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Collaborations - Targeted Therapies in Melanoma P01

NIH Program Project
Targeted Therapies in Melanoma
PI: Meenhard Herlyn, D.V.M., D.Sc.
Co-PI: Ronen Marmorstein, Ph.D.

Funding period: 5/16/08-4/30/13

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).  In the United States, 62,190 new melanoma cases and 7,910 deaths from melanoma are expected in 2006 (ACS Statistics from April, 2006).  Despite worldwide efforts in prevention, diagnosis, and treatment, cases of melanoma continue to rise at an alarming rate of 2.5 % annually in the United States. In 2000, 550,860 individuals lived in the United States with the diagnosis of melanoma. Mortality rates have fortunately leveled off (-0.2% change from 1992 to 2001), likely due to higher awareness and detection of biologically early primary melanomas, which are curable through surgery. Treatment of advanced disease remains difficult and the strategies employed in the last 30 years have not significantly improved cure rates, which are less than 3%, with overall five year survival rates of patients with advanced disease at 15.4%. Among men, there is a lifelong probability of developing melanoma at 1 in 52 and for women of 1 in 77. For men, melanoma is the fifth most frequent cancer (after prostate, lung and bronchus, colon and rectum, and bladder carcinoma); for women it is the sixth most common cancer (after breast, bronchus and lung, colon and rectum, uterus and non-Hodgkin’s lymphoma). Thus, there is a continuing challenge for a major research effort in melanoma. The long-term objective of this program project is to develop new strategies for therapy of melanoma that are based on a mechanistic understanding of etiology and progression of the disease.

 

The specific goals for this highly interactive program project are summarized below:

1. Target mutant BRAF for therapy of melanoma. We are using several approaches to explore mutant BRAF as a target for therapy: 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, M. Herlyn); ii. Induce specific cellular immunity against BRAFV600E that leads to tumor growth inhibition in a genetic melanoma model in mice (Project 2 [D. Herlyn]); and iii. Develop a new generation of highly selective and potenet organic and organometallic inhibitors for BRAFV600E based on high-throughput small molecule screening, crystal structures of BRAFV600E/inhibitor complexes and medicinal chemistry (Projects 3 and 4 [R. Marmorstein and E. Meggers]). We expect the development of new therapies of melanoma that focus on BRAFV600E as a molecular target through these 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 consider the PI3 kinase pathways highly important for melanoma cell survival. In two projects, Projects 3 (R. Marmorstein) and 4 (E. Meggers), we will identify a novel generation of organometallic inhibitors against the PI3Kα isoform. The inhibitors will be developed based on the screening of ruthenium pyridocarbazole analogues prepared in Project 4 (E. Meggers)  and X-ray crystal structure characterization of these inhibitors bound to PI3Kα, a pharmalog of PI3Kα in Project 3 (R. Marmorstein).  In addition, we will explore these novel PI3Kα inhibitors in our in vitro and in vivo models and how they synergize with BRAF inhibitors (Projects 1 [M. Herlyn] and 2 [D. Herlyn]).

3. Target GSK3ß for induction of apoptosis.  Targeting GSK3ß with organometallic inhibitors has surprising apoptosis-inducing activities on melanoma cells. These inhibitors were developed in Project 4 (E. Meggers) and tested for activity in complex in vitro models in Project 1 (M. Herlyn). Based on preliminary studies we can now investigate the mechanisms of apoptosis induction, which may occur through activation of p53. Most melanomas are not mutated in this gene, but p53 can also be downregulated by HDM2, which is frequently overexpressed in melanoma.

 

Projects:

Project 1 – Targeting the MAPK and PI3K pathways in melanoma
Project Leader – Meenhard Herlyn, D.V.M., D.Sc.
Specific Aims:
Aim 1: Target melanoma cells with mutant BRAF in two-dimensional (2D) conventional cell culture and three-dimensional (3D) organotypic models using small molecule inhibitors.
Aim 2: Determine how the inhibition of GSK3ß induces apoptosis of melanoma cells.

Project 2 – Mutant BRAF as a therapeutic target for melanoma
Project Leader – Shyam Somasundaram, Ph.D.
Specific Aims:
Aim 1: Test the hypothesis that BRAFV600E vaccines induce cellular immunity in mice. 
Aim 2: Test the hypothesis that BRAFV600E vaccines and small molecule inhibitors induce tumor-protective immunity in mice and determine the mechanism underlying tumor growth inhibition
Aim 3: Test the hypothesis that BRAFV600E induces cellular immune responses in melanoma patients' peripheral blood mononuclear cells (PBMC)

Project 3 – Structure based design of BRAF and PI3K inhibitors
Project Leader – Ronen Marmorstein, Ph.D.
Specific Aims:
Aim 1: Develop potent and specific BRAF and BRAFV600E inhibitors. 
Aim 2: Develop potent and specific PI3Kα inhibitors.

Project 4 – Organometallic Protein Kinase inhibitors as anticancer agents
Project Leader – Eric Meggers, Ph.D.
Specific Aims:
Aim 1: Development of ruthenium complexes as inhibitors for BRAF and BRAFV600E.
Aim 2: Development of ruthenium complexes as inhibitors for PI3Kα.
Aim 3: Development of ruthenium complexes as inhibitors for GSK-3ß.

Projects interactions (note project #'s in blue):


Advisors to the Program Project:

Internal Advisors:
Clayton Buck, Ph.D., The Wistar Institute
Anthony Capobianco, Ph.D., The Wistar Institute
Wafik El-Diery, M.D., Ph.D.,  University of Pennsylvania
Dupont Guerry, IV, M.D., University of Pennsylvania
Russel Kaufman, M.D., The Wistar Institute
Yvonne Paterson, Ph.D., University of Pennsylvania
Anil Rustgi, M.D., University of Pennsylvania
Lynn Schuchter, M.D., University of Pennsylvania
Amos Smith, Ph.D., University of Pennsylvania
Mark Tycocinski, M.D., University of Pennsylvania

External Advisors:
Menashe Bar-Eli, Ph.D., MD Anderson Cancer Ctr.
Ronald DePinho, M.D., Dana Farber Cancer Inst.
Eric Fearon, M.D., Ph.D., University of Michigan
Mark Nelson, Ph.D., University of Arizona
Yigong Shi, Ph.D., Princeton University