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Collaborations - Human Melanoma P01

NIH Program Project
Human Melanoma – Etiology Progression & Therapy

PI: Meenhard Herlyn, D.V.M., D.Sc.
Co-PI: Boris Bastian, M.D.

Funding period: 4/1/11 – 3/31/16

Summary
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 include 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 cores, for the cycle until 2004 we had four projects and five cores and for the current cycle we have three projects and four cores. For the renewal we will maintain only an administrative core to guarantee viably funded projects. Throughout the tenure of the grant, the program encompassed several fields of melanoma research, including pathology, immunology, biology, genetics, and more recently structural biology and small molecule screening and development. We have continued to maintain a balance among different disciplines while adjusting the scientific scope of the program.

The specific goals for this highly interactive program project are summarized below:
1. Identify somatic alterations in KIT-mediated signaling pathways and determine whether they are targets for therapy. Our group (Project 2, Bastian) has recently identified KIT mutations in subsets of melanoma that are mutually exclusive to BRAF and NRAS mutations. We now plan to scrutinize the KIT pathway for additional genetic alterations to determine their role as mediators of primary resistance and as novel therapeutic targets in melanoma. Some of these genes may also regulate the slow-cycling cells described in Project 1 (Herlyn). Preliminary studies have implicated several altered genes, including the genes encoding p70S6 kinase, a critical regulator of protein synthesis and cell growth.  Therefore, we will characterize its role in melanoma and develop potent and specific inhibitors to this kinase (Project 3, Marmorstein).

2. Identify sub-populations in melanoma that are drivers for tumor progression and are specific targets for therapy. Our group (Project 1, Herlyn) has identified melanoma cells with self-renewing properties that can differentiate to diverse cell types including adipocytic and chondrocyte cells. Tumor-mediated cell-cell interactions result in a sub-population that is very slowly cycling if at all. We have identified a marker for non-cycling cells with high proliferation potential, the histone 3 K4 demethylase JARID1B (Project 1, Herlyn). In this proposal we describe the in-depth characterization of this sub-population that shows remarkable analogies to cancer stem cells although we do not propose that JARID1B+ cells harbor such properties. Instead, we propose a dynamic model of tumor progression that also encompasses the tumor microenvironment. JARID1B is an excellent target for therapy and Project 3 (Marmorstein) will characterize the biochemical activity of JARID1B and develop potent and specific inhibitors. Project 1 (Herlyn) will also develop cell-based assays to complement the efforts of Project 3 to identify JARID1B inhibitors.

This Program Project continues to function beyond the traditional boundaries of a P01 by attracting new investigators to the field, fostering interactions between investigators outside of the Program Project, and coordinating the many related activities that define a "melanoma research center."  The Program Project developed and has supported important resources:  1) cell lines from melanocytic lesions of different stages of progression; 2) monoclonal antibodies against melanoma-associated antigens; and 3) viral vectors for gene transfection. The long-established and interactive collaborations among members of the Program Project at The Wistar Institute, The University of Pennsylvania, and The Memorial Sloan Kettering Cancer Center allow unique multidisciplinary research on tumor genetics, progression growth regulation, tumor progression, structural biology, inhibitor development and experimental therapy. Our experimental models in the laboratory and in animals closely mimic the disease in patients and the mechanistic investigation of disease etiology and progression will help to develop clinically relevant treatment strategies.

Program Project Interactions:


Projects

Project 1: Cellular mechanisms of therapy resistance in melanoma
Project Leader: Meenhard Herlyn, D.V.M, D.Sc.
Specific Aims:
Aim 1: Characterize the ‘biologic signature’ of slow-cycling, tumor-maintaining melanoma cells that survive conventional therapies.
Aim 2: Develop combination therapies based on the genetic and biologic signatures of melanomas.

Project 2: The KIT signaling pathway as a therapeutic target in melanoma
Project Leader: Boris Bastian, M.D.
Specific Aims:
Aim 1: Characterize genetic alterations of the KIT pathway in patient samples.
Aim 2: Determine the functional role of genetic alterations in the KIT pathway in melanoma.
Aim 3: Determine predictive factors of therapy response and resistance in melanoma patients treated with KIT inhibitors.

Project 3: Molecular basis for p70S6 kinase and JARID1B demethylase activity and inhibition in melanoma
Project Leader: Ronen Marmorstein, Ph.D.
Specific Aims:
Aim 1. Molecular basis for p70S6 kinase activity and development of small molecule inhibitors.
Aim 2. Molecular basis for JARID1B demethylase activity and development of small molecule inhibitors.

 


Advisors to the Program Project:

External:
John Denu, Ph.D. University of Wisconsin
David Fisher, M.D., Massachusetts General Hospital
Keith Flaherty, M.D., Massachusetts General Hospital
Martin McMahon, M.D., University of California San Francisco
Avraham Raz, Ph.D., Wayne State University
Ze’ev Ronai, Ph.D., Burnham Institute
Michael Weber, Ph.D., University of Virginia

 

Internal:
Dupont Guerry III, M.D., University of Pennsylvania
Russel Kaufman, M.D., The Wistar Institute
Lynn Schuchter, M.D., University of Pennsylvania
Ramin Shiekhattar, Ph.D., The Wistar Institute
Celeste Simon, Ph.D., University of Pennsylvania
David SPeicher, Ph.D., The Wistar Institute