2009
MRA awarded six investigators who have committed their research careers to oncology and are pursuing novel ideas in melanoma research $225,000 over the next two years.

• Dr. Martin McMahon, University of California, San Francisco
  Proposal Title: Targeting signaling pathways for therapy in a new mouse model of melanoma
  

  McMahon

  
  Melanoma, a cancer most frequently arising from pigment producing cells of the skin, is the fastest growing form of cancer among the North American population. When detected early, melanoma is often cured by surgical resection. However, melanoma has a striking ability to metastasize to distant sites such as in the kidney, lung or brain. Melanoma also has a remarkable capacity to lie dormant, only to re-emerge in a form that is highly resistant to cancer therapy. Consequently, treatment options and survival prospects for metastatic melanoma patients are extremely poor. These facts underscore the urgent need for new research to develop a better understanding of the biology and biochemistry of malignant melanoma. Armed with a better understanding of melanoma, it should then be possible to develop new treatments to combat this disease.
  
  Most cancers arise due to alterations in the expression or activity of tumor suppressors and oncogenes. In melanoma, the earliest and most frequently altered oncogene is BRAF. However, since mutation of BRAF is insufficient to promote melanoma on its own, it is likely that BRAF cooperates with mutations in tumor suppressor genes such as INK4A/ARF or PTEN to promote malignant melanoma. Dr. McMahon has recently developed and published in Nature Genetics a mouse model of metastatic melanoma in which the most important genetic events that occur in human melanoma can be controlled. He has also conducted proof-of-concept experiments that demonstrate the utility of these mice in evaluating new therapies to prevent or treat melanoma in humans. In this proposal, Dr. McMahon seeks to take these experiments to the next level by using our mouse model of melanoma to evaluate new therapeutics that target two of the key signal transduction pathways in melanoma either alone, in combination with one another, and in combination with conventional chemotherapy. These experiments have direct relevance to the design and evaluation of new therapies to treat humans with melanoma and will speed the translation of basic science explorations in this disease into improved patient care.



• Dr. Lynda Chin, Dana Farber Cancer Institute, Harvard University
  Proposal Title: Development of intra-tumoral prognostic biomarkers for primary melanoma
  
  A major effort in cancer research is focused on identifying new cancer indicators, or biomarkers, that allow clinicians to differentiate early stage tumors into benign versus aggressive subtypes. Current melanoma diagnostic methods are inadequate in genome-wide comparisons of numerous mouse and human melanomas with a function-based genetic screen for pro-metastasis genes that led us to identify 20 "metastasis determinants" that actively promote tumor formation and cell invasion, an early step in metastasis. Expression of the metastasis determinants also correlates with advanced tumor grade in other non-melanoma tumor types that include breast adenocarcinoma, where determinant expression levels can separate breast cancer patients into two subgroups with significant differences in overall and metastasis-free survival. Therefore, Dr. Chin believes that these determinants are ideal biomarker candidates for a multi-gene prognostic test to predict metastatic risk in early stage melanoma patients. In this study, using these metastasis determinants as a starting point, she will develop and validate multi-gene prognostic tests in patient outcome-annotated clinical melanoma samples. Additionally, through examination of their mechanism of action, she plans to glean insight that can guide optimal and rational therapeutic choices in an adjuvant setting for these early stage melanoma patients.



• Dr. TC Wu, Johns Hopkins University
  Proposal Title: Treatment of melanoma combining cancer gene therapy and immunotherapy
  
  Melanomas are a highly deadly disease and malignant melanoma accounts for 75 percent of all deaths associated with skin cancer. There is an urgent need for innovative therapies for the control of melanomas. Suicidal DNA vectors have emerged as an important strategy for cancer gene therapy since they express high levels of the encoded protein for a prolonged period and cause the transfected cells to undergo apoptic cell death, making them potentially suitable for inducing cancer cell death. Suicidal DNA vectors can be used to encode an immune-stimulatory protein capable of triggering potent immune responses against tumors. Heat shock proteins (HSP) represent ideal proteins for enhancing immunity against tumors and can be encoded by suicidal DNA vectors for cancer immunotherapy. HSP70 has been shown to activate dendritic cells and prime tumor antigen-specific T cells, eliciting strong antitumor responses, representing a potentially ideal protein to be encoded by suicidal DNA vector for cancer gene therapy. One major limitation of this strategy is the limited transfection efficiency in vivo, which may limit the potency of suicidal DNA. Low-energy laser beam treatment represents a novel approach to increase the efficiency of the delivery of DNA to the tumor. In the current proposal, Dr. Wu plans to test whether intratumoral injection of naked suicidal DNA encoding a secreted form of heat shock protein 70 (sHSP70) followed by laser treatment will lead to wide-spread tumor cell death and potent tumor-specific immunity, leading to the control of melanomas in animal models.



• Dr. F. Stephen Hodi, Dana-Farber Cancer Institute, Harvard University
  Proposal Title: A phase I trial of bevacizumab plus ipilimumab in melanoma patients
  

  Hodi

  
  Improved understanding of mechanisms of immune function has recently provided new means to take the brakes off the immune system to treat cancer. One way to accomplish this has been to block the molecule Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4, a natural inhibitory signal to the immune system). Experience with blocking CTLA-4 in patients has shown that this can be accomplished to effectively treat melanoma. Part of the anti-tumor response involves an immune attack of the blood vessels feeding the tumors. The major factor known to be involved in the formation of blood vessels that feed tumors, vascular endothelial growth factor (VEGF), has also been found to suppress the immune system. An antibody that blocks VEGF has been shown to be highly effective when combined with other treatments such as chemotherapy against many types of cancer. Dr. Hodi proposes to combine an antibody that blocks CTLA-4 to take the brakes off the immune system with an antibody that blocks VEGF to block blood vessel formation to tumors. He aims to understand synergies in combining these two drugs that together could target the blood vessels feeding melanoma deposits.



• Dr. Alexander Levitzki, Hebrew University of Jerusalem
  Proposal Title: Targeting the IGF1R pathway in melanoma
  

  Levitzki

  
  Melanoma is one of the most aggressive cancers in humans and remains one of the leading causes of cancer death in developed countries. At present there are no clinical protocols to treat metastatic melanomas, although progress has been made in the development of signal transduction inhibitors as well as immune therapy. Preliminary results suggest that Dr. Levitzki has discovered a new family of molecules that target at the same time the IGF1R signaling pathway as well as Stat3, which in combination may hold great promise for the treatment of metastatic melanoma.



• Dr. Roya Khosravi-Far, Beth Israel Deaconess Medical Center
  Proposal Title: Targeted strategy for treatment of melanoma
  

  Khosravi-Far

  
  Disseminated melanoma is one of the most treatment-resistant and deadly cancers. Increasing incidence of melanoma worldwide in the absence of effective treatments makes a search for therapeutic strategies of vital importance. Dr. Khosravi-Far has discovered a novel biologic that potently induces death (apoptosis) of tumor cells in multiple cancer cell lines and in tumor models by targeting the anti-apoptotic factor c-FLIP. She hypothesizes that this peptide can be used either as a sensitizer or a stand-alone therapeutic agent for treatment of melanoma. Given this success, apoptosis-activating peptides could become a new class of agents for treatment of malignant melanoma.

 

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, Director, Cutaneous Biology Research Center, Director, Melanoma Program in Medical Oncology, Massachusetts General Hospital/Harvard University; President, Society for Melanoma Research
  
  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.