Awarded: Aug 02, 2004
$6 million over 5 to 7 years
In 2004, four 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.
2004 DCSA Grantees
David E. Fisher, M.D., Ph.D.
Children's Hospital of Boston /
Harvard Medical School
Sanjiv S. Gambhir, M.D., Ph.D.
Stanford University School of Medicine
Robert S. Negrin, M.D.
Stanford University School of Medicine
Philip J. Rosenthal, M.D.
University of California, San Francisco
David E. Fisher, M.D., Ph.D.
Children's Hospital of Boston/Harvard Medical School
Biography
David Fisher was born in Highland Park, New Jersey to a scientist father and musician mother. He graduated from Swarthmore College (Biology & Chemistry) and the Curtis Institute of Music (cello) and subsequently obtained his Ph.D. at Rockefeller University and M.D. at Cornell Medical College. His Ph.D. work was carried out with Henry Kunkel and Gunter Blobel on the topic of small nuclear ribonucleoprotein biogenesis and recognition by auto-antibodies (cell biology & immunology). Fisher completed residency training in Internal Medicine at Massachusetts General Hospital, followed by specialization in Adult Oncology and Pediatric Hematology/Oncology at the Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School. He carried out postdoctoral research training with Dr. Philip Sharp at the Center for Cancer Research at MIT before joining the Harvard Medical School faculty in 1993 in the Department of Pediatric Hematology/Oncology. In this capacity he continues to treat Pediatric Oncology patients, teach graduate and medical students, and lead a basic science research group with a focus on the interface between clinical oncology and molecular medicine.
Dr. Fisher's research has focused on the process of gene transcription, an event which underlies normal growth as well as disease states. He is renowned for his studies on development of melanocytes, the cells in skin which make pigment as well as the analysis of mechanisms which regulate the process of cell death. His work has had major impact in the field of melanoma biology, and Dr. Fisher recently became Director of the Melanoma Program in Medical Oncology at the Dana-Farber Cancer Institute, Harvard Medical School. His research related to the Doris Duke Distinguished Clinical Scientist Award involves novel therapeutic and prevention strategies for melanoma.
Dr. Fisher has received numerous honors and awards including the Gertrude B. Elion Award for Cancer Research from the American Association for Cancer Research, the Pew Foundation Scholars Award, the American Society of Hematology Scholar Award, and the McDonnell Foundation Research Scholar Award. He also sits on the council of multiple biomedical foundations including the William Guy Forbeck Pediatric Cancer Research Foundation, the Melanoma Research Foundation, and the American Society of Clinical Investigation. He lives with his wife Claire Fung (physician, Harvard Medical School) and their four children in Newton, MA.
Abstract
Novel Strategies for Treatment and Prevention of Melanoma
The incidence of melanoma is rising more steeply than any other malignancy in man. However, therapeutic success beyond early detection remains very limited. Despite this enormous challenge, several recent key discoveries have been made which suggest mechanism-based new strategies to confront this terrible disease. These findings include work from multiple labs, including ours, and involve breakthroughs in our understanding of pathways which regulate melanocyte growth and survival, production of UV-protective pigmentation, and signals from neighboring cells and the environment which govern melanocyte responsiveness or autonomous growth. A particularly important discovery is the observation that approximately two-thirds of melanomas harbor an identical activating mutation in the BRAF kinase. We have shown that this mutation effectively hijacks signaling pathways which are normally under tight homeostatic control, resulting in both predictable (MAPK) and unpredictable (BCL-family) anti-apoptotic consequences. These discoveries carry exciting opportunities for direct translation into patient-directed clinical interventions. This proposal focuses specifically on this translation, with sections devoted to both melanoma prevention and treatment. The first Aim is based upon our finding that it is possible to mimic the specific pathway of UV-induced pigmentation through use of a topical small molecule agonist. This strategy stands to offer clinical benefit for melanoma prevention. Aim 2 is a Kinome Sequencing study, in which primary melanoma specimens will be subjected to complete exon sequencing of all known kinase genes. BRAF mutations occur very early in melanomagenesis, based on their frequency in benign moles. Additional mutational events are extremely likely to accompany progression to invasive cancer. While such mutations may or may not reside within kinase genes, the kinases are particularly drug-able targets, and we wish to utilize a newly established intrastructure at our Institute to carry out this search. Aim 3 focuses on the clinical application of a new BRAF inhibitor drug, which we have collaborated in the development of with a large pharmaceutical company. Laboratory correlative studies will accompany this clinical analysis. Aim 4 examines clinical targeting of CDK2, a kinase which was found to exhibit distinct functional importance in melanoma (vs. other tumors) due to the localization of the CDK2 gene to a pigment gene genomic locus. Finally, as newly named Director of Melanoma in the Department of Medical Oncology at Dana-Farber Cancer Institute, I focus this proposal on building a broad, interdisciplinary Melanoma Program, bringing together clinicians from multiple specialties with lab-based physician scientists, to promote mentoring and bench-to-bedside research.
