PI, Meenhard Herlyn
Co-PI, Ronen Marmorstein
The long-term objective of this program project is to develop new strategies for the treatment of melanoma, based on a mechanistic understanding of key proteins that are associated with the disease and the development of small molecule inhibitors to these proteins. The group proposes to pursue the following goals 1. Target oncogenic BRAF for therapy of melanoma. The oncogenic BRAF mutant, BRAFV600E, has evolved as, arguably, the most important target in melanoma. We will use several approaches to explore the use of BRAFV600E, as a target for therapy: We will: i. Use currently available inhibitors of the MAPK pathways with activity for either BRAF or MEK using complex in vitro and orthotopic in vivo models (Project 1); ii. Induce specific cellular immunity against BRAFV600E that leads to tumor growth inhibition in a melanoma model in mice (Project 2); iii. Develop a new generation of inhibitors for BRAFV600E based on the crystal structure of a BRAFV600E/Hsp90/p50Cdc37 complex (Project 3); and iv. Develop new organic inhibitors and a new generation of organometallic inhibitors using a ruthenium pyridocarbazole molecular scaffold to BRAFV600E with increased specificity and efficacy (Projects 3 and 4). We expect the development of new therapies of melanoma that focus on BRAFV600E as a molecular target to result from these combined biological, immunological, structural and chemical studies. 2. Target the PI3 kinase pathway with a new generation of inhibitors and use these in combination with BRAF inhibitors for therapy of melanoma. Based on preliminary studies in project 1, we hypothesize that PI3α kinase pathways are highly important for melanoma cell survival. Projects 3 and 4 combine structural and chemical strategies to identify a novel generation of inhibitors to the PI3Kα/γ isoforms. The inhibitors will be developed based on the organometallic scaffold described above for the BRAF kinases (Project 4), and supported by inhibitor screens in vitro (Project 4) and in vivo (Projects 1) and x-ray crystal structures of PI3Kγ/inhibitor complexes (Project 3). In addition, we will explore novel Akt/PKB inhibitors using in vitro and in vivo models and investigate how they synergize with BRAF inhibitors (Projects 1 and 2). 3. Target GSK3ß for induction of apoptosis. We have found that targeting GSK3ß with organometallic inhibitors (developed in Project 4) has surprising apoptosis-inducing activities on melanoma cells (Project 1). Based on these preliminary studies we will now investigate the mechanisms of apoptosis induction, which may occur through activation of p53 (Project 1). We will also continue to prepare more potent and specific organometallic GSK3? inhibitors in project 4 for treatment of melanoma cells in project 1. Most melanomas are not mutated in GSK3?, but p53 can also be downregulated by HDM2, which is frequently overexpressed in melanoma. Together, the collaborations among members of the Program Project will combine expertise in tumor biology, tumor immunology, biochemistry, chemistry and structural biology to generate unique approaches and reagents for use in melanoma therapy.
Intracellular signaling for the MAP kinase and PI3 kinase pathways. Growth factors activate signaling cascades for the MAP kinase pathway resulting in activation of RAS, RAF, MEK, and ERK. They also activate the PI3 kinase cascade resulting in PKB/AKT activation, which in turn blocks endogenous G
Advisors to the Program Project
The External Advisory Committee will meet annually. The External Advisors will advise the PIs to make major readjustments of the program. It is composed of experts in the melanoma and related fields. External Advisors are important to provide an outside review of the entire spectrum of the program.
Menashe Bar-Eli, Ph.D., Professor of Cancer Biology, Department of Cancer Biology, UT MD Anderson Cancer Center. Dr. Bar-Eli is a molecular biologist and biologist who has investigated the biology of melanoma for over two decades. His major interests are in transcription factors and their roles in the regulation of expression and function of major melanoma-associated molecules, such as AP-2, CD146 or IL-8. Dr. Bar-Eli’s expertise relates to Project 1 and Cores B and C
Young-Tae Chang, Ph.D., Associate Professor, New York University. Dr. Chang is an accomplished chemist with expertise in combinatorial chemistry and the development of strategies for target identification and forward chemical genetic screens. His insight into signaling and signaling inhibitors make him an ideal advisor for projects 4 and 3.
Ronald A. DePinho, M.D., Professor of Medicine and Genetics, Dana-Farber Cancer Institute, Harvard medical School, and the Director of the Center for Advanced Cancer Science, at the Dana-Farber Cancer Institute, Boston, MA. Dr. DePinho is at the forefront of cancer biology by developing mouse models that mimic the human disease. He has made contributions to cancer and senescence and to the biological consequences of genetic aberrations in cancer. His expertise relates to Projects 1, 3, and 4 and Cores A, B, and C.
