Awarded: Aug 05, 2002
$7.25 million over 5 to 7 years
In 2002, five outstanding physician-scientists at the mid-career level each received grants of up to $1.5 million to be used over 5 to 7 years.
Charis Eng, M.D., Ph.D., F.A.C.P.,
Cleveland Clinic Foundation
James L.M. Ferrara, M.D.,
University of Michigan Medical School
D. Gary Gilliland, Ph.D., M.D.,
Brigham and Women's Hospital
Daniel A. Haber, M.D., Ph.D.,
Harvard University
Daniel J. Rader, M.D.,
University of Pennsylvania School of Medicine
Charis Eng, M.D., Ph.D., F.A.C.P.,
Cleveland Clinic Foundation
Biography
Dr. Charis Eng is the Chair and founding Director of the Genomic Medicine Institute of the Cleveland Clinic Foundation, founding Director and attending clinical cancer geneticist of the institute's clinical component, the Center for Personalized Genetic Healthcare, and Professor and Vice Chairman of the Department of Genetics at Case Western Reserve University School of Medicine. She holds a joint appointment as Professor of Molecular Medicine at the Cleveland Clinic Lerner College of Medicine and is a full member of Cleveland Clinic's Taussig Cancer Center and a member of the CASE Comprehensive Cancer Center. She was recently honored by the designation National Scholar of the Davis Heart and Lung Research Institute of The Ohio State University, and continues to hold an honorary appointment at the University of Cambridge. Dr. Eng's research interests may be broadly characterized as clinical cancer genetics translational research. Her work on RET testing in multiple endocrine neoplasia type 2 and the characterization of the widening clinical spectra of PTEN gene mutations have been acknowledged as the paradigm for the practice of clinical cancer genetics.
Dr. Eng grew up in Singapore and Bristol, UK and entered the University of Chicago at the age of 16. After completing an MD and PhD at its Pritzker School of Medicine, she specialized in internal medicine at Beth Israel Hospital, Boston and trained in medical oncology at Harvard's Dana-Farber Cancer Institute. She was formally trained in clinical cancer genetics at the University of Cambridge and the Royal Marsden NHS Trust, UK, and in laboratory-based human cancer genetics by Bruce Ponder, MB, PhD At the end of 1995, Dr. Eng returned to the Farber as Assistant Professor of Medicine, and in January, 1999 was recruited by The Ohio State University as Associate Professor of Medicine and Director of the Clinical Cancer Genetics Program. In 2001, she was honored with the conferment of the Davis Professorship and appointed Co-Director of the Division of Human Genetics in the Department of Internal Medicine. In 2002, she was promoted to Professor and Division Director, and was conferred the Klotz Endowed Chair. She moved to the Cleveland Clinic in September 2005. Dr. Eng has published over 230 peer reviewed original papers in such journals as the New England Journal of Medicine, Lancet, JAMA, Nature Genetics, Nature and Molecular Cell. She has received numerous awards and honors including election to the American Society of Clinical Investigation, the Association of American Physicians and as Fellow of AAAS, the Doris Duke Distinguished Clinical Scientist Award and named a Local Legend from Ohio bestowed by the American Medical Women's Association in conjunction with the U.S. Senate on women physicians who have demonstrated commitment, originality, innovation and/or creativity in their fields of medicine. Dr. Eng is the 2005 recipient of the ATA Van Meter Award at the 13th International Thyroid Conference, November 2005, and will be the recipient of the 2006 Ernst Oppenheimer Young Investigator Award of The Endocrine Society. She was the North American Editor of the Journal of Medical Genetics from 1998 to 2005, is Senior Editor of Cancer Research and Associate Editor of the Journal of Clinical Endocrinology and Metabolism. Dr. Eng has recently been elected to the Board of Directors of the American Society of Human Genetics.