Sanjiv S. Gambhir, M.D., Ph.D.
Stanford University School of Medicine
Biography
Sanjiv Sam Gambhir is a Professor of Radiology and Bio-X at Stanford University. He is the Head of Nuclear Medicine and Director of the Molecular Imaging Program at Stanford (MIPS). He trained at the University of California Los Angeles (UCLA) Medical Scientist Training Program, where he obtained both his M.D. and Ph.D. He completed his Medicine and Nuclear Medicine training at UCLA and was a Professor of Molecular Pharmacology, Vice-chair of Molecular & Medical Pharmacology and Director of the Crump Institute for Molecular Imaging before moving to Stanford University in 2003. Dr. Gambhir, his wife Aruna and six-year-old son Milan live in Portola Valley, California.
Dr. Gambhir has a translational laboratory that focuses on molecular imaging including new probe development for positron emission tomography (PET) and multimodality molecular imaging including the use of optical imaging. His laboratory has developed methods to image gene therapy in living subjects including humans. He has also developed many strategies for imaging basic cell/molecular biology events including signal transduction, gene expression, and cell trafficking. Dr. Gambhir also has extensive experience with FDG PET and has developed many of the management algorithms for cancer patients including cost-effectiveness models.
Dr. Gambhir currently oversees the activities of over 20 graduate students and post-doctoral fellows in his own lab and over 50 scientists in the Molecular Imaging Program at Stanford. He is funded by the National Institutes of Health and the Department of Energy. He recently received the 2004 gold medal award by the Society of Molecular Imaging, the 2004 distinguished scientist award by the Academy of Molecular Imaging, and the 2003 Holst Medal for his contributions to the field of molecular imaging. He is also President Elect of the Academy of Molecular Imaging (AMI).
Abstract
Molecular Imaging of Cancer with a Voltage Sensor
My laboratory has been bridging the fields of biomedical imaging with cell/molecular biology, oncology, molecular pharmacology, and chemistry in order to advance molecular imaging of cancer in living subjects. My lab has developed several assays which allow for imaging of cell surface receptors, intracellular enzymes, and reporter genes in living subjects including humans. Through use of technologies such as positron emission tomography (PET) it is becoming increasingly possible to monitor events related to cancer progression and efficacy of anti-cancer therapies. The next generation of imaging tools/assays should allow for customized imaging in which specific imaging agents are available for each individual based on their underlying molecular abnormalities.
