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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.