Abstract
Genetics of PTEN and Molecular-Based Patient Care
Tumor suppressors act like automobile brakes to prevent cell overgrowth. Our project utilizes a single model tumor suppressor gene called PTEN as a model for translating laboratory discoveries to evidence-based patient care. Germline gene mutations represent faults or alterations in DNA, which is the stuff of genes. Germline mutations of PTEN cause Cowden syndrome (CS). CS which was believed to be rare, is actually under-recognized particularly by non-cancer genetics professionals and therefore, diagnoses are not made. This is rather dangerous because CS is a hereditary condition characterized by breast and thyroid cancers and perhaps cancer of the uterus.
Because PTEN-associated CS is so difficult to recognize the first objective of our study is to statistically and genetically model the clinical features of over 1000 patients with features reminiscent of CS so that the fewest and most parsimonious features may be objectively identified. Identifying these features will help primary caregivers identify such individuals for purposes of referral to cancer genetics professionals.
It is not known if women with only breast cancer and no obvious features of CS might have unsuspected germline PTEN mutations. Therefore, the second objective of our study is to examine a large population-based series of women diagnosed with breast cancer to see what proportion of such women have germline PTEN mutations. Having germline PTEN mutations would not only put them at increased risk of other cancers, but also has implications for their families.
Somatic gene mutations are present only in cancer cells and cannot be inherited. Because somatic mutations of PTEN have been described in sporadic (not familial, not genetic) breast tumors, our third objective is to seek out and characterize non-traditional, non-genetic alterations of PTEN as new targets of therapy and prevention.
James L.M. Ferrara, M.D.,
University of Michigan Medical School
Biography
Dr. Ferrara is a Professor of Medicine and Pediatrics at the University of Michigan Medical School and the Director of the Blood and Marrow Transplant Program at the University of Michigan Comprehensive Cancer Center. He received his BA from Xavier University and an MA from Oxford University before obtaining his medical degree in 1980 from Georgetown Medical School. He was an intern and resident in Pediatrics at Children's Hospital in Boston and completed his Pediatric Hematology/Oncology training at the Dana Farber Cancer Institute before joining the faculty of Harvard Medical School where he remained until 1998. Dr. Ferrara is one of the world's leading authorities on the immunologic complications of bone marrow transplantation and his research interests focus on making transplantation safer and more available to a wider group of patients. He currently serves on the National Board of Directors of the American Society for Blood and Marrow Transplantation and has received numerous honors for his contributions to this field including the Stohlman Scholar Award from the Leukemia and Lymphoma Society and the Alexander von Humboldt Award from the German government.
Abstract
Novel Strategies to Improve Allogenic BMT
Allogeneic bone marrow transplantation (BMT) is an important curative therapy for a number of hematologic malignancies, but it is complicated by Graft-vs.-host disease (GVHD) and idiopathic pneumonia syndrome (IPS). Research in Dr. Ferrara's laboratory has demonstrated agents that protect the GI tract provide new opportunities for prevention of the cascade of inflammatory cytokines that can reduce these complications. This project will support several clinical trials designed to test novel agents that can reduce the toxic complications of BMT. Funding from the Doris Duke Charitable Foundation will facilitate the laboratory evaluation of patient samples from all of these trials, support the design of new trials of these agents and enhance the mentoring of junior faculty members involved in translational BMT studies.
Keratinocyte growth factor (KGF) is a protein that stimulates the grown of epithelial cells including those of the GI tract. Recombinant human KGF (rHuKGF) protects the GI tract, prevents severe GVHD and preserves donor T cell function needed for the beneficial graft-versus-leukemia effect. Specific aim 1 is to perform a single arm, dose-esclation, safety trial of rHuKGF plus standard GVHD prophylaxis.
Tumor Necrosis Factor (TNF)-alpha is a major inflammatory cytokine effector of these two disorders. Neutralization of TNF-alpha with soluble dimeric TNF-alpha binding protein (etanercept) can prevent both GVHD and acute lung injury in preclinical studies. Specific Aim 2 is to perform a single arm Phase I-II trial of etanercept plus standard treatment (steroids) to treat newly diagnosed GVHD. Specific Aim 3 is to perform a single-arm, open label Phase I-II study of etanercept plus standard treatment (steroids) to IPS after BMT.
