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MRA awarded eight investigators whose work shows great promise in melanoma research, $200,000 over two years.

• Boris Bastian, M.D.
  Professor of Dermatology and Pathology, University of California, San Francisco
  
  Proposal Title: The novel melanoma oncogene GNAQ provides new opportunities for therapeutic intervention
  
  Summary: Dr. Bastian’s laboratory has discovered somatic mutations in GNAQ in a subset of melanomas. This mutation is linked to activation of the MAP kinase pathway. In this project, Dr. Bastian will look at the signaling events downstream of GNAQ with the goal to identify targets for therapy. Any targets will be validated as relevant using RNA interference and existing drugs or chemicals which might inhibit the targets will be tested. Finally, any additional oncogenes within the GNAQ pathway activation will be identified.



• Glenn Dranoff, M.D.
  Associate Professor of Medicine, Medical Oncology Department
  Dana Farber Cancer Institute
  
  Proposal Title: Systemic MFG-E8 blockade as melanoma therapy
  
  Summary: MFG-E8 is a milk fat globule that has been found to be over expressed in melanoma cells when they acquire the ability to apread. Dr. Dranoff’s research will generate anti- antibodies to this target and then evaluate the anti-melanoma activity of the antibodies in both murine tumor models and clinical samples from patients with melanoma.



• David Fisher, M.D., Ph.D.
  Chief, Department of Dermatology, MGH Cancer Center, Director, Cutaneous Biology Research Center, Massachusetts General Hospital, Edward Wigglesworth Professor of Dermatology, Harvard Medical School
  
  Proposal Title: Targeted strategies for melanoma treatment and prevention
  
  Summary: Dr. Fisher's research approaches melanoma prevention by testing the use of specific phosphodiesterase inhibitors as cAMP inducing factors, for the production of skin pigment. This aim is based upon epidemiologic evidence that epidermal melanin is associated with profound protection against melanoma, building upon evidence that modulation of cAMP dynamics in melanocytes is a drugable means to "rescue" pigmentation in fair-skinned, cancer-prone individuals. In addition, studies will focus on improved strategies for treatment of advanced melanoma through examination of signaling events which control survival in BRAF-mutant melanomas. Specifically, opportunities for BRAF-dependent synergy will be examined, particularly those which are amenable to small molecule targeting.
  
  
• Levi Garraway, M.D., Ph.D.
  Assistant Professor of Medicine
  Dana Farber Cancer Institute
  
  Proposal Title: Synthetic lethality to MAP kinase pathway inhibition in BRAF-mutant melanoma
  
  Summary: In recent years, genetic studies have revealed that most cutaneous melanomas contain activating point mutations in the BRAF or NRAS oncogenes, indicating a profound reliance on the MAP kinase pathway for carcinogenesis. However, results from clinical trials of single agents targeting the MAP kinase pathway have had limited success. Dr. Garraway’s research aims to identify a candidate set of melanoma genes that may provide rationale for combining therapeutics targeting the MAP kinase pathway.



• Daniel Pinkel, Ph.D.
  Professor of Laboratory Medicine
  University of California, San Francisco
  
  Proposal Title: Genetics of melanoma metastasis
  
  Summary: A better understanding of the metastatic potential (prognosis) of a newly diagnosed (primary) tumor is important for treatment recommendations. Dr. Pinkel’s study will analyze primary melanomas and their associated metastases to detect genetic factors within the tumors that are associated with metastasis, assess their function, and test their utility for prognostication.



• Ton Schumacher, Ph.D.
  Professor of Immunotechnology, Leiden University Medical Center
  Full Member, Department of Immunology, The Netherlands Cancer Institute
  
  Proposal Title: Platform for MHC-exchange based T cell therapy for melanoma
  
  Summary: Dr. Schumacher’s laboratory has developed a peptide exchange technology that could allow enrichment of melanoma-reactive T cells. This project will attempt to generate adoptive T cell therapy for melanoma in a selective manner, which is expected to increase effectiveness of therapy and potentially to reduce toxicity. A phase 1 trial would follow.



• Michael Weber, Ph.D.
  Director, University of Virginia Cancer Center
  
  Proposal Title: A pathway to rational combination therapies for melanoma: Synthetic lethal screening with small molecule inhibitors, guided by phosphoproteome analysis
  
  Summary: Dr. Weber will clarify how the MAP kinase pathway is networked to other cell regulatory systems. He will use an assembled library of over 100 small molecule inhibitors to search for “super-additive” inhibition of growth when used in combination. Reverse Phase Protein Arrays (RPPAs) before and after treatment will profile the phosphorylation-driven cell signaling networks of the cell lines, xenografts and patient materials. A subset of promising drugs and drug combinations that are identified will be tested in xenograft and ex vivo patient samples to assess promise as therapy.



• Jedd Wolchok, M.D., Ph.D.
  Associate Director, Ludwig Center for Cancer Immunotherapy
  Director, Immunotherapy Clinical Trials
  Memorial-Sloan Kettering Cancer Center
  
  Proposal Title: Immunologic signatures of response to ipilimumab
  
  Summary: Dr. Wolchok’s research goal is to extend the preliminary observations regarding changes in immune parameters occurring after CTLA-4 blockade to a larger set of melanoma patients. With more detailed knowledge of the T cell phenotype and antigen recognition found in patients who experience clinical response or immune related adverse events, we aim to improve treatment results in patients with melanoma.