Eric Fearon, M.D., Ph.D., Professor, Director of Basic Science Research, Division of Molecular Medicine/Genetics, University of Michigan Science Center, University of Michigan, Ann Arbor, MI. Dr. Fearon has made major contributions to our understanding of colon and tumor progression. He has identified several important oncogenes and has investigated the signaling for these oncogenes and tumor suppressor genes. His expertise is mostly for Projects 1 and 3, and Cores B and C.
Mark Nelson Ph.D., Associate Professor in the Department of Pathology, University of Arizona, and the Director of Research at the University of Arizona, Tucson, AZ. Dr. Nelson has major research interests in apoptosis-related genes in melanoma. He is a cancer biologist with expertise closely relating to Projects 1, and 3, and Cores B and C.
Yigong Shi, Ph.D., Professor, Department of Molecular Biology at Princeton University, Princeton, NJ. Dr. Shi is a structural biologist and biochemist, and he has major interests that relate to Project 3.
The Internal Advisory Committee meets once a year, and will provide specific recommendations to progress and plans. The Internal Advisors also participate in annual retreats for exchange of the global view of the scientific progress on melanoma on the Penn-Wistar campus. The PI frequently communicates with the Internal advisors and they also attend work-in-progress P01 meetings on an ad hoc basis.
Clayton Buck, Ph.D., Professor, The Wistar Institute. Dr. Buck is the former director of the Wistar Institute and current Associate Director for Academic Affairs. Dr. Buck is an accomplished biologist and biochemist. He has collaborated with members of the P01 for many years on experimental biology. He is an expert in studies related to Project 5, and Cores A, B, and C.
Anthony Capobianco, Ph.D., Associate Professor, The Wistar Institute. Dr. Capobianco is a molecular biologist with a major interest in cell signaling. Dr. Capobianco’s primary interest is in Notch signaling, which is also important for melanocyte differentiation and melanoma progression. He is an expert in studies related to Projects 1, 2, and 3.
Wafik El-Deiry, M.D., Ph.D., Associate Professor, Department of Medicine, University of Pennslvania. Dr. El-Deiry has made major contributions to the cell cycle and apoptosis fields. He is the PI of a pending program project in colorectal cancer (with D. Herlyn as one of the project leaders). Dr. El-Deiry’s expertise relates to Projects 1, 2, and 4 and Core A.
DuPont Guerry, M.D., Professor of Medicine, Director Melanoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA has been associated with melanoma research at the campus for over 25 years. He is Co-PI of the SPORE on Skin Cancer. Dr. Guerry is an expert in many areas of melanoma including immunology, pathology, and epidemiology, and he provides valuable input for all projects and cores.
Russel Kaufman, M.D., President and CEO, Director of the Cancer Center, The Wistar Institute. Dr. Kaufman, prior to becoming Director at Wistar in June 2002, had a senior leadership role at Duke University. Dr. Kaufman’s expertise is in biological and immunological areas related to the P01 all administrative issues. Dr. Kaufman’s role will be in reviewing Projects 1 and 2, and Core A.
Yvonne Patterson, Ph.D., Professor, Department of Microbiology, University of Pennsylvania. Dr. Patterson is an immunologist who is involved in preclinical and translational studies for the development of new cancer vaccines. Dr. Patterson will play a major role in evaluating Project 2.
Anil Rustgi, M.D., Professor, Chief of Gastroenterology, Director of Center for Gastrointestinal and Liver Diseases, University of Pennsylvania. Dr. Rustgi is the PI of a Program Project on esophageal carcinoma (CA98101) that includes a project with M. Herlyn as project leader. Dr. Rustgi’s expertise relates to the studies presented in Projects 1, 2 and Cores A, B, C, and D.
Lynn Schuchter, M.D., Associate Professor, Department of Medicine, University of Pennsylvania, is a clinical oncologist, who has spearheaded a variety of clinical trials in melanoma patients, including treatment of patients with BAY43-9006. Dr. Schuchter’s expertise will be invaluable in translating the laboratory findings into clinical settings. Her expertise relates to projects 1, 2, and Core D.
Amos Smith, Ph.D., Professor of Chemistry, University of Pennsylvania, has major interests in chemical product synthesis, bioorganic chemistry and materials science. He has developed more than 75 architecturally complex natural and has developed a series of peptidomimetics of neuropeptideic hormone/transmitters and protease enzyme inhibitors. His expertise is importance for project 4 and project 3.
Mark Tykocinski, M.D., Professor and Chair, Department of Pathology and Laboratory Medicine, University of Pennsylvania, has collaborated with members of the program. Dr. Tykocinski is an expert in molecular immunology and immunotherapy. His work closely relates to that in Project 2 and in cores A, B, and D.