Awarded: Aug 06, 2001
$10.5 million over 5 to 7 years
In 2001, seven outstanding physician-scientists at the mid-career level each received grants of $1.5 million to be used over 5 to 7 years.
2001 DCSA Grantees
Nina Bhardwaj, M.D., Ph.D.
New York University School of Medicine
Brian J. Druker, M.D.
Oregon Health and Science University
Steven A.N. Goldstein, M.A., Ph.D., M.D.
Yale University School of Medicine
(currently at The University of Chicago)
Dianna M. Milewicz, M.D., Ph.D.
University of Texas Health Science Center at Houston
Charles L. Sawyers, M.D.
UCLA School of Medicine
Margaret A. Shipp, M.D.
Harvard University, Dana-Farber Cancer Institute
Robert F. Siliciano, M.D., Ph.D.
The Johns Hopkins University School of Medicine
Nina Bhardwaj, M.D., Ph.D.
New York University School of Medicine
Biography
Dr. Bhardwaj was born in Nairobi, Kenya. She came to the United States in 1971 as a college student, graduating from Wellesley College in 1975 with a BA in Biology with honors. Dr. Bhardwaj subsequently spent six years at the New York University where she obtained her M.S., M.D., and PhD degrees. This was followed by a residency in Internal Medicine at the Brigham and Women's Hospital in Boston and a fellowship in Rheumatology at the Hospital for Special Surgery and Weill Medical College in New York. Dr. Bhardwaj continued her research at the Rockefeller University where she was a post-doctoral fellow. She is now an Professor of Medicine in the Department of Pathology and Oncology at New York University School of Medicine. Her focus is on the biology of human dendritic cells and their application in vaccines and immunotherapies for the treatment of chronic virus infections and cancers.
Abstract
Enhancement of anti-HIV Immunity
Although the institution of highly active anti-retroviral therapy (HAART) has reduced morbidity and mortality from HIV-1 infection, the virus persists in tissue reservoirs and rebound viremia occurs when treatment is halted. Recent findings that intermittent compliance with drug therapy stimulates T cell responses have led to the concept that antigenic stimulation through re-exposure to virus, or the boosting of T cell responses via immunization, will be necessary as an adjunct to HAART. We have shown that a highly effective way to generate human anti-viral T cell responses in vivo is by presenting antigens on dendritic cells (DCs) a system of antigen presenting cells (APCs) that stimulate innate and acquired immune responses. This proposal will apply this new modality of enhancing immunity to HIV-1 infection.
The specific aims are to:
- Advance methodology for DC generation from human blood precursors to facilitate DC vaccinations. DCs are currently generated from proliferating or nonproliferating progenitors over 7-14 days. To hasten the generation period and obtain DCs in "good tissue practice" conditions, new procedures and "closed culture" systems will be evaluated.
- Identify effective vaccine vehicles to induce anti-HIV immunity in DC-based immunizations. Current vaccines do not elicit effective cellular immunity against HIV-1, possibly because they fail to target DCs. Innovative vaccines, such as novel DNA constructs, heat shock proteins and chemically inactivated HIV-1, in addition, to nonreplicating pox vectors will be tested for their potential to charge DCs with antigens.
- Establish the safety and immunogenicity of antigen bearing DCs in seronegative and seropositive adults. Clinical trials will be initiated to test the immunogenicity of DCs pulsed with promising vaccines vehicles. We will consider the subset of DC that is the most immunogenic in addition to routes of delivery, schedule and comparison to adjuvants in clinical use.
These studies will provide a basis for designing vaccines which target DCs in situ. In addition, they will support the creation of a vaccine research program at Rockefeller University to train clinical investigators in a new area of immune based therapies.
Brian J. Druker, M.D.
Oregon Health and Science University
Biography
Brian J. Druker, M.D., is the Director of the OHSU Cancer Institute Leukemia Center. As a Professor of Medicine, Division of Hematology and Medical Oncology, he has joint appointments in the Department of Cell and Developmental Biology and the Department of Biochemistry and Molecular Biology. Upon graduating from UC San Diego medical school in 1981, Dr. Druker completed his internship and residency in internal medicine at Barnes Hospital: Washington School of Medicine in St. Louis, Missouri. He then trained in Oncology at Harvard's Dana-Farber Cancer Institute. Upon completion of his clinical training, Dr. Druker returned to the lab to begin a research career studying the regulation of the growth of cancer cells and how this knowledge could be applied to cancer therapies. His work has been instrumental in the development of a drug that has shown remarkable success in the treatment of patients with chronic myeloid leukemia. The clinical trials with STI571, commonly known as Gleevec, have been heralded as a new paradigm in cancer therapy. His role in the development of STI571 and application in the clinic have resulted in numerous awards for Dr. Druker, including the AACR Richard and Hinda Rosenthal Award, the John J. Kenney Award from the Leukemia and Lymphoma Society, the Warren Alpert Prize from Harvard Medical School, and The American Society of Hematology's Dameshek Prize.
Abstract
Molecularly Targeted Therapies for Leukemia
Molecular studies have identified a number of distinct signal transduction pathways that are deregulated in human cancers. A major priority for the cancer research community is the translation of this growing body of knowledge into therapeutics targeted specifically to these pathways. Our work with STI571, an inhibitor of the molecular pathogenetic tyrosine kinases in chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST) have validated this approach. In performing these clinical trials, we have gained a significant amount of experience in the design and implementation of studies with molecularly targeted agents. These studies have confirmed our opinion that an essential part of these studies are molecular endpoints for determination of optimal therapeutic benefit and that a new paradigm needs to be established in which basic science investigations are an integral part of clinical trials of these agents. Having established this paradigm with STI571, we now are turning our attention to the FLT3 tyrosine kinase, which is constitutively activated by mutation in over 30% of cases of acute myeloid leukemia (AML), making this the most common mutation in AML. Our goals are to identify a suitable FLT3 inhibitor for clinical trials, to prepare all of the reagents necessary for mutation detection and determination of the activation state of FLT3, and perform clinical trials with a FLT3 inhibitor. We believe that our experience with STI571 makes our group uniquely suited to this task.
Steven A.N. Goldstein, M.A., Ph.D., M.D.
Yale University School of Medicine
(currently at The University of Chicago)
Biography
Steve A. N. Goldstein is Professor and Chairman of Pediatrics at The University of Chicago. He received his B.A. and M.A. in Biochemistry from Brandeis University (1978), his M.D. and Ph.D. from Harvard University (1986), his training in pediatric medicine and cardiology at Children's Hospital, Boston (1986-1993) and his training in ion channel biophysics with Christopher Miller (Brandeis University, 1989-1993). He was recipient of the E. Mead Johnson Award (2001) for his work on ion channel biophysics and cardiovascular medicine, and he was formerly Professor of Pediatrics and Cellular and Molecular Physiology, Chief of the Section of Developmental Biology and Biophysics and member of the Boyer Center of Molecular Medicine at Yale University.
Abstract
Cardiac Ion Channel Mutations in Sudden Childhood Death
Over the past 6 years, as genes for ion channels have been identified, the molecular mechanisms underlying normal cardiac function and sudden life-threatening diseases of the heart have become increasingly clear. Ion channels control the electrical activity of muscles and nerves. Dysfunction of ion channels leads to dangerous cardiac rhythms and may produce Sudden Infant Death Syndrome (SIDS). In some children, inherited mutations in ion channels cause disease directly; in others, gene variations lead to an unstable situation, a genetic predisposition, where a secondary challenge such as drug therapy incites a disorder. This proposal seeks to understand, diagnosis and prevent (a) inherited pediatric arrhythmia; (b) drug-induced pediatric arrhythmia; and, (c) SIDS, through pursuit of four Specific Aims:
- To identify children with these disorders.
- To evaluate ion channel genes in these children (and their relatives) for mutations and polymorphisms and assess the clinical significance (risk) of specific genetic variants.
- To study how genetic variation alters ion channel function to cause (or predispose to) disease.
- To develop improved methods to identify genetic variants associated with ion channel disease.
This proposal is feasible because our team cares for the majority of children in Connecticut with abnormal ECG findings, syncope/near syncope, palpitations, aborted sudden cardiac demise, seizures and many treated with arrhythmia-associated medications; moreover, all cases of SIDS in the State are now referred to the Goldstein laboratory for genetic study, and a collaboration with the NIH Pediatric Pharmacology Research Network (NICH-PPRU) is being designed. The proposal is timely and practical because the tools we need to proceed are now available. Thus, we have recently used these approaches to link both rare mutations and common polymorphisms in ion channel genes to inherited LQTS, drug-induced arrhythmia and periodic paralysis in adults and, thereby, elucidated some of the changes in ion channel physiology that lead to disease. Potential benefits of the proposal include the knowledge to avoid drug-induced arrhythmia (through pre-prescription genotyping), genotype-based risk assessment for sudden childhood deaths, interventions based on pathophysiology, and development of genetic tests for inherited and acquired pediatric arrhythmia (a real need as children are often quite difficult to diagnose). Through proven approaches and forays in new directions we seek to improve child health and train a remarkable group of students, fellows and junior faculty in bench-to-bedside research.
Dianna M. Milewicz, M.D., Ph.D.
University of Texas Health Science Center at Houston
Biography
Dianna M. Milewicz, M.D. Ph.D., is Professor and Vice Chairman of the Department of Internal Medicine at The University of Texas Medical School at Houston. She is Director of the M.D./Ph.D. Program and co-Director of the Biomedical Engineering Center, both of which are joint programs between The University of Texas Health Science Center at Houston and M.D. Anderson Cancer Center. Her research interests include the genetic basis of cardiovascular diseases, and understanding the effect of identified mutations on protein function. She has recently established a genetic core laboratory to provide molecular biology and genetic expertise to clinicians who want to initiate genetic studies on their patient populations.
Dr. Milewicz graduated from Rice University, received her M.D. and Ph.D. from The University of Texas Southwestern Medical School, and completed her residency in internal medicine at the same institution. She did her fellowship training in medical genetics at the University of Washington Medical School and joined the faculty at The University of Texas Medical School at Houston in 1991. Dr. Milewicz's awards include a Pfizer Scholars Award, March of Dimes Basil O'Connor Scholar Award, American Heart Association Established Investigator Award, membership in the American Society of Clinical Investigation (ASCI), and the 1999 Antoine Marfan Award from the National Marfan Foundation. She is an Associate Editor of Circulation and a member of the National Marfan Foundation Professional Advisory Board.
Abstract
Genetic Basis of Aortic Aneurysms and Dissections
The major disease processes affecting the aorta are aortic aneurysms and dissections. Aortic aneurysms are a major health problem in the United States, representing the 13th major cause of death, accounting for nearly 15,000 deaths annually. Ten to twenty percent of all aneurysms result from a genetic predisposition for the disorder. Although some familial aneurysms are due to inherited defects in extracellular matrix proteins, including Marfan syndrome and Ehlers-Danlos syndrome type IV, the majority of inherited aneurysms occur as an isolated cardiovascular abnormality, segregating in families as a monogenic autosomal dominant disorder. We have identified 25 families with autosomal dominant inheritance of thoracic aortic aneurysms and dissections, in whom the disease is characterized by variable expression and decreased penetrance. Using DNA obtained from family members and polymorphic markers spaced throughout the human genome, we have mapped a defective gene causing the disorder in 12 of these families to 5 Mb region at 5q13-14. Dr. Craig Basson and his colleagues (Cornell University Medical College) have mapped a second locus for familial aneurysms in one large family to 11q23. We have confirmed further genetic heterogeneity for this disorder by the identification of families in whom the inheritance of the phenotype is not linked to the two identified loci. The long-term goal of the proposed project is to identify the mutant genes that predispose an individual to thoracic aortic aneurysms or dissections.
The specific aims are the following:
- to identify, characterize, and collect samples from families with thoracic aortic aneurysms and dissections;
- to narrow the critical interval at 5q13-14 and identify candidate genes;
- to screen for mutations in candidate genes using samples from families with autosomal dominant inheritance of thoracic aortic aneurysms and dissections;
- to characterize mutations in sporadic cases of thoracic aortic aneurysms and dissections.
The proposed studies will identify the defective gene at a major locus for thoracic aortic aneurysms and dissections. Identification of the genetic etiology of aortic aneurysms and dissections will enable preclinical diagnosis in families at risk. In addition, identification of the defective genes will lead to the development of experiment models of vascular pathology to increase understanding of the molecular pathology and provide the basis for rationale intervention.
Charles L. Sawyers, M.D.
UCLA School of Medicine
Biography
Dr. Sawyers is Professor of Medicine and Director of the Prostate Cancer Program Area at the UCLA Jonsson Comprehensive Cancer. He is a member of the UCLA Molecular Biology Institute and a practicing oncologist in the UCLA prostate cancer clinic. Dr. Sawyers is well-known in leukemia circles for his work on the BCR-ABL tyrosine kinase in chronic myelogenous leukemia. He was a primary participant in the design and conduct of clinical trials of the ABL tyrosine kinase inhibitor STI571 (Gleevec), and his lab was the first to identify mechanisms of drug resistance due to Bcr-Abl gene mutation and amplification. He has also applied his expertise in signal transduction to human prostate cancer. His group has developed a novel set of human prostate cancer xenografts which have allowed molecular biological investigations into the mechanisms of hormone-refractory prostate cancer progression and metastasis. Most recently his laboratory has implicated deregulation of the PTEN/AKT pathway as a major event in advanced prostate cancer.
