2008 Research Awards » Established Investigator Awards
MRA awarded eight investigators whose work shows great promise in melanoma research, $200,000 over two years.
- Boris Bastian
- Glenn Dranoff
- David Fisher
- Levi Garraway
- Daniel Pinkel
- Ton Schumacher
- Michael Weber
- Jedd Wolchok
The novel melanoma oncogene GNAQ provides new opportunities for therapeutic intervention
Boris Bastian, M.D.
Professor of Dermatology and Pathology, University of California, San Francisco
Dr. Bastian discovered that a vast majority (83 percent) of uveal (ocular) melanomas have mutations in two genes -- GNAQ and GNA11. Functional studies showed that mutations induce spontaneously metastasizing tumors in a mouse model and activate the MAP kinase pathway. The functional similarities between these two genes form the basis to develop mechanism-based therapies for most uveal melanomas, and Dr. Bastian will continue this work in a 2010 MRA Team Science Award.
Publications:
Systemic MFG-E8 blockade as melanoma therapy
Glenn Dranoff, M.D.
Associate Professor of Medicine, Medical Oncology Department
Dana Farber Cancer Institute
Dr. Dranoff showed that the protein MFG-E8 is expressed at high levels when melanomas advance to the stage at which they acquire the capacity for invasion and metastasis. In addition to its direct action on melanoma cells, MFG-E8 aids in tumor angiogenesis and inhibits anti-melanoma immunity. His lab found that a combination of antibodies to MFG-E8 and chemotherapy killed tumors in mice and that blocking MFG-E8 enhanced the function of human T cells in vitro. Next steps include translating these findings into phase 1 clinical testing.
Publications:
- Milk fat globule epidermal growth factor-8 blockade triggers tumor destruction through coordinated cell-autonomous and immune-mediated mechanisms
- Milk fat globule EGF-8 promotes melanoma progression through coordinated Akt and twist signaling in the tumor microenvironment
Targeted strategies for melanoma treatment and prevention
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
Dr. Fisher studied the mechanism of action of imatinib (Gleevec) on a cell line model for Kit mutated cancer (some melanomas harbor activating mutations in the c-Kit receptor tyrosine kinase) and found that the programmed cell death protein BIM plays an important role. These insights will be important for developing strategies to address resistance to c-KIT targeted therapies. Dr. Fisher has also identified several candidate drugs for topical use to prevent melanoma in fair skinned individuals. This work will continue with funding from the NIH.
Publications:
- Lineage-specific transcriptional regulation of DICER by MITF in melanocytes
- Key roles for transforming growth factor beta in melanocyte stem cell maintenance
- An oncogenic role for ETV1 in melanoma
- Integrative analysis of the melanoma transcriptome
Synthetic lethality to MAP kinase pathway inhibition in BRAF-mutant melanoma
Levi Garraway, M.D., Ph.D.
Assistant Professor of Medicine
Dana Farber Cancer Institute
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. Dr. Garraway is continuing this work under a 2009 MRA Team Science Award with Michael Weber.
Publications:
- COT drives resistance to RAF inhibition through MAP kinase pathway reactivation
- An oncogenic role for ETV1 in melanoma
- Integrative analysis of the melanoma transcriptome
- p85 Associates with Unphosphorylated PTEN and the PTEN-Associated Complex
- MEK1 mutations confer resistance to MEK and B-RAF inhibition
Genetics of melanoma metastasis
Daniel Pinkel, Ph.D.
Professor of Laboratory Medicine
University of California, San Francisco
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.
Platform for MHC-exchange based T cell therapy for melanoma
Ton Schumacher, Ph.D.
Professor of Immunotechnology, Leiden University Medical Center
Full Member, Department of Immunology, The Netherlands Cancer Institute
Dr. Schumacher is developing and applying technology to better understand melanoma T cell reactivity and to selectively isolate these cells for improved adoptive T cell therapy. This research led to the development of a method that allows the generation of large collections of protein complexes that can be used to detect melanoma-specific T cell populations in small amounts of patient material. A clinical grade reagent was developed in order to purify melanoma-reactive T cells that recognize an epitope of interest. In addition, this is in use to monitor T cell reactivity during other immunotherapeutic treatments, in particular anti-CTLA-4.
Publications:
- MHC-based detection of antigen-specific CD8+ T cell responses
- Parallel detection of antigen-specific T-cell responses by multidimensional encoding of MHC multimers
A pathway to rational combination therapies for melanoma: Synthetic lethal screening with small molecule inhibitors, guided by phosphoproteome analysis
Michael Weber, Ph.D.
Director, University of Virginia Cancer Center
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. Dr. Weber is continuing this work under a 2009 MRA Team Science Award.
Immunologic signatures of response to ipilimumab
Jedd Wolchok, M.D., Ph.D.
Associate Director, Ludwig Center for Cancer Immunotherapy
Director, Immunotherapy Clinical Trials
Memorial-Sloan Kettering Cancer Center
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.
Publications:
- Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival
- Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial
- Correlation of clinical and immunological data in a metastatic melanoma patient with heterogeneous tumor responses to ipilimumab therapy
- CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit