PI, Meenhard Herlyn
Co-PI, David E. Elder
This program project was initiated in 1980 by Hilary Koprowski and Wallace H. Clark. Emphasis was initially placed on monoclonal antibodies (MAbs) against melanoma-associated antigens for diagnosis and treatment of melanoma. In the second cycle from 1985 to 1989, the program was expanded to genetic and biological studies of melanoma. In 1990 Meenhard Herlyn became the Principal Investigator. The eight projects on nevi and melanoma spanned molecular genetics, biology, and immunology. For the cycle from 1995 to 1998 we had five projects and four cores and for the current cycle four projects and five cores. For each competitive renewal we have re-organized the program due to changes in scientific priorities and personnel. Throughout the tenure of the grant, the program encompassed several fields of melanoma research, including pathology, immunology, biology, and genetics. For the competing renewal we have continued to maintain a balance between different disciplines while adjusting the scientific scope of the program.
Summary
Clinical, histopathological, and experimental biological investigations have defined the characteristics of human melanocytes as they progress from benign to malignant lesions. Each of the five clinicopathologic steps of progression has been delineated in its relation to others and in its clinical significance???However, the molecular mechanisms of melanoma development and progression are still poorly understood. This program project has three major objectives which are investigated with unique models and tools: 1. Delineate the role of the microenvironment in melanocyte transformation, melanoma progression and host response. Project 1 (M. Herlyn) investigates the microenvironment that controls melanocyte stem cell differentiation. When stem cells are activated to divide and differentiate they are likely highly susceptible to UV-induced DNA damage, which then leads to genetic aberrations (Project 2 B. Bastian). The group determines the endogenous and exogenous mechanisms of cells escaping from the normal homeostatic environment in skin and of subsequent transformation to melanoma. Likely, the microenvironment also controls attraction of T cells to the tumor and determines their specificity and biological activity (Project 3 D. Herlyn).
2. Identify molecular mechanisms of transformation and progression. The group is testing the hypothesis that UV response genes are causatively involved in lentigo maligna melanoma (LMM) development from lentigo maligna, based on epidemiological data and our findings that chromosomal deletions in LMM include the XPG and HUS1 genes that are part of the replication checkpoint and nucleotide excision repair pathways (Project 2). The functional significance of the contribution of the replication checkpoint genes for melanoma development and maintenance is tested in Projects 2 using models of human melanoma development and progression developed in Projects 1 and 3.
3. Develop new targets for melanoma therapy. The group will identify new targets for therapy through genetic, biological, and immunological approaches. Comparative genomic hybridization (CGH) analyses of melanoma lesions (Project 2) will identify chromosomal regions with aberrations. T helper cells from melanoma patients will define new antigens that are immunogenic in patients (Project 3). Immunological approaches to melanoma marker identification have characterized in recent years a variety of proteins that are coded by mutated genes. The biological models developed in projects 1 and 3 will be utilized to select, verify and validate new targets for a growing pipeline of novel strategies for melanoma diagnosis, prognosis, prevention and therapy.
Advisors to the Program Project
We are fortunate to have obtained a group of highly experienced on-campus and external advisors for our Program Project who have an active interest in its progress. The external group has met in 1999, 2000, and 2002 to discuss the progress and plans. They have participated extensively in the research evaluation and their work has been highly appreciated by the members of the program.
Dr. Dorothea Becker, Ph.D., Professor, Department of Pathology, University of Pittsburgh, PA, has expertise in molecular biology, biochemistry, and biology of melanoma, and her research interests match those of M. Herlyn, B, Bastian, and T. Halazonetis (Projects 1-3).
Dr. Carlos Cordon-Cardo, M.D., Associate Professor of Pathology, Director, Division of Molecular Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, is a molecular pathologist who has braod expertise for projects 1 and 2, and Pathology Core B.
Dr. Olivera Finn, Ph.D., Professor and Chair, Department of Immunology, University of Pittsburgh, PA, is our advisor for the immunology project (4) of D. Herlyn. Her expertise is in cellular immunology.
Dr. David Fisher, M.D., Ph.D., Associate Professor, Division of Pedriatic Oncology, Dana Farber Cancer Institute, Havard Medical School, Boston, MA is a molecular biologist with expertise in oncogenes and tumor suppressor genes. His expertise is for reviewing projects 3 and 2.
Dr. Shahin Rafii, Ph.D., Cornell University, New York, NY is an expert stem cell differentiation. He will officially join the groups in spring of 2004 but he is intimately familiar with all aspects of the program. Due to his expertise, he will advise on investigations for project 1.
Dr. Avram Raz, Professor, Director, Basic Research Division, Barabara Ann Karmanos Cancer Center, Wayne State University, Detroit, Michigan, is a cancer biologist who will provide input for projects 1 and 2.
Ze'ev Ronai, Ph.D., Professor, Burnham Institute, La Jolla, CA, is a molecular biologist whose expertise will be important for projects 1 and 2.
Maria Soengas, Ph.D., Assistant Professor, University of Michigan is a biologist and molecular biologist, whose expertise is important for all projects. She has active collaborations with projects 1 and 2.
Organization of Internal Advisory Committee
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.
Internal Advisory Committee for the PO1.
Steven M. Albelda, M.D., Ph.D., Professor, Department of Medicine, University of Pennsylvania. Dr. Albelda has been collaborating with members of the PO1 for many years on experimental biology and therapeutics. He is an expert in studies related to Projects 1 and 4, and Cores A, B, and C.
Alan Gewirtz, M.D., Professor, Department of Medicine, University of Pennsylvania. Dr. Gewirtz is a molecular biologist who has broad knowledge in many areas of novel cancer therapeutics. He is experienced in studies related to Projects 2, 3, and Cores A, B, and D.
Dr. DuPont Guerry, M.D., Professor of Medicine, Director Melanoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA has been associated with the program since it's beginning. He is an expert in many areas of melanoma including immunology, pathology, and epidemiology.
Carl H. June, M.D., Department of Pathology, University of Pennsylvania. Dr. June is an eminent translational immunologist, whose major expertise is related to Project 4.
Russel Kaufman, M.D., Director 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. His expertise is in biological and immunological areas related to the PO1 all administrative issues. His role will be in reviewing Projects 1 and 4, and Core A.
David Speicher, Ph.D., Professor and Co-Leader, Program of Molecular and Cellular. Dr. Speicher has been with the P01 since 1990 as project or core leader. He has shifted his research activities more towards Systems Biological approaches but his expertise in proteomics and his critical input will be important for all projects and cores.