging of the brain, multimodality imaging with microPET/SPECT/ CT and EPR, development and testing of new contrast agents and imaging methods, and veterinary services. Directors: Gregory Karczmar, PhD, and Brian Roman, PhD. Website: http://mris. bsd.uchicago.edu. Shared Resources Magnetic Resonance Imaging and Spectroscopy (MRIS) Facility Pharmacology Core Facility The Pharmacology Core Facility evaluates pharmacokinetic, pharmacodynamic, and pharmacogenetic parameters in support of investigators conducting clinical and preclinical drug development studies. The Facility analyzes drug and metabolite concentrations in biological fluids and develops pharmacological assays of anticancer agents. Director: Mark Ratain, MD. Website: http://pharmacology.bsd.uchicago.edu. The SIRAF provides services for medical imaging, including a high performance computer cluster and direct archival capabilities, in collaboration with the Magnetic Resonance Imaging and Spectroscopy (MRIS) Facility and the University of Chicago’s Optical Imaging Core Facility. SIRAF offers investigators free access to all computers, centralized archiving, and specialized software packages that support image acquisition, construction of databases, reconstruction techniques, image analysis (including computer-aided diagnosis), and technology assessment. The Facility supports basic research involving modeling and simulations, applied research involving the development of new image analysis methods, and the development of grid-based technologies. Director: Robert Nishikawa, PhD. Website: http://siraf-login.bsd.uchicago.edu:8010/siraf-wiki. Transgenic Mouse and Embryonic Stem Cell Facility UCCCC SCIENTIFIC REPORT 2010 – 2011 Scientific Image Reconstruction and Analysis Facility (SIRAF) The Transgenic Mouse and Embryonic Stem Cell Facility produces genetically manipulated mice through transgenic technology or embryonic stem (ES) cell manipulation for investigators. The Facility provides a comprehensive set of technical services, offers gene construction and targeting services, develops and maintains ES cell lines, provides various breeding services, and offers training in Mouse Handling and Breeding. Director: Eric Svensson, MD, PhD. Website: http:// transgenic.bsd.uchicago.edu. Epidemiology and Research Recruitment Core (ERRC) The ERRC assists investigators with study design, surveillance development, recruitment of study participants, and collaborations with the UCCCC’s community outreach program. The ERRC also works with the Human Tissue Resource Center to assist investigators with biological specimen collection for a wide range of hospital- and community-based cancer population studies. Director: Brian Chiu, PhD. Website: http://cancer.uchicago.edu/research/core-facilities/ epidemiology.shtml. 139 Education and Training Education and Training UCCCC members participate in a variety of training and educational opportunities, including graduate and post-graduate training programs offered by departmental committees. These committees span a range of disciplines, including Cancer Biology; Clinical Pharmacology and Pharmacogenomics; Genetics, Genomics & Systems Biology; Immunology; Molecular Biology; Medical Physics; and Molecular Metabolism and Nutrition. Many UCCCC members participate in one or more of these training programs, the majority of which are supported by NIH training grants. Fellowship training programs in surgical oncology, medical oncology, radiation oncology, and pediatric oncology are also offered by the UCCCC SCIENTIFIC REPORT 2010 – 2011 UCCCC. In addition, members participate in a variety of seminar series, joint programmatic meetings, and departmental retreats, which are instrumental in fostering inter- and intraprogrammatic research collaborations. Committee on Cancer Biology The Committee on Cancer Biology offers a multidisciplinary and integrated graduate training program of study leading to a PhD in cancer biology. Directed by Geoffrey Greene, PhD, the Committee is supported by an NCI training grant and has a broad curriculum focusing on several areas of cancer biology, including apoptosis, cancer genetics, cell cycle, chromosome damage/repair, drug resistance, hormone action, metastatic progression, cell signaling, and tumor biology/immunology. The Committee fosters interactions between basic, translational, and clinical researchers. Committee on Clinical Pharmacology and Pharmacogenomics The Committee on Clinical Pharmacology and Pharmacogenomics administers a 2-year postgraduate training program, accredited by the American Board of Clinical Pharmacology and supported by an NIH training grant, for MDs, PhDs and PharmDs. The Committee is led by M. Eileen Dolan, PhD, and consists of diverse faculty from departments across the University. The goal of the interdisciplinary program is to train individuals in various subspecialties of clinical pharmacology, including principles of therapeutics, molecular pharmacology, and pharmacogenomics. The program offers training through various didactic exercises, seminars, and research projects. Committee on Genetics, Genomics & Systems Biology The Committee on Genetics, Genomics & Systems Biology, offers a PhD program in genetics that combines training in sophisticated modern genetic analysis with genetic-based strategies for investigating clinical and basic science questions in the context of physiological, developmental, and evolutionary systems. The program is supported by an NIH training grant and consists of faculty from 16 different departments and represents a broad interdisciplinary approach to 140 Committee on Immunology Committee on Medical Physics The Committee on Medical Physics offers research training leading to a MS or PhD degree. The program, led by Maryellen Giger, PhD, and supported by an interdisciplinary NIH training grant, applies the principles of the physical sciences to biomedicine. The Committee includes members of the UCCCC Advanced Imaging Program and faculty from the Departments of Radiology, and Radiation and Cellular Oncology. Specific areas of focus include diagnostic radiography, magnetic resonance imaging and spectroscopy, computer-aided diagnosis and quantitative image analysis, electron paramagnetic resonance imaging, nuclear medicine imaging, and computer applications in radiation therapy. UCCCC SCIENTIFIC REPORT 2010 – 2011 The Committee on Immunology provides multidisciplinary training toward a PhD degree in fundamental immunology and approaches to understanding immunological diseases. The program has been continuously funded by NIH training grants for over 30 years and represents one of the oldest and most prestigious immunology programs in the country. The Committee integrates the basic biological sciences with the clinical sciences to develop new approaches