Dr. Sawyers received his undergraduate degree from Princeton University and his medical degree from the Johns Hopkins School of Medicine. He completed a residency in Internal Medicine at the UCSF Medical Center, and a clinical fellowship in Hematology/Oncology at the UCLA School of Medicine. He also completed a post-doctoral fellowship in Molecular Biology at the UCLA School of Medicine. Dr. Sawyers is board certified in Internal Medicine, Medical Oncology, and Hematology. He has published over 60 scientific and medical papers in such journals as the New England Journal of Medicine, Science and Cell. Dr. Sawyers has won numerous honors and awards, including the Franklin D. Murphy Prize, Stohlman Scholar of the Leukemia and Lymphoma Society, and he was recently appointed the Peter Bing Professor at the UCLA School of Medicine.
Abstract
Kinase Inhibitor Therapy for Cancers with Aberrant PTEN/Akt Pathway Signaling
My research has focused on characterizing signal transduction pathway abnormalities in human cancers—first in chronic myeloid leukemia (CML) and now in prostate cancer. In addition, I have first hand experience in clinical research, through the design and conduct of the phase I-II trials of STI-571 in CML in collaboration with Brian Druker. Most recently, I have linked these two aspects of my career by showing that resistance to STI-571 can occur through Bcr-Abl gene amplification or mutation. In addition, to teaching us about CML and kinase inhibitor therapy, this work clearly demonstrates the value of molecular target analysis in patients treated with signal transduction inhibitors. Several years ago, my lab demonstrated that the PTEN/Akt pathway is dysregulated in up to 50 percent of men with advanced prostate cancer. We and others have demonstrated that aberrant signaling through this pathway is sufficient to cause prostate cancer (and other cancers) in mouse models. Now we have pre-clinical evidence that an inhibitor of the mTOR kinase, which is a downstream component of the PTEN/Akt pathway, is effective treatment for prostate cancers and gioblastomas with PTEN/Akt pathway abnormalities. One mTOR inhibitor (CCI-779) has completed phase I safety testing and is well tolerated at doses above that required to inhibit mTOR. My goal for the Doris Duke award is to apply the STI-571/CML model for developing kinase inhibitor therapy to cancers in which the PTEN/Akt pathway signaling is dysregulated. We will develop the appropriate molecular assays to identify cancers with perturbations in the PTEN/Akt pathway and conduct clinical trials of CCI-779 in these patients.
Margaret A. Shipp, M.D.
Harvard University, Dana-Farber Cancer Institute
Biography
Margaret A. Shipp, M.D. is an Associate Professor of Medicine at Harvard Medical School and the Director of the Lymphoma Program at both the Dana-Farber Cancer Institute and the newly expanded Dana-Farber/Harvard Comprehensive Cancer Center. Dr. Shipp obtained her medical degree from Washington University School of Medicine and completed her residency in Internal Medicine at Barnes Hospital in St. Louis, Missouri. Thereafter, she completed a fellowship in Medical Oncology at the Dana-Farber Cancer Institute and subsequently joined the faculty. Dr. Shipp's clinical and laboratory research focuses on the clinical and molecular heterogeneity of the most common lymphoid malignancy, diffuse large B-cell lymphoma (DLBCL). Dr. Shipp coordinated the development of the International Prognostic Index which is used worldwide to individualize treatment approaches to DLBCL and other aggressive lymphomas. More recently, she has led efforts to identify and evaluate rational treatment targets in DLBCL. Dr. Shipp is the recipient of numerous awards including an American Cancer Society Junior Faculty Award, a Leukemia Society of America Scholar Award, membership in the American Society of Clinical Investigation and designation as a Stohlman Scholar of the Leukemia and Lymphoma Society of America.