D. Gary Gilliland, Ph.D., M.D.,
Brigham and Women's Hospital
Biography
Dr. Gary Gilliland received his PhD in Microbiology from UCLA and his MD at UCSF. He completed Medical Residency and Hematology/Oncology Fellowship training at the Brigham and Women's Hospital and Dana-Farber Cancer Institute, and was Chief Medical Resident at Brigham and Women's Hospital. He is currently Associate Professor of Medicine at Harvard Medical School (HMS), and is on the faculty of the Biomedical and Biological Sciences Program in the Department of Genetics at HMS. He is also an Associate Investigator in the Howard Hughes Medical Institute, and is the Director of the Leukemia Program at the Dana-Farber/Harvard Cancer Center. His research efforts have focused on genetics and treatment of hematologic malignancies.
Abstract
Clinical Translational Approaches to Therapy of Myeloid Blood Diseases
This is a highly integrated and synergistic proposal that covers the entire spectrum of clinical translational research in myeloid blood diseases. These include the myeloproliferative disorders (MPD), myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Most adults and children who develop MPD, MDS or AML eventually succumb to complications related to their disease or therapy. Unfortunately, our therapeutic approaches to these diseases have changed little over the past two decades. There is thus a compelling need to develop more effective and less toxic therapies for these potentially fatal blood disorders.
We have devoted a substantial effort to understanding the genetic basis of these MPD, MDS and AML, with the hope that these insights will allow us to develop therapies that target the specific genetic defect that causes the disease. Molecular targeting may allow for more specific and less toxic therapies, and may improve outcome either alone, or in conjunction with more conventional therapies. To this end, this proposal utilizes a comprehensive clinical translational approach to these blood disorders, including (i) cloning of disease alleles, (ii) characterization of the transforming properties in cell culture systems, (iii) development and testing of specific inhibitors in the model systems for transformation, (iv) translation of inhibitors into clinical trials. We have already demonstrated proof-of-principle for this approach in the application of FLT3 inhibitors in therapy of advanced MDS and AML.
An attribute of this application is the seamless dovetailing of laboratory and clinical investigation - this is not a unidirectional approach from bench to bedside, but rather a highly interactive and interdependent team of young investigators that derive synergy from the crosstalk between the laboratory and the clinic. However, perhaps the most important strength of the proposal is the dedicated and devoted focus on the career development of the physician-scientists. I have a strong track record of nurturing and supporting the career development of female and male physician-scientists. With the resources of the DCSA, which are entirely devoted to the salary and laboratory support of an exceptionally talent group of medical students, medical residents, hematology/oncology fellows, and junior faculty, I hope to help build the next generation of physician-scientists who will realize our collective dream and fervent hope of developing cures for these devastating blood disorders.