for the diagnosis and treatment of various immune diseases and cancer. Areas of basic and applied immunology research include autoimmunity; hematopoiesis, lymphoid and myeloid development; T-cell differentiation; signal transduction in lymphoid development and activation; and tumor immunity. Education and Training teaching and research. Strengths of the program include gene expression and developmental genetics, chromosome organization and behavior, population and evolutionary genetics, and genetics of human disease with an emphasis on genetic alterations in cancer. Committee on Molecular Metabolism and Nutrition The Committee on Molecular Metabolism and Nutrition is an interactive research program supported by an NIH training grant that offers interdisciplinary doctoral training in the molecular basis of biological processes related to nutritional status, metabolic homeostasis, and human disease. The program focuses on metabolism and metabolic diseases including, for example, diabetes and obesity, using biochemical, clinical, physiological, cell, and molecular biological approaches. The Committee works closely with the Digestive Disease Research Core Center and Kovler Diabetes Center at The University of Chicago. Department of Health Studies The Department of Health Studies, chaired by Ronald Thisted, PhD, is a cross-disciplinary program focused on biostatistics, epidemiology, and health services research that studies the environmental and organizational factors influencing the health of human populations. The Department offers an MS degree in Health Studies for Clinical Professionals (MSCP), and a certificate program, the Clinical Research Training Program (CRTP). The MSCP program is designed to educate doctoral-level individuals in the theory, methods, and concepts of biostatistics, epidemiology, and 141 Education and Training health services research required to develop clinical and epidemiologic research studies. The CRTP, an NIH-supported program designed for clinicians or clinical researchers, offers formal training opportunities in areas relevant to the design, implementation, and analysis of clinical research. In addition, the Department offers a PhD program in biostatistics, epidemiology, and health services research based on a core curriculum in population-based health research. UCCCC SCIENTIFIC REPORT 2010 – 2011 Graham School of General Studies 142 MacLean Center for Clinical Medical Ethics The MacLean Center for Clinical Medical Ethics is internationally recognized as a leading program for research and training in medical ethics. The Center is directed by Mark Siegler, MD, and consists of several UCCCC members and faculty in medicine, law, business, public policy, and social sciences. Established in 1984 with support from the family of Dorothy J. MacLean, the Center offers both a 2-year master’s degree and a 1-year part-time fellowship program. The master’s degree program provides a health services research curriculum and is intended for physicians interested in pursuing an academic career with a focus on health policy and clinical medical ethics. The 1-year, part-time fellowship program offers clinicians, not necessarily pursuing academic medicine, training in medical ethics. The University of Chicago Graham School of General Studies offers a Clinical Trials Management Certificate Program. This post-baccalaureate program provides comprehensive training in clinical practices, drug development, statistical concepts for clinical research, and clinical site management and monitoring. The program enables graduates to initiate clinical research, apply effective monitoring methods, and understand regulations and good clinical practices. All staff in the Cancer Clinical Trials Office have completed this training program. UCCCC members serve as principal investigators for 13 cancer-related NIH T32 and T35 training grants. These grants support training programs in diverse areas of basic, behavioral, and clinical research related to addictions research, cancer biology, clinical therapeutics, genetics, immunology, medical oncology, medical physics, molecular biology, and nutrition. TITLE PRINCIPAL INVESTIGATOR TOTAL ANNUAL COST CLASS FUNDING AGENCY $476,312 T32 Eugene Chang $388,918 T32 National Institute of Diabetes and Digestive and Kidney Diseases Marcus Clark $1,082,136 T32 National Institute of General Medical Sciences RESEARCH TRAINING IN MEDICAL PHYSICS Maryellen Giger $264,696 T32 National Institute of Biomedical Imaging and Bioengineering MOLECULAR AND CELLULAR BIOLOGY TRAINING PROGRAM Benjamin Glick $1,229,690 T32 National Institute of General Medical Sciences INTERDISCIPLINARY PROGRAM IN IMMUNOLOGY RESEARCH TRAINING IN DIGESTIVE DISEASES AND NUTRITION MEDICAL SCIENTIST NATIONAL RESEARCH SERVICE AWARD GRADUATE TRAINING PROGRAM IN CANCER BIOLOGY Geoffrey Greene $520,558 T32 National Cancer Institute CARDIOVASCULAR SCIENCES TRAINING GRANT Elizabeth McNally $385,910 T32 National Heart, Lung and Blood Institute SHORT-TERM AGING-RELATED RESEARCH PROGRAM David Meltzer $62,694 T35 National Institute on Aging BASIC MEDICAL ONCOLOGY RESEARCH TRAINING IN MEDICAL ONCOLOGY Olufunmilayo Olopade $369,817 T32 National Cancer Institute CLINICAL THERAPEUTICS Mark Ratain $185,567 T32 National Institute of General Medical Sciences Nancy Schwartz $433,317 T32 National Institute of Child Health & Human Development Julian Solway $643,401 T32 National Heart, Lung and Blood Institute Paul Vezina $489,041 T32 National Institute on Drug Abuse GRADUATE TRAINING IN GROWTH AND DEVELOPMENT RESEARCH TRAINING IN RESPIRATORY BIOLOGY NEUROPSYCHOPHARMACOLOGY TRAINING FOR DRUG ABUSE RESEARCH UCCCC SCIENTIFIC REPORT 2010 – 2011 Albert Bendelac National Institute of Allergy and Infectious Diseases Education and Training Training Grants In addition, the NCI-funded Paul Calbresi K12 Scholars Program supports the training of junior investigators pursuing careers in clinical and translational research. Led by Olufunmilayo Olopade, MBBS, the mentored training program provides “hands-on” clinical research training that results in a master’s degree in health studies. 