Abstract
Rational Risk-Related Treatment Strategies in Diffuse Large B-Cell Lymphoma
Diffuse large B-cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is currently curable in only 40% of patients. Clinical prognostic factor models such as the International Prognostic Index identify patients who are unlikely to be cured with standard therapy. However, these clinical models do not provide additional insights regarding more effective treatment strategies. In the absence of molecular insights into the observed heterogeneity of DLBCL, therapeutic approaches to "high-risk" patients have largely focused on modifying doses and schedules of conventional chemotherapeutic agents and adding stem cell support. However, these approaches have not significantly improved DLBCL patient survival, underscoring the need to identify more rational, molecularly defined approaches to treatment. The clinical features used to identify "high-risk" DLBCL are likely to be surrogate variables for intrinsic molecular heterogeneity in the disease. For this reason, we have used a variety of approaches to define the molecular bases for outcome differences, characterize biologically discrete subsets of DLBCL and identify rational treatment strategies in the disease. Most recently, we have successfully utilized gene expression profiling and supervised learning methods to predict outcome and identify novel treatment targets in a pilot series of patients with DLBCL. We propose to build upon our previous studies to:
Define molecular signatures of cured versus fatal disease;
Characterize the contribution of cell of origin and specific signaling pathways to these outcome signatures; and
Utilize the molecular signatures of relapsed and newly-diagnosed high-risk DLBCL to develop rational risk-related approaches to therapy.
To accomplish these goals, we will work closely with colleagues from the university-wide DF/HCC Lymphoma Program with specific expertise in hematopathology, genomics/bioinformatics, biostatistics and basic B-cell biology. In the 5-yr funding period of this grant, our goal is to dramatically increase the cure rate in DLBCL by developing therapeutic strategies based on newly-identified rational targets and testing these approaches in the clinic.
Robert F. Siliciano, M.D., Ph.D.
The Johns Hopkins University School of Medicine
Biography
Dr. Robert F. Siliciano is Professor of Medicine at the Johns Hopkins University School of Medicine. He received his BA from Princeton in 1974 and then completed an MD and a PhD in Immunology at Johns Hopkins. After a postdoctoral fellowship at Harvard Medical School with Ellis Reinherz, he returned to Johns Hopkins. His research has focused on AIDS vaccine development and mechanisms of HIV persistence in patients on combination antiretroviral therapy. His group has identified a latent reservoir for HIV in resting memory CD4+ T cells that allows the virus to persist indefinitely despite strong antiviral immune responses and potent antiretroviral therapy. The discovery of this reservoir has led to a major change in strategies for the treatment of HIV infection, with a shift towards a more conservative approach to the initiation of therapy now that eradication of the infection with antiretroviral drugs no longer a realistic goal. His group is currently working on strategies for optimizing the treatment of HIV infection. Dr. Siliciano is the recipient of an NIH Merit Award and has served as chair of the NIH Study Section on AIDS and Related Research. At Johns Hopkins, he directs the MD-PhD program.
Abstract
Latent Reservoirs for HIV-1: Basic Mechanisms and Clinical Significance
Treatment of HIV infection with combinations of antiviral drugs ("cocktail therapy") represents the best current hope for prolonging the lives of the staggering number of people infected with this virus. In many patients, this form of treatment drop levels of the free virus in blood down so far that they can no longer be detected using even the most sensitive of current blood tests. The dramatic effect of combination therapy on free virus levels initially raise hopes that prolonged treatment might cure the infection. However, work from our laboratory has shown that in the vast majority of patients, treatment cannot cure the infection because the virus perists in a silent form in a very stable reservoir of long lived T cells. The discovery of a silent or latent reservoir for HIV that allows lifetime persistence of the virus in most patients has led many physicians to rethink the overall strategy for the treatment of HIV infection. New guidelines suggest that it may be better to delay the initiation of treatment with potentially toxic drug combinations now that virus eradication no longer appears possible. Most recently, we have shown that although combination therapy is unlikely to be curative, it can come close to stopping the evolution of the virus. The overall objective of the proposed studies is to use new information about how HIV persists to develop new approaches and strategies for treatment. The first goal is to develop a way to determine whether the virus is still evolving. A major problem is that the virus rapidly evolves to become resistant to the treatment drugs. With better ways of detecting viral evolution, it should become easier to select the drug combination that do the best job of stopping the evolution of the virus with the fewest side effects for the patient. In addition, this assay will be useful in deciding when therapy needs to be changed. A second major goal is to improve the treatments available for patients who already have developed resistance to some AIDS drugs. Some of the resistant virus can be present in a silent form, making it difficult for physicians to know which drugs to chose. We will attempt to develop new approaches that give a complete picture of the drug resistant viruses present in a patient, including those stored in the latent reservoir. In addition, we will develop ways for physicians to test various alternative combinations of antiviral drugs for ability to inhibit growth of the patient's virus in the test tube. We hope that this will facilitate the selection of treatments for patients whose options have been narrowed by the evolution of drug resistance.