Elucidating the survivin pathway in melanoma

University Of Utah, Salt Lake City UT

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Abstract

DESCRIPTION (Taken from the applicant's abstract): The long-term goal of this project is to understand how apoptosis influences the development and growth of malignant melanoma (MM). Preliminary studies indicate that survivin, a newly recognized inhibitor of apoptosis, is broadly expressed in human nevi, MM lesions and melanoma cell lines, but not in normal melanocytes. A four-year mentored program is proposed to investigate the hypothesis that expression of survivin is an important early step in the transformation from normal melanocyte to melanoma and represents a potential therapeutic target in MM. This program will incorporate both didactic and research training in three general areas: apoptosis, melanocyte and melanoma biology, and adenoviral-mediated gene transfer. The training will be guided by a mentor (Dario Altieri, M.D.), 2 collaborators (Ruth Halaban, Ph.D., Alfred Bothwell, Ph.D.), and an advisory committee of 5 additional senior scientists with expertise in these areas. Three specific aims are proposed. First, modulation of survivin expression and function will be studied in cultured human melanocytes in vitro. Melanocytes will be stimulated by UV radiation and growth factors to induce survivin expression, and the effects of (adenoviral-mediated) survivin expression on apoptosis resistance, proliferation, dendricity and melanogenesis will be examined. Second, mechanisms of survivin inhibition of apoptosis in nevi and melanoma cells will be investigated. Nevus cells will be transfected with survivin antisense and a dominant negative survivin point mutant to block survivin function. Melanoma cell lines expressing these antagonists under the control of a tetracycline-regulated promoter will be used to investigate the timing of apoptosis and identify the intracellular target(s) of survivin action. Third, an in vivo model will be developed using these cell lines in SCID mice to study the role of survivin in melanoma tumor development. In addition, survivin antagonists will be directly targeted to tumors using adenoviruses. The proposed studies promise to elucidate the mechanisms of apoptosis regulation in MM, and may identify new molecular approaches for the therapeutic intervention in cancer.