Daniel A. Haber, M.D., Ph.D.,
Harvard University
Biography
Dr. Daniel Haber was born in Paris, France in 1957. He came to the US in 1973 to attend college at Massachusetts Institute of Technology, where he received BS and MS degrees. He continued his studies at Stanford University under the Medical Scientist Training Program. He obtained his PhD in the laboratory of Dr. Robert Schimke in 1981, studying gene amplification as a mechanism of chemotherapeutic drug resistance, and received his MD in 1983. He subsequently completed a medical internship and residency at Massachusetts General Hospital, followed by a clinical fellowship in medical oncology at Dana Farber Cancer Institute (1986). Dr. Haber then pursued postdoctoral research training with Dr. David Housman at MIT, working on the characterization of the Wilms Tumor suppressor gene WT1. He was appointed Assistant Professor of Medicine at Harvard Medical School in 1991, and established his laboratory at the Massachusetts General Hospital Cancer Center to study the genetics of Wilms tumor and breast cancer. He was promoted to Associate Professor in 1996 and Professor in 2001. In addition, Dr. Haber serves as Associate Chief for Research in the Hematology Oncology Unit at MGH, as Chair of the Cancer Genetics Program for the Dana Farber-Harvard Comprehensive Cancer Center, and as Director of the MGH Center for Cancer Risk Analysis. He is on the Editorial Board of Cell and Cancer Cell, and serves as Genetics Editor for the New England Journal of Medicine. He has received numerous awards, including the McDonnell Cancer Scholar Award (1990), the American Association for Cancer Research and National Foundation for Cancer Research Professorship in Basic Cancer Research (2000), and a MERIT Award from the National Cancer Institute (2002). He was elected to the American Society for Clinical Investigation in 1995. He is the author of 122 publications dealing with various aspects of the genetics of pediatric kidney cancer and adult breast cancer. The Doris Duke Distinguished Clinical Scientist Award was awarded for his work on the characterization of CHK2, a cell cycle checkpoint kinase that is mutated in the germline of women with predisposition to breast cancer.
Abstract
CHK2: A Common Low Penetrance Familial Breast Cancer Gene
Germline mutations in BRCA1 account for ~50% of high risk familial breast cancer, while mutations in BRCA2 are responsible for ~25% of cases. These findings have provided important insight into the pathogenesis of breast cancer, and they have made it possible to offer genetic counseling to family members at risk, with consideration of preventive surgery, hormonal chemoprophylaxis, intensive screening regimens, and eventually the possibility of genotype-directed therapy. The etiology of familial breast cancer cases lacking mutations in the BRCA genes is uncertain, and the absence of clear genetic linkage to a third locus has led to the suggestion that these cases may result from a number of lower penetrance genes, which in aggregate, may contribute to both breast cancer kindreds, as well as individuals with less dramatic family histories. A major step in this direction has been the observation that 1% of the population carries a specific truncating mutation in CHK2 (1100delC), while this mutation is present in 5% of familial breast cancer cases (ie. a common low penetrant mutation). CHK2 encodes a kinase, which itself is activated by the DNA damage responsive kinase ATM, and which is capable of phosphorylating p53, CDC25 and BRCA1. As such, CHK2 is positioned at the intersection between DNA damage response sensors and the effectors of cellular checkpoints implicated in cell cycle arrest, apoptosis and DNA damage repair. Our laboratory was the first to identify mutations in CHK2, including 100delC which we discovered in a family with the multicancer phenotype Li-Fraumeni Syndrome, but which lacked the characteristic mutation in p53. CHK2 has now been shown to phosphorylate p53 at the critical 20Serine residue required for its activation following DNA damage. The recent discovery that the specific CHK2 mutation 1100delC is common in the population and confers a moderate risk for breast cancer has raised the possibility that additional mutations in this gene and in other related genes may play a significant role in human breast cancer. In this proposal, we propose 1. to undertake mutational analyses of CHK2 and related genes in familial breast cancer cases lacking mutations in BRCA genes; 2. to define the penetrance (ie. breast cancer risk) and clinical phenotype associated with these mutations; 3. to develop functional assays that allow interpretation of CHK2 missense mutations present in familial breast cancer cases; and 4. to use CHK2 as a model with which to explore how analysis of low penetrance mutations should be integrated into clinical practice. These questions will have significant impact, both in terms of high risk breast cancer care, as well as the more general integration of increasingly complex genetic information into the clinic.
Daniel J. Rader, M.D.,
University of Pennsylvania School of Medicine
Biography
Dr. Daniel J. Rader is an Associate Professor of Medicine and Pathology at the University of Pennsylvania School of Medicine in Philadelphia, Pennsylvania. He is Director of Preventive Cardiology and the Lipid Clinic and Associate Director of the General Clinical Research Center. Dr. Rader runs a basic research laboratory focused on genetic regulation of lipoprotein metabolism and atherosclerosis and directs a clinical research program focused on human genetics of lipid disorders and atherosclerosis, imaging of atherosclerosis, and novel approaches to treatment of dyslipidemia and regression of atherosclerosis. He has a particular interest in HDL metabolism, factors and genes involved in its regulation, the nature of the relationship of HDL metabolism to atherosclerosis, and novel approaches to raising HDL cholesterol levels as a tool for treating and preventing atherosclerosis. Dr. Rader is a member of the American Society of Clinical Investigation and serves on the executive committee of the Arteriosclerosis, Thrombosis and Vascular Biology Council of the American Heart Association and the scientific board of the Sarnoff Foundation. He is an Established Investigator of the American Heart Association and a recipient of the Burroughs Wellcome Trust Clinician-Scientist Award in Translational Research.
Dr. Rader received his MD from the Medical College of Pennsylvania in Philadelphia, Pennsylvania. He then completed an internship and residency in internal medicine at Yale-New Haven Hospital in New Haven, Connecticut and was a Chief Resident in internal medicine at Yale. Dr Rader then did a fellowship at the Molecular Disease Branch of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health in Bethesda, Maryland, where he subsequently was appointed staff scientist. He was recruited to the University of Pennsylvania in 1994.
Dr. Rader is on the editorial boards of Arteriosclerosis Thrombosis and Vascular Biology, American Journal of Physiology (Endocrinology and Metabolism), Circulation, Circulation Research, and Trends in Molecular Medicine and is a reviewer for many journals, including Nature, Nature Medicine, Science, New England Journal of Medicine, and Journal of Clinical Investigation. Dr. Rader has authored over 120 peer-reviewed publications as well as many reviews and book chapters. He has written the chapters on lipid disorders and management for several textbooks including Kelley's Textbook of Internal Medicine, Topol's Textbook of Cardiovascular Medicine, and Nelson's Textbook of Pediatrics. He is a frequently invited speaker nationally and internationally on his basic and clinical research in lipoprotein metabolism, atherosclerosis, genetics, and gene therapy and on clinical topics such as novel approaches to cardiovascular risk assessment and management of lipid disorders.
Abstract
Genetics of Lipid Metabolism and Atherosclerosis
Atherosclerotic cardiovascular disease (ASCVD) remains epidemic in the U.S. and most of the world. Effective prevention requires accurate identification of those at risk and institution of therapies that reduce risk. Stabilization and regression of atherosclerosis require development of new therapeutic interventions that are effective and complement existing therapies. A better understanding of the genetics of atherosclerosis and its risk factors will provide greater ability to predict future risk as well as lead to new targets for therapeutic intervention. Plasma lipoprotein metabolism is intimately related to the development of atherosclerosis. Plasma low-density lipoprotein (LDL) cholesterol is directly associated and plasma high-density (HDL) cholesterol inversely associated with ASCVD. Reduction of LDL-C is proven to reduce risk although only by about one-third over 5 years. The effects of raising HDL-C are uncertain as highly effective HDL-raising interventions are not yet available. Our broad goal is to investigate the role of genetic variation in determining levels of LDL-C and HDL-C and translate those findings into new abilities to predict, prevent, and regress atherosclerosis.
Specific Aims:
- Determine the safety and efficacy of pharmacologic inhibiton of the microsomal transfer protein (MTP) in patients with homozygous FH. Investigate the effects of MTP inhibition in homozygous FH patients on in vivo lipoprotein metabolism and atherosclerosis.
- Investigate the molecular etiology of dominantly-inherited high HDL cholesterol using both linkage analysis and candidate gene approaches.
- Develop methods for quantitation of peripheral cholesterol mobilization and reverse cholesterol transport in humans and apply them to the investigation of existing and novel therapeutic approaches targeted toward HDL metabolism.
These studies work toward an era in which genetics will allow us to identify high-risk individuals well before their clinical event and to design new therapies that will allow us to effectively prevent and regress atherosclerosis.