In the current proposal, I would like to test in human volunteers and cancer patients a new class of imaging probe that accumulates in cancer cells that have up-regulated their mitochondrial membrane potential. Many types of cancer are currently imaged with 18F-2-fluoro-2-deoxyglucose (18F-FDG) which measures glucose utilization in tumors. 18F-FDG has limitations due to poor uptake by several tumor types and reduced specificity due to accumulation in inflammatory tissues, skeletal muscle, bowel, as well as many normal tissues which depend on glucose. My lab has recently validated that a Fluorine-18 labeled tetraphenylphosphonium analog (18F-TPP) can accumulate very well in many tumor types, that this accumulation is correlated with mitochondrial membrane potential, and has excellent pharmacokinetics because it clears from blood and other tissues very rapidly. Furthermore 18F-TPP has almost no uptake in inflammatory tissues and bowel, which should lead to a much better specificity than 18F-FDG. In the current proposal we will test 18F-TPP with PET in human volunteers for stability, biodistribution, pharmacokinetics, and radiation dosimetry (Aim 1). Subsequently we will test 18F-TPP against 18F-FDG in patients with rising CEA levels and GI malignancies to determine its ability to outperform 18F-FDG (Aim 2). Finally, we will compare 18F-TPP and 18F-FDG in predicting response to treatment in colorectal cancer patients undergoing chemotherapy.
Robert S. Negrin, M.D.
Stanford University School of Medicine
Biography
Robert S. Negrin is a Professor of Medicine at Stanford University. He received his undergraduate degree from the University of California at Berkeley and his M.D. from Harvard Medical School. He performed his internship, residency and fellowship in Hematology at Stanford University. He joined the faculty at Stanford University in 1990 and was promoted to Associate Professor in 1997 and full professor in 2004. He has served as the President of the International Society of Cellular Therapy and will assume the presidency of the American Society of Blood and Marrow Transplantation in the year 2006. His research interests involve characterizing graft-versus-host and graft-versus-tumor reactions and developing cell-based therapeutics for the treatment of malignancies and other disorders. He is currently the Director of the Bone Marrow Transplant Program at Stanford University and Medical Director for the Stanford Cell Therapeutics Laboratory.
Abstract
Regulatory T Cells in Bone Marrow Transplantation
Regulation of the immune response holds great promise for the treatment of a variety of clinical conditions. In hematopoietic cell transplantation the transfer of immunity from donor to recipient is capable of curing malignancy in a reaction termed the graft vs tumor (GVT) effect. Equally potent and clinically dangerous is graft vs host disease (GVHD), which is the major limitation to successful allogeneic transplantation and limits the use of this treatment approach to patients with life threatening malignancies. Animal studies have clearly demonstrated that allogeneic hermatopoietic cell transplantation is capable of curing autoimmune disorders and enhances the survival of transplanted organs in the setting where GVHD can be controlled. Therefore, strategies, which are capable of controlling GVHD yet allow for GVT reactions, hold great promise in clinical medicine. In this proposal we will directly extend our recently discovered findings that a naturally present population of regulatory T cells with the defined cell surface phenotype of CD4+ CD25+ are capable of controlling GVHD in animal models across major histocompatibility barriers. Importantly, the Treg cells did not inhibit GVT effects. Further experimentation has demonstrated that the mechanism of this effect is due to the ability of the Treg to control proliferation of alloreactive conventional T cells which upon activation and expansion cause GVHD. In the presence of Treg alloreactive T cells still become activated which allows for GVT reactions, yet prevention of massive T cell expansion controls GVHD. An analogous population of human Treg cells with very similar properties with respect to cell surface phenotype and function can be found in the blood. In this proposal we will directly extend our bench results to the bedside where we will isolate, characterize and transplant highly defined populations of conventional and regulatory T cells. In the first Specific Aim, we will focus on the characterization and expansion of human Treg cells. We have developed a novel assay of cytotoxicity which will allow for the probing of effects of Treg cells on conventional T cell activation, expansion and cytotoxic function. We will explore the impact of freshly isolated and expanded Treg cells on the activity of conventional T cells in these assays and probe specific molecules using molecular and cellular biological techniques to explore mechanisms. In the second Specific Aim, we will directly extend these findings to the clinic where we will isolate pure populations of Treg cells with high speed cell sorting and pursue allogeneic transplantation in patients with malignancies. These studies will define both the biological and clinical activity of this unique population of T cells with immune regulatory function.