143 Patient and Community Services Patient and Community Services The UCCCC is committed to translating breakthroughs in interdisciplinary basic and clinical cancer research into state-of-the-art patient care. UCCCC clinicians and researchers strive to improve the quality-of-life for patients by also providing access to numerous resources aimed at supporting the physical, social, and emotional needs of cancer patients and survivors. Vital to these efforts is sustained engagement with the community to enhance public awareness of these resources and advances in cancer research. UCCCC SCIENTIFIC REPORT 2010 – 2011 Breast Cancer Survivorship Program The Breast Cancer Survivorship Program, led by Susan Hong, MD, MPH, offers a personalized approach to breast cancer survivorship from the time of diagnosis through treatment. A multidisciplinary team of specialists, including medical and radiation oncologists, radiologists, surgeons, and psycho-oncologists, educates patients on topics related to long-term side effects of treatment, family history of disease, fertility issues, nutrition and healthy lifestyles, and disease recurrence. Services are focused on individualized treatment and wellness. Cancer Resource Center The UCCCC, in partnership with the American Cancer Society, offers a comprehensive resource center to provide patients and their families access to cancer-related information and social services. The Center is staffed by a certified health education specialist and a licensed clinical social worker who are dedicated to helping patients obtain individualized cancer information, including facts about specific types of cancer, education on treatment and pain management, information about innovative clinical trials, and community resources. The Center facilitates access to support groups for caregivers and patients, and offers onsite access to a wide variety of activities through a partnership with Gilda’s Club Chicago, including additional support/networking groups, healing arts workshops, and various educational programs. The Center also provides one-on-one counseling, patient navigation services, assistance with medical insurance, referrals for social and support services, and various outreach activities. Cancer Risk Clinic The Cancer Risk Clinic is a comprehensive cancer risk assessment and prevention program designed for individuals who may be at an increased risk for cancer. The Clinic is directed by Dr. Olufunmilayo Olopade and staffed by a team of specialists who assess cancer risk, provide genetic counseling, educate patients about cancer risk and prevention, and develop personalized riskreduction strategies. Strategies may include systematic monitoring or screening for early detection, lifestyle changes, and the use of cancer preventive procedures or drugs. The Clinic also has an active community outreach program, which has increased patient enrollment in clinical studies for evaluating new therapies, prevention methods, and risk-reduction strategies. 144 The Childhood Cancer Survivors Center, led by Tara Henderson, MD, MPH, is an integrated program for pediatric and adult survivors of childhood cancer. The program is aimed at the prevention and treatment of long-term issues associated with cancer therapy, including heart and renal problems, secondary cancers, endocrine disorders, fertility issues, and social or psychological concerns. Specialists focus on educating survivors and their families about these health issues and developing individualized recommendations for health maintenance and screening. Patient and Community Services Childhood Cancer Survivors Center Office of Community Engagement and Cancer Disparities UCCCC SCIENTIFIC REPORT 2010 – 2011 The UCCCC established the Office of Community Engagement and Cancer Disparities (OCECD) in 2010 as a renewed effort to serve local communities through research, education, advocacy, and outreach. Directed by Karen E. Kim, MD, MS, the program represents the UCCCC’s expanded commitment to understand and serve the unique needs of its surrounding neighborhoods. The OCECD has formed strategic partnerships with various organizations within The University of Chicago and with community- and faith-based organizations to develop innovative programs to increase access to healthcare, reduce cancer risk, increase participation in cancer clinical trials, and improve the quality of life of cancer patients and survivors. For example, the OCECD successfully launched the Empowering Neighborhood Resources in Combating Health Disparities (ENRICH’D™) program to increase breast cancer awareness and improve mammography utilization rates among various racial and ethnic groups in the Chicago area. Chicago-area organizations also participate in the OCECD’s wellness program, Everyone Developing an Understanding of Cancer Awareness Treatment and Education (ED-U-CATE), which educates employees about cancer risks, screening, and treatment. Various workshops and conferences within surrounding communities are also organized to disseminate information on cancer advances, clinical trials, and research trends. These activities maintain a bidirectional exchange of ideas and perspectives and help the UCCCC better understand and meet the needs of its patients. Program in Integrative Sexual Medicine The University of Chicago Medical Center’s Program in Integrative Sexual Medicine (PRISM) for Women and Girls with Cancer is the first multidisciplinary clinical and research program in Illinois dedicated to the comprehensive assessment, prevention, and treatment of sexual health concerns in female cancer patients and survivors. Under the direction of Stacy Tessler Lindau, MD, MAPP, specialists provide education on the potential impact of cancer therapies on sexuality, treatment for sexual problems, and counseling on common sexual concerns of girls and women who have had cancer. Physician researchers apply newly identified strategies from clinical studies to treat sexual dysfunction related to cancer symptoms and therapy. These strategies may be offered in collaboration with specialists in physical therapy, psychiatry, and urogynecology as part of a multidisciplinary treatment approach. Specialized Oncology Care & Research in the Elderly Directed by William Dale, MD, PhD, the Specialized Oncology Care & Research in the Elderly (SOCARE) clinic addresses the specific needs of elderly cancer patients and survivors. The Clinic is staffed by physicians with expertise in geriatric medicine, geriatric oncology, and palliative care who help patients and their families understand the risks and limitations of cancer therapy in older adults. Comprehensive, individualized treatment plans are developed for patients that take into account co-existing disease, cognitive deficits, and functional limitations. 