Pro-melanomagenic role of Interferon-gamma: A paradigm shift

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DESCRIPTION (provided by applicant): The candidate has a doctorate in Biochemistry and Molecular Biology with extensive experience in using mouse models to perform basic cancer research. During his postdoctoral fellowship, the candidate has generated a novel mouse model that has allowed new insights into how ultraviolet radiation (UV) may cause development of melanoma, the deadliest form of skin cancer. He has made an important discovery that interferon (IFN)-gamma, a signaling protein involved in immunological functions and conventionally thought to be anti-tumorigenesis, may under some circumstances aid the outgrowth and progression of UV- induced melanoma. This high-impact research has formed the basis for the research proposed in this application. The candidate's immediate goal is to elucidate the molecular mechanism(s) of the pro- melanomagenic role of IFN-gamma, and to explore whether inhibition of IFN-gamma could be used as an anti- melanoma therapeutic and/or preventive strategy. In the long-term, the candidate wants to focus on the delineation of the molecular mechanisms of UV-induced melanoma initiation and progression. Environment: The candidate is currently a postdoctoral research fellow in the Laboratory of Cancer Biology and Genetics at the National Cancer Institute, and is seeking an independent research faculty position in an academic or non-profit research institution. He has set up collaborations with a world-class team of scientists with relevant expertise to advise throughout this project, ensuring timely conclusion and high-impact outcome. Research: The candidate has proposed a paradigm-shifting hypothesis that IFN-gamma plays a pro- tumorigenic role in the context of UVB-induced melanomagenesis. The proposed research will elucidate the molecular mechanisms of the pro-melanomagenic effects of IFN-gamma, and will explore whether inhibition of IFN-gamma pathway is a viable treatment and/or preventive strategy for human melanoma. In Specific Aim 1, UV-induced melanomagenesis experiments will be performed in a mouse model of UVB-induced melanomagenesis in the IFN-gamma knockout genetic background to test whether IFN-gamma is required for melanomagenesis. Specific Aim 2 will elucidate the downstream target genes of IFN-gamma signaling that mediate the pro-melanomagenic effects of IFN-gamma, using both human and mouse melanoma cell lines. The applicability of the results will be validated in human melanoma cell lines and tissues. In Specifi Aim 3, novel peptide-based IFN-gamma inhibiting compounds will be validated and tested for their efficacy in preventing UVB-induced melanomagenesis and treating established melanomas in mouse models. It is anticipated that the results obtained from the proposed research will provide significant new translational opportunities for prevention and treatment of human melanoma.