Philip J. Rosenthal, M.D.
University of California, San Francisco
Biography
Dr. Rosenthal is a Professor of Medicine at the University of California, San Francisco. He is a member of the Biomedical Sciences Graduate Program, the Sandler Center for Basic Research in Parasitic Diseases, and the Global Health Sciences Program at UCSF. He also directs a Fogarty International Center UCSF/Makerere University Training Grant for the training of African clinician scientists in malaria research. Dr. Rosenthal received a B.S. in Biochemistry from the State University of New York at Stony Brook and an M.D. from New York University. He then trained in Medicine at the University of Michigan and in Infectious Diseases at the University of California, San Francisco. He also served as a consultant for the World Health Organization. Dr. Rosenthal's research interests focus on malaria, including basic science, clinical, and translational research. Basic science studies include the characterization of a family of parasite cysteine proteases that includes promising targets for new antimalarial drugs. In collaboration with chemistry collaborators, his group is now pursuing drug discovery directed against cysteine proteases. Another project is exploring antibiotics as antimalarial drugs. Dr. Rosenthal's group also evaluates the clinical and molecular epidemiology of malaria, with studies based in Uganda. These studies include clinical trials of new antimalarial agents and drug combinations, evaluations of the roles of parasite and host genetic polymorphisms in drug resistance, considerations of the importance of the complexity of malaria infections, and studies of molecular mechanisms of drug resistance. Dr. Rosenthal is on the editorial boards of Antimicrobial Agents and Chemotherapy and The American Journal of Tropical Medicine and Hygiene. He has received an NIH Physician Scientist Award and was an Established Investigator of the American Heart Association. He receives research funding from the National Institutes of Health, the Centers for Disease Control and Prevention, and the Medicines for Malaria Venture.
Abstract
Translational Studies of Antimalarial Drug Resistance
Malaria is one of the greatest infectious disease problems in the world, and its control is severely limited by drug resistance. A better understanding of mechanisms of antimalarial drug resistance is greatly needed, but few groups are equipped to perform the translational studies needed to answer many key questions. We have been engaged in basic malaria research since the late 1980s and in clinical studies of antimalarial drug efficacy and resistance in Uganda since the late 1990s. This project will bridge our ongoing basic science and clinical malaria research programs to perform translational studies of antimalarial drug resistance. Tied to our research will be a major training effort, with mentoring of American junior faculty, postdoctoral fellows, and medical students and Ugandan junior scientists in translational malaria research. The broad objectives of our program will be to perform cutting edge translational research on malaria, primarily focusing on antimalarial drug resistance, to support the development of American clinical scientists with expertise in translational malaria research, and to support the development of African clinical scientists. In this research project we will test the hypotheses that the rate of antimalarial drug resistance development is dependent on the complexity and diversity of infections, that resistance develops due both to the migration of resistant clones and the spontaneous selection of resistant mutants, and that specific molecular mechanisms of resistance can be identified using modern molecular techniques.
Our specific aims will be as follows:
(1) Assessment of associations between the complexity and diversity of malaria infections and treatment outcomes. We will use samples from prior and ongoing clinical studies in Uganda to test the hypothesis that increased parasite complexity in an individual and diversity in a community favors the selection of drug-resistant parasites.
(2) Characterization of the selection of drug resistant malaria parasites. We will study laboratory isolates selected for resistance and isolates from patients with sensitive and resistant clinical outcomes to study the steps that lead to the elaboration of antimalarial drug resistance, in particular the relative contributions of migration of resistant clones into a community and the spontaneous selection of resistant parasites in an individual.
(3) Determination of molecular mechanisms of antimalarial drug resistance. We will compare sensitive and resistant laboratory and clinical isolates to evaluate putative resistance-mediating genes, including enzyme targets and potential drug transporters, and we will use genomic and proteomic techniques to screen for alterations that accompany drug resistance. Our project will provide important insights into mechanisms of antimalarial drug resistance and help to train a much-needed new generation of translational malaria researchers.