Targeted Chemoprevention Through Inhibition of Akt3 Signaling

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DESCRIPTION (provided by applicant): Malignant melanoma is the most invasive and deadly form of skin cancer with no effective therapy to treat advanced disease, leading to poor survival rates. Targeted chemoprevention focusing on inhibition of proteins or pathways leading to melanoma development is needed. Regrettably, relatively few targets have been identified that are involved in the vast majority of sporadic melanomas or no chemopreventive agents are available to inhibit them. Recently, we identified elevated Akt3 activity occurring in ~70% of sporadic melanomas compared to normal cells. Functionally, active Akt3 reduces responsiveness of early premalignant melanoma cells to agents that would normally kill via apoptosis, thereby promoting melanoma development. Unfortunately, no chemopreventive agents are available to inhibit the Akt3 signaling cascade in early melanoma cells. The central hypothesis for this application is that targeting Akt3 signaling would be an effective chemopreventive approach for inhibiting melanoma development. The hypothesis will be tested by characterizing the chemopreventive utility of novel synthetic isoselenocyanate derivatives that inhibit Akt3 signaling in preclinical mouse models of melanoma. The approach to be used involves developing the novel synthetic selenium containing compounds derived from isothiocyanate, which inhibit melanoma development by targeting the Akt3 signaling cