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
Melanoma has been one of the fastest rising malignancies in the last four decades with cases increasing from below three per 100,000 people to above 13 (18.9 if only whites are counted). The following discoveries have been made that serve as the basis for this program project: 1. Mutations in genes of the MAP kinase pathway are frequent in melanoma and mutually exclusive. Mutations are most frequent in BRAF (50%) followed by NRAS (15%) and c-kit (4%). 2. Within each mutation group there are sub-groups due to additional critical mutations. 3.The biological characteristics of melanomas including progression and metastasis are driven by both tumor and microenvironment forces. 4. Small molecule inhibitors for tumor-associated kinases lead to powerful effects on melanoma cells both in vitro and in vivo. Our first objective is to identify somatic alterations in growth factor mediated signaling pathways and determine whether they are targets for therapy. Our group (Project 2, Bastian) has recently identified c-kit mutations in melanoma, particularly in acral and mucosal melanomas, that are mutually exclusive to BRAF and NRAS mutations, and anecdotal reports suggests that drugs therapeutic targeting c-kit induce dramatic clinical responses in some patients with these mutations. We now plan to analyze the role of other genetic alterations identified downstream in the c-kit signaling pathways and determine their role as mediators of primary resistance and as novel therapeutic targets in melanoma (Project 2, Bastian). Some of these genes encode for p70S6 kinases, which are critical regulators of protein synthesis and cell growth and important for survival of melanoma cells during hypoxia (Project 3, Xu). Therefore, we will characterize the biochemical function of p70S6K and develop potent and specific inhibitors to this kinase (Project 4, Marmorstein). A complementary objective in characterizing therapy resistance in melanoma is to identify sub-populations of tumor cells that are drivers for tumor progression and may require refined strategies compared to the bulk of tumor cells. Our group (Project 1, Herlyn, Project 3, Xu) has already identified melanoma cells with self-renewing and pluripotent properties, which are very slowly cycling but have a high proliferative reserve. They are characterized by expression of the histone 3 K4 demethylase JARID1B (Project 1, Herlyn). In this proposal we will characterize this subset, its role in tumor progression, its interaction with the environment, and and inhibitors of JARID1B (Project 4, Marmorstein) as a therapeutic target(Project 1, Herlyn) to eradicate this critical subset.
In summary, the renewal application focuses on the development of mechanism-based strategies of overcoming therapy resistance by targeting specific signaling components that were already determined to provide critical oncogenic functions at the nexus of metabolism, microenvironment and differentiation.
Advisors to the Program Project
We are fortunate to have obtained a group of highly experienced external advisors for our Program Project who have an active interest in its progress. Several members of the external group met in 2006 and 2008 to discuss the plans. They have all participated extensively in the research evaluation and their work has been highly appreciated by the members of the program.
Dr. John Denuu, Ph.D., Professor, Department of Biomolecular Chemistry, University of Wisconsin Madison is an enzymologist and biochemist with expertise in chromatin regulation and reversible protein modification.
Dr. David Fisher, M.D., Ph.D. ,Professor and Chair, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA is a molecular biologist with expertise in oncogenes and tumor suppressor genes.
Dr. Keith Flaherty, M.D., Dr. Flaherty recently moved from the University of Pennsylvania to Massachusetts General Hospital, where he will continue his work on signaling therapies and consortia for combination therapies. His expertise is in translating laboratory findings to the clinics.
Martin McMahon, Ph.D., Professor, University of California San Francisco. He has been associated with our programs for many years and has been conducting research related to experimental therapy.
Avram Raz, Ph.D., Professor, Director, Basic Research Division, Barbara Ann Karmanos Cancer Center, Wayne State University, Detroit, Michigan, is a cancer biologist.
Ze'ev Ronai, Ph.D., Professor and Program Leader, Burnham Institute, La Jolla, CA is a molecular biologist.
Michael Weber, M.D., Professor and Director, University of Virginia Cancer Center. Dr. Weber is a molecular biologists and biologists.
Project 1. Cellular mechanisms of therapy resistance in melanoma.
M. Herlyn, Project leader
Overall hypothesis. Our working hypothesis is that therapy resistance in melanoma is due to a defined subpopulation of malignant cells that evades multiple antagonistic threats through a moderate or complete lack of proliferation. Because most chemotherapeutic agents affect rapidly-dividing cells, slow-cycling populations serve as a reservoir for melanoma regeneration after chemotherapeutic intervention. Our preliminary studies demonstrate that slow-cycling, self-renewing cells retain a high proliferation potential capable of recapitulating the tumorigenic and heterogeneous nature of advanced melanomas. We therefore hypothesize that melanomas can be effectively killed through a dual-tiered therapeutic approach: first, through a genetic-based treatment aiming to eradicate the bulk of melanoma growths, followed by the targeting of the remaining slow-cycling, self-renewing subpopulation.
Specific Aims
1. Characterize slow-cycling, self-renewing (SCSR) melanoma cells that survive conventional therapies.
We are testing the hypothesis that slow-cycling, self-renewing melanoma cells defined by the histone 3 K4 demethylase JARID1B (SCSR JARID1B+) represent a non-proliferating cells with high proliferation potential that escapes antagonistic insults, and are thus responsible for the intrinsic resistance of melanoma cells to therapy. We will determine how the slow-cycling nature of cells expressing JARID1B contributes to resistance upon treatment with traditional chemotherapeutic compounds, as well as more modern compounds targeting specific elements along key signal transduction pathways.
2. Eliminate all cellular populations responsible for the malignant phenotype of advanced melanoma.
Cutaneous malignant melanomas are notoriously genetically heterogenous tumors.. We hypothesize that all melanoma cells can be effectively eliminated through a two-tiered therapeutic approach whereby the bulk of the population is killed through genetic-based targeted therapies and subsequently targeting the remaining slow-cycling population. Debulking the tumor prior to targeting the highly resistant slow-cycling population characterized in Aim #1 should facilitate sustained response rates. These studies will enable the rational development of therapeutic modalities whereby clinicians can eliminate both the major proliferating melanoma population, as well as the smaller slow-cycling cell population responsible for recurrence and drug resistance.