145 Dedicated Research Facilities The University of Chicago Medical Center and Dedicated Research Facilities The University of Chicago Medical Center occupies over 30 buildings, which house all hospital and clinical areas of the campus as well as teaching and research space. The UCCCC’s primary clinical facilities within the Center include the Bernard A. Mitchell Hospital, Comer Children’s Hospital, and the outpatient clinics in the Duchossois Center for Advanced Medicine (DCAM). Dedicated UCCCC research space spans two state-of-the-art facilities, including the Ellen and Melvin Gordon Center for Integrative Science (GCIS) and the Gwen and Jules Knapp Center for Biomedical Discovery (KCBD). UCCCC SCIENTIFIC REPORT 2010 – 2011 Bernard A. Mitchell Hospital The Bernard A. Mitchell Hospital, the primary adult inpatient facility which includes an emergency department and intensive care unit, provides more than 60 beds dedicated to adult medical oncology. Patients participating in clinical pharmacology studies are hospitalized in the General Clinical Research Center (GCRC), an NIH-funded facility with dedicated nursing and research staff for clinical research. The facility provides more than 4,000 square feet of space for specialized research and patient care, and operates a core laboratory for rapid routine assays and sample processing. Comer Children’s Hospital Comer Children’s Hospital is a tertiary care teaching facility specializing in the treatment of childhood diseases through patient education, care, and research. The stateof-the-art facility provides 242,000 square feet of space that accommodates more than 150 beds, 25% of which are dedicated to the treatment of children and adolescents with cancer. The facility houses one of the country’s largest and most advanced pediatric intensive care units equipped to treat complex medical cases and children with multiple traumas. Duchossois Center for Advanced Medicine (DCAM) DCAM is a state-of-the-art facility that integrates the majority of the Medical Center’s diagnostic and outpatient treatment services. The 550,000-square-foot facility houses outpatient clinics for gynecologic, medical, and radiation oncology. Facilities include an apheresis unit, modern radiation therapy units, and contemporary chemotherapy infusion suites. The multidisciplinary Breast Center is also located in DCAM and provides examination and consulting rooms, mammography services, patient information, and cancer risk assessment conveniently in one location to serve patients with breast cancer. 146 Currently under construction is the New Hospital Pavilion, a $700 million, 1.2-million-square-foot facility that will provide an optimal setting for collaborative clinical research and patient care. The high-technology facility will house many of The University of Chicago Medical Center’s most distinguished clinical programs, including those that provide complex specialty care with a focus on cancer, gastrointestinal disease, medical imaging, neuroscience, and advanced surgery. Completion of the facility is planned for early 2013. The GCIS was completed in 2005 and represents one of the few research facilities in the country that bridges physical and biological sciences under one roof. The seven-story, 430,000-square-foot building houses 20 UCCCC members in state-of-the-art modular laboratories as well as the Ben May Department for Cancer Research, Department of Biochemistry and Molecular Biology, Howard Hughes Medical Institute, Institute for Biophysical Dynamics, and select laboratories of the Physical Sciences Division. UCCCC SCIENTIFIC REPORT 2010 – 2011 Ellen and Melvin Gordon Center for Integrative Science (GCIS) Dedicated Research Facilities New Hospital Pavilion Gwen and Jules Knapp Center for Biomedical Discovery (KCBD) Opened in 2009, the $244 million KCBD is a 12-story facility that fosters groundbreaking initiatives in the Division of Biological Sciences. The 330,000-square-foot facility includes a stateof-the-art vivarium and dedicated core facility space for the Genomics, Transgenic Mouse/ES Cell, and Integrated Microscopy Facilities. Research programs from the Departments of Medicine (Section of Hematology/Oncology) and Pediatrics (Section of Pediatric Hematology/Oncology), UCCCC, Ludwig Center for Metastasis Research, and Institute for Genomics and Systems Biology are located in the KCBD. The UCCCC has 22,000 square feet of dedicated space. Collectively, the KCBD houses dozens of UCCCC researchers. The KCBD, GCIS, and Knapp Center for Molecular Medicine are connected by pedestrian bridges that facilitate collaboration among 80% of the UCCCC’s laboratory researchers who are located in these state-of-the-art facilities. 147 HIGHLIGHTS 148 New Faculty Recruitments and UCCCC Members in 2010-2011 nDaniel Catenacci, MD, is an instructor of medicine and member of the UCCCC Pharmacogenomics and Experimental Therapeutics Program. His research focuses on receptor tyrosine kinases, including RON and MET, and the development of novel therapeutic agents for the treatment of gastroesophageal malignancies. nJill de Jong, MD, PhD, focuses her research on the genes that regulate normal hematopoietic stem cell (HSC) function in the bone marrow and whether those genes may contribute to the development of leukemia under aberrant expression. Dr. de Jong is an assistant professor of medicine and a member of the UCCCC Hematopoiesis and Hematological Malignancies Program. She utilizes the zebrafish model as a unique discovery mechanism to uncover new genetic regulators of HSCs. nJoshua Hemmerich, PhD, was recruited as an assistant professor of medicine. Dr. Hemmerich is a cognitive psychologist and member of the UCCCC Cancer Prevention and Control Program with research interests centered on treatment decisions in older patients, specifically with non-small cell lung cancers and their clinical outcomes. nPeter O’Donnell, MD, joins the UCCCC Pharmacogenomics and Experimental Therapeutics Program as an instructor of medicine. Dr. O’Donnell’s research interests are in pharmacogenomics, specifically the incorporation of host genetic factors and use of other novel biomarkers to identify appropriate individualized therapies. Dr. O’Donnell is working closely with Dr. Mark Ratain on clinical implementation of pharmacogenomic markers. nBrandon Pierce, PhD, an assistant professor of health studies and member of the UCCCC Cancer Prevention and Control Program, is a genetic epidemiologist focused on identifying and characterizing the genetic and molecular factors that play a role in the risk and prognosis for breast and prostate cancer. His research interests include the role of DNA copy number and telomere length in cancer causation and novel methods for causal inference in genetic epidemiology. UCCCC SCIENTIFIC REPORT 2010 – 2011 nJennifer McNeer, MD, is a clinical researcher focused on improving treatment strategies for high-risk leukemia patients. Dr. McNeer, an assistant professor of pediatrics, is a member of the UCCCC Hematopoiesis and Hematological Malignancies Program and specializes in the development of new, experimental therapeutics for the treatment of pediatric leukemia and lymphoma. New Faculty Recruitments and UCCCC Members nIssam Awad, MD, is a professor of surgery and member of the UCCCC Advanced Imaging Program. Dr. Awad, an expert in neurovascular disease, combines molecular biology methods with state-of-the-art imaging techniques to study angiomatous tumors. nIris Romero, MD, is an assistant professor of obstetrics and gynecology. As a physician scientist and member of the UCCCC Cancer Prevention and Control Program, Dr. Romero is identifying novel approaches to prevent ovarian cancer with an emphasis on molecularly targeted interventions. nMichael Spiotto, MD, PhD, an instructor of radiation and cellular oncology, investigates novel methods to treat head and neck cancer. His research focuses on developing in vivo screens to identify genes involved in the metastasis of primary tumors. Dr. Spiotto, as a member of the UCCCC Molecular Mechanisms of Cancer Program, is also developing targeted inhibitors against the human papilloma virus (HPV) oncogenic proteins E6 and E7. nRussell Szmulewitz, MD, is an instructor medicine and member of the UCCCC Pharmacogenomics and Experimental Therapeutics Program. He is a translational scientist with research interests in prostate cancer biomarker development and prostate cancer metastatic latency and progression. Dr. Szmulewitz is currently investigating the molecular mechanisms of how stress-activated protein kinase members inhibit prostate cancer metastatic colonization. 149 Selected Awards and Honors UCCCC SCIENTIFIC REPORT 2010 – 2011 nVictoria Villaflor, MD, joins the UCCCC Pharmacogenomics and Experimental Therapeutics Program as an assistant professor of medicine. Her research focuses on the evaluation of targeted agents for the treatment of lung and head and neck cancers. nSamuel Volchenboum, MD, PhD, MS, an assistant professor of pediatrics, uses a systems biology approach to study pediatric cancer in the UCCCC Molecular Mechanisms of Cancer Program. Using neuroblastoma as a paradigm system, he is developing novel techniques for the integration of orthogonal datasets as well as novel algorithms to facilitate high-throughput mass spectrometry analysis for improving patient diagnostics and assessing response to therapy. nPatrick Wilson, PhD, an assistant professor of medicine and member of the UCCCC Immunology and Cancer Program, has developed technologies that allow rapid cloning and sequencing of antibody molecules from plasmablasts in patients. He aims to use this strategy to identify B cell antibody specificities in cancer patients, which will facilitate the development of new therapeutic monoclonal antibodies. Selected Awards and Honors Molecular Mechanisms of Cancer Program Kay Macleod, PhD, associate professor of the Ben May Department for Cancer Research, was named to a 4-year term on the National Institutes of Health Cancer Molecular Pathobiology (CAMP) Study Section 2011. Carrie Rinker-Schaeffer, PhD, associate professor of surgery and director of urologic research, was elected the 2011 president of The Metastasis Research Society (MRS), which is dedicated to understanding tumor metastasis and bringing new potential therapeutics into clinical trials. Hematopoiesis and Hematological Malignancies Program Jianjun Chen, PhD, assistant professor of medicine, was awarded a 2011 Research Scholar Award from the American Cancer Society (ACS) to support his research in determining the role of miR-126 in the development of core-binding factor (CBF) leukemias. Richard Larson, MD, professor of medicine and director of The University of Chicago Hematologic Malignancies Clinical Research Program, was elected treasurer of the American Society of Hematology in 2010 to serve a 4-year term. Michelle Le Beau, PhD, professor of medicine, director of the Cancer Cytogenetics Laboratory, and director of the UCCCC, was named the inaugural Arthur and Marian Edelstein Professor for her contributions as a scientist and leader and elected as vice president/president-elect 150 Janet Rowley, MD, DSc, the Blum-Riese Distinguished Service Professor of Medicine, Molecular Genetics & Cell Biology, and Human Genetics, received the Jessie Stevenson Kovalenko Medal from the National Academy of Sciences in 2010 for her contributions in identifying chromosomal abnormalities in leukemias and lymphomas. Dr. Rowley also received the 7th annual American Association of Cancer Research (AACR) Lifetime Achievement in Cancer Research Award, Margaret Kripke Legend Award from The University of Texas MD Anderson Cancer Center, and Enrico Fermi History Maker Award for Distinction in Science, Medicine, and Technology from the Chicago Historical Society in 2010. In addition, Dr. Rowley was one of two cancer geneticists to receive the 2010 Pearl Meister Greengard Prize from The Rockefeller University in recognition of outstanding female scientists. In 2011, Dr. Rowley was awarded the Alumni Medal by The University of Chicago Alumni Association and received an honorary doctoral degree in medical sciences from Yale University for her revolutionary work in human genetics and cancer research. Dr. Rowley was also selected for the Ernest Beutler Lecture and Prize by the American Society of Hematology for her pivotal work in the diagnosis and treatment of chronic myeloid leukemia. Immunology and Cancer Program Thomas Gajewski, MD, PhD, professor of pathology, was elected in 2010 as president of the International Society for Biological Therapy of Cancer (iSBTc), an international non-profit dedicated to improving cancer patient outcomes by advancing the application of biological therapy/ immunotherapy. Dr. Gajewski was also selected as The University of Chicago principal investigator in 2011 for the Cancer Immunotherapy Trials Network (CITN), a new initiative funded by the National Cancer Institute (NCI). UCCCC SCIENTIFIC REPORT 2010 – 2011 Sonali Smith, MD, associate professor of medicine, was appointed director of The University of Chicago Lymphoma Program in the Section of Hematology/Oncology. Dr. Smith was also elected to the Lymphoma Research Foundation Scientific Advisory Board in 2011 for a 5-year term. Selected Awards and Honors of the Association of American Cancer Institutes (AACI) in 2011. Dr. Le Beau will be the association’s first female president and will serve 2 years each as AACI vice president/president-elect, president, and immediate past-president. Bana Jabri, MD, PhD, professor of medicine, was elected in 2011 to the Association of American Physicians in recognition of her contributions as an international leader in the study of celiac disease and mucosal immunology. Vinay Kumar, MD, PhD, professor and chair of pathology, was named the Donald N. Pritzker Professor in 2011 for his contributions to scholarship and leadership of the Department of Pathology. Pharmacogenomics and Experimental Therapeutics Program Ezra Cohen, MD, associate professor of medicine, was appointed co-director of The University of Chicago Head and Neck Cancer Program in 2010, which specializes in the treatment of head and neck, lung, and esophageal cancers. Dr. Cohen was also elected editor-in-chief of Oral Oncology in 2010, the official journal of the European Association of Oral Medicine, International Association of Oral Pathologists, and the International Academy of Oral Oncology. M. Eileen Dolan, PhD, professor of medicine, was appointed chair of The University of Chicago Committee on Clinical Pharmacology and Pharmacogenomics in 2010 to oversee the training of graduate students and clinical and post-doctoral fellows. Dr. Dolan also received the 151 Selected Awards and Honors 2010 Distinguished Alumni Award from the Purdue University School of Pharmacy and the 2011 Purdue University Distinguished Women Scholars Award in recognition of her outstanding professional and scientific achievements. Alessandro Fichera, MD, associate professor of surgery, won the Best Video Award at the 2011 American Society of Colon & Rectal Surgeons for his video on “Single Incision Laparoscopic Total Proctocolectomy for Refractory Crohn’s colitis.” Chuan He, PhD, professor of chemistry, received the Early Career Award from the Society of Biological Inorganic Chemistry (SBIC) in 2010 for his distinguished research and impact. Dr. He was also the recipient of the American Chemical Society’s (ACS) Akron Section Award in 2010 for young scientists. UCCCC SCIENTIFIC REPORT 2010 – 2011 Bruce Minsky, MD, professor of radiation and cellular oncology, was named by the Association of Residents in Radiation Oncology (ARRO), in partnership with the American Society for Radiation Oncology (ASTRO), as one of 40 Educators of the Year. Mitchell Posner, MD, the Thomas D. Jones Professor and vice chairman of surgery, and section chief of general and oncologic surgery, was elected president of the Society of Surgical Oncology in 2010. Mark Ratain, MD, the Leon O. Jacobson Professor of Medicine, was named director of The University of Chicago’s Center for Personalized Therapeutics in 2010. Dr. Ratain was also selected as the 2011 recipient of an Honorary Fellow Award from the American College of Clinical Pharmacology in recognition of his contributions to the field of clinical pharmacology. In addition, Dr. Ratain was selected as the 2011 recipient of the American Society of Clinical Oncology (ASCO) Translational Research Professorship (TRP), which provides flexible funding to outstanding translational researchers. Advanced Imaging Program Stephen Archer, MD, the Harold Hines Jr. Professor of Medicine and chief of cardiology, was elected president of the American Heart Association’s (AHA) Metro Chicago board of directors in 2010. Dr. Archer was also selected by the American College of Cardiology as the recipient of its 2011 Distinguished Scientist Award in recognition of his major contributions to the advancement of scientific knowledge. Richard Baron, MD, professor of radiology, was appointed as The University of Chicago’s dean for clinical practice in 2010. Maryellen Giger, PhD, professor of radiology, chair of the Committee on Medical Phyics, and vice chair for basic science research of radiology, was elected to the National Academy of Engineering in 2010, one of the highest professional distinctions accorded to an engineer. Patrick La Riviere, PhD, associate professor of radiology, was elected in 2011 to The University of Chicago College Council for a 3-year term to set policies on admissions, curricula, and degree requirements. Xiaochun Pan, PhD, professor of radiology, was the 2010 recipient of a technical award from the IEEE Engineering in Medicine and Biology Society (EMBS) for significant contributions to medical imaging. Dr. Pan was also elected chair of the National Institutes of Health Biomedical Imaging Technology (BMIT) Study Section in 2010. 152 Cancer Prevention and Control Program Nancy Cox, PhD, professor of medicine, was elected to a 4-year term in 2011 as a member-atlarge on the Section on Biological Sciences for the American Association for the Advancement of Science (AAAS). Selected Awards and Honors Kenji Suzuki, PhD, assistant professor of radiology, was appointed deputy editor for Academic Radiology in 2011, the Association of University Radiologists’ peer-reviewed journal. Dr. Suzuki was also appointed in 2011 to the editorial board for Chest Disease Reports, a new, peer-reviewed international medical journal reporting on the diagnosis and treatment of chest-related diseases. William Dale, MD, PhD, associate professor of medicine, chief of the section of geriatrics, and associate director of the MD/PhD Program in Medicine, Social Sciences, and Humanities (MeSH), was elected by the International Society of Geriatric Oncology in 2010 to serve on the editorial board of the Journal of Geriatric Oncology as a founding member. Nora Jaskowiak, MD, associate professor of surgery, received the Favorite Faculty Award from The University of Chicago Pritzker School of Medicine Class of 2011 in recognition of her commitment to medical education. David Meltzer, MD, PhD, professor of medicine, was selected in 2011 for a methodology committee to assist the Patient Centered Outcomes Research Institute, a national nonprofit, with building a consensus on methodologies for binding researchers to a common approach in furnishing comparative effectiveness data. Olufunmilayo Olopade, MBBS, the Walter L. Palmer Professor of Medicine and Human Genetics, associate dean for global health, and director of The University of Chicago Center for Clinical Cancer Genetics, was elected to the American Academy of Arts & Sciences (AAAS) in 2010. Dr. Olopade was also elected to the board of directors for the American Board of Internal Medicine (ABIM), received an honorary doctoral degree from Princeton University for her efforts in breast cancer research and treatment, and received the Distinguished Service Award from the American Cancer Society (ACS) in 2010. In 2011, Dr. Olopade was appointed by President Barack Obama to serve on the National Cancer Advisory Board (NCAB), the highest level board that oversees the activities of the National Cancer Institute (NCI). Dr. Olopade was also elected to the American Philosophical Society and named a “Women Deliver 100” honoree, which recognizes 100 individuals committed to improving the lives of girls and women around the world. UCCCC SCIENTIFIC REPORT 2010 – 2011 Karen E. Kim, MD, MS, associate professor of medicine, was named director of the UCCCC’s Office of Community Engagement and Cancer Disparities (OCECD) in 2010 to oversee efforts in building partnerships with local communities to enhance healthcare. Dr. Kim was also appointed by the National Institutes of Health to serve on the Health Advisory Committee on Research on Women’s Health in 2010 to address scientific, legal, and ethical issues affecting the health of our nation’s women through biomedical and behavioral research and related cancer opportunities. 153 Integrated Research Initiatives Integrated Research Initiatives The UCCCC emphasizes collaboration among its members from a broad range of disciplines to elucidate the determinants of cancer, implement new approaches to screening and prevention, and develop new diagnostics and personalized therapeutics to detect and control cancer. The UCCCC stimulates interdisciplinary collaborations through several integrated research initiatives including the Specialized Program of Research Excellence in Breast Cancer, Leukemia and Lymphoma Society Specialized Center of Research, Institute for Genomics and Systems Biology, Ludwig Center for Metastasis Research, Systems Biology Approach for the Study of Therapy-Related Acute Myeloid Leukemia, and Center for UCCCC SCIENTIFIC REPORT 2010 – 2011 Personalized Therapeutics. Specialized Program of Research Excellence (SPORE) in Breast Cancer PRINCIPAL INVESTIGATOR: OLUFUNMILAYO OLOPADE, MBBS CO-PRINCIPAL INVESTIGATORS: GINI FLEMING, MD, AND MARYELLEN GIGER, PHD The University of Chicago Breast Cancer SPORE brings together a multidisciplinary team of basic, clinical, and population science investigators to perform innovative research using a global strategy to reduce suffering from breast cancer. Awarded by the National Cancer Institute (NCI), the program is one of only 11 Breast SPOREs in the United States. The University of Chicago Breast SPORE aims to translate recent genetic and imaging advances to benefit women who are at increased risk of developing an aggressive form of breast cancer, which disproportionately affects young African American women. The UCCCC integrates researchers from its Pharmacogenomics and Experimental Therapeutics, Advanced Imaging, and Cancer Prevention and Control Programs. Basic researchers in genetics, bioinformatics, molecular biology, biophysics, and structural biology collaborate with clinical researchers specializing in epidemiology, medical oncology, surgical oncology, and radiation oncology to facilitate the translation of scientific advances to patients. The SPORE comprises four translational research projects, each co-led by basic and applied investigators from the UCCCC. These projects aim to 1) develop mammography and MR image-based markers for assessing breast density to quantify breast cancer risk and monitor therapeutic response; 2) determine whether MR imaging with improved spectral, temporal, and spatial sampling leads to improved detection of early breast cancer; 3) evaluate whether variations in genes involved in hormone and xenobiotic metabolism influence breast cancer risk; and 4) identify population-specific genetic variants that influence toxicity to breast cancer chemotherapy. These projects are supported by core facilities in Analytic and Informatics; Biospecimen, Pathology and Genotyping; and Administration, each built on the unique strengths of existing UCCCC shared resources. 154 PRINCIPAL INVESTIGATOR: MICHAEL THIRMAN, MD The SCOR, a multidisciplinary initiative awarded by the Leukemia and Lymphoma Society of America, is an integrated program aimed at developing cell-permeable peptides and small molecules as novel therapeutics for hematologic malignancies. The program comprises a highly interactive group of chemists, molecular biologists, and clinicians who might not otherwise have the opportunity to work together in a translational research program in leukemia and lymphoma. The SCOR represents a collaborative effort among three institutions, involving 11 University of Chicago senior researchers as well as two project leaders from an NCI-designated Cancer Center at the University of California, San Diego (UCSD), and from Cornell University (CU). Institute for Genomics and Systems Biology (IGSB) DIRECTOR: KEVIN WHITE, PHD The IGSB represents a collaborative effort between The University of Chicago and Argonne National Laboratory (ANL) to advance technology development for genome analysis and accelerate the transition of basic discoveries in genome science to translational and clinical research. Research focuses on genomics and systems biology approaches to understand genome function evolution, uncover new diagnostic and therapeutic targets, and discover new strategies for complex human diseases with a major focus on cancer. The IGSB promotes 10 areas of investigation, including proteomics and structural genomics, computational biology and informatics, microbial systems biology, evolutionary genomics and systems, biological engineering and technology development, cellular and genomic networks, chemical genomics, cancer, population genomics and complex diseases, and clinical genomics. UCCCC SCIENTIFIC REPORT 2010 – 2011 Efforts are focused on developing a common therapeutic strategy based on the targeting of proteinprotein interactions in leukemia and lymphoma, rather than focusing on a single disease entity. SCOR projects center on 1) targeting transducible anticancer peptide therapeutics to kill tumor cells in vivo (UCSD); 2) developing peptide and small molecule therapeutics for MLL-associated leukemia (UCCCC); and 3) developing anti-BCL-6 targeted therapy for B-cell lymphomas (CU). Six associated cores, including Peptide Therapeutics, Small Molecule Therapeutics, Patient Demographics and Cell Bank, Hematopathology, Clinical Trials and Minimal Residual Disease Monitoring, Hematopathology, Clinical Trials and Minimal Residual Disease Monitoring, and Stem Cell Processing and Purging provide valuable reagents and expertise for each of the projects. Integrated Research Initiatives Leukemia and Lymphoma Society Specialized Center of Research (SCOR) More than 70 IGSB investigators from ANL and over 20 departments in the Biological Sciences and Physical Sciences Divisions at The University of Chicago are performing research on complex biological systems using a variety of experimental, computational, and theoretical approaches. Current research initiatives include 1) the 1000 Chicago Cancer Genome Project, a joint effort with The University of Chicago Medical Center to sequence the transcriptomes of 1000 tumors to identify new therapeutic targets; 2) discovery of genomic variation and expression patterns in metabolic diseases and diabetes for evaluating drug therapy outcomes; and 3) determination of the relationship between bacteria and inflammatory bowel disease. 155 Integrated Research Initiatives The IGSB features four core facilities to support its research, including the Cellular Screening Center (CSC) for high-throughput RNAi and chemical compound screening, the High-Throughput Genome Analysis Core (HGAC) for ultra-high-throughput sequencing and microarray processing, the Micro-Western Array Core (MWAC) for quantitative protein studies, and the BAC-Recombineering Core (BRC) for imaging and measuring spatiotemporal expression of fluorescently tagged proteins in model organisms. Ludwig Center for Metastasis Research UCCCC SCIENTIFIC REPORT 2010 – 2011 CO-DIRECTORS: RALPH WEICHSELBAUM, MD, AND GEOFFREY GREENE, PHD 156 The Ludwig Center for Metastasis Research aims to improve our understanding of metastasis and translate laboratory concepts into novel therapeutics for the prevention and treatment of metastasis. The Center, established in 2006 by an endowment from the Ludwig Fund, is closely affiliated with the UCCCC and fosters collaborations among researchers from various disciplines, including molecular and cell biology, bioinformatics, chemistry, genetics, imaging, and medicine. Investigators are initially targeting metastasis of breast and prostate cancers by developing radiolabeled steroid receptor modulators and novel receptor-targeted nanoscale reagents to selectively image and treat tumors expressing estrogen or androgen receptors. Researchers are also identifying small molecule reagents for the sensitization of tumors to ionizing radiation or chemotherapy. Systems Biology Approach for the Study of Therapy-Related Acute Myeloid Leukemia (t-AML) PRINCIPAL INVESTIGATOR: MICHELLE LE BEAU, PHD Supported by generous funding from the Cancer Research Foundation (CRF) since 2009, The University of Chicago is employing a multidisciplinary systems biology and genomics approach to study t-AML. Therapy-related acute myeloid leukemia, which affects approximately 8%-10% of all patients treated for cancer, is a direct result of mutational events that are induced by chemotherapy or radiotherapy used in the treatment of primary malignancies. Patients who have received immunosuppressive agents for organ transplantation and the elderly are also at risk for developing t-AML and AML. An interdisciplinary team of scientists, representing the UCCCC and the IGSB, is using a comprehensive approach to identify individuals at risk for developing t-AML, identify genetic susceptibility factors that are involved, and design effective prevention and treatment strategies for this disease. The team has extensive research expertise in clinical oncology, hematopathology, genetics, genomics, systems biology, computational modeling of molecular networks, and hematopoiesis. Using a systems approach, these investigators are integrating six research projects involving high-throughput screening, stem cell biology, pharmacogenetics, clinical trial design, and computation to understand the basic biology of t-AML. Taken together, these projects are furthering our understanding of the molecular basis of the disease and will lead to improved therapies, earlier detection, and prevention strategies. PRINCIPAL INVESTIGATOR: MARK RATAIN, MD The UCCCC’s newly established Center for Personalized Therapeutics is developing individualized prevention and treatment strategies for cancer based on genetic, social, environmental, and behavioral factors. The Center, which combines the expertise of basic and clinical researchers in pharmacogenomics, is focusing its efforts on the 1200 Patients Project, a clinical study that incorporates broad genetic information into routine clinical practice to guide medical treatment decisions. This information will help clinicians predict which patients will respond favorably to specific medications, experience severe side effects from certain therapies, or respond positively to higher drug dosing. The Center facilitates collaborations among researchers who are performing genome-wide discovery and clinical validation of pharmacogenomic markers for chemotherapy, developing tools for improved analysis of therapeutic response, and developing targeted therapies. These efforts are facilitating the development of a new medical system that emphasizes personalized medical care. Integrated Research Initiatives Center for Personalized Therapeutics UCCCC SCIENTIFIC REPORT 2010 – 2011 157 158 Cancer Registry patients diagnosed or treated at The University of Chicago Medical Center (UCMC). Vital statistics, including patient demographics, tumor site and histology, stage of disease, treatment, and outcomes Cancer Registry Since the 1920s, the UCCCC Cancer Registry has documented all for each case are collected and reported to national cancer surveillance programs. The data are also essential for epidemiologic and health disparity grant applications, cancer program planning, and other cancer research initiatives. 2010 Cancer Cases by Site NEWLY DIAGNOSED RECURRENT/ PROGRESSIVE DISEASE TOTAL % OF TOTAL CASES DIGESTIVE SYSTEM 563 65 628 18.5% MALE GENITAL SYSTEM 496 72 568 16.8% BREAST 308 38 346 10.2% RESPIRATORY SYSTEM 286 47 333 9.8% URINARY SYSTEM 242 42 284 8.4% ENDOCRINE SYSTEM 173 25 198 5.8% FEMALE GENITAL SYSTEM 149 28 177 5.2% ORAL CAVITY & PHARYNX 127 34 161 4.7% PRIMARY SITE LYMPHOMA 112 26 138 4.1% BRAIN & OTHER NERVOUS SYSTEM 99 20 119 3.5% LEUKEMIA 97 28 125 3.7% MISCELLANEOUS 59 10 69 2.0% SKIN EXCLUDING BASAL & SQUAMOUS 49 19 68 2.0% MYELOMA 43 5 48 1.4% SOFT TISSUE 40 12 52 1.5% MESOTHELIOMA 40 7 47 1.4% BONES & JOINTS 21 3 24 0.7% KAPOSI SARCOMA 3 0 3 0.1% EYE & ORBIT TOTAL 1 2 3 0.1% 2,908 483 3,391 100% UCCCC SCIENTIFIC REPORT 2010 – 2011 In 2010, a total of 3,391 patients were diagnosed and/or treated for cancer at the UCMC. Of these patients, 2,908 (85.8%) were new diagnoses and 483 (14.2%) were initially treated elsewhere and referred to the UCMC for recurrent or progressive disease. The most frequent primary sites diagnosed and/or treated for cancer include the digestive system, male genital system, breast, respiratory system, and urinary system. 159 Financials Financials The University of Chicago Comprehensive Cancer Center Reporting Date: 7/31/11 SUM OF DIRECT COSTS SUM OF TOTAL COSTS (DIRECT + INDIRECT) ACS $1,050,166 1,190,000 NCI $24,512,845 $34,060,007 FUNDING AGENCY NSF $178,398 $256,044 OTHER NIH $38,741,794 $53,051,976 OTHER PEER-REVIEWED $5,524,377 $7,430,788 $70,025,580 $95,988,815 INDUSTRY $6,688,233 $8,734,630 OTHER NON-PEER REVIEWED $7,335,483 $7,779,197 SUBTOTAL OF NON-PEER REVIEWED $14,023,716 $16,513,827 $84,049,296 $112,502,642 UCCCC SCIENTIFIC REPORT 2010 – 2011 SUBTOTAL OF PEER-REVIEWED 160 GRAND TOTAL (ALL PROJECTS) EXECUTIVE EDITOR Hoyee Leong, PhD Director for Scientific Communications and Strategic Partnerships GRAPHIC DESIGN Rogue Element Inc. PRINTING Service Communications and Solutions, LLC For more information about the UCCCC: Connect by phone at 1-773-702-6180 (UCCCC Administrative Office) Make an appointment at 1-855-702-8222 (adults) or 1-773-702-6808 (pediatrics) Visit us online at cancer.uchicago.edu The University of Chicago Comprehensive Cancer Center 5841 S. Maryland Ave., MC1140 H212 Chicago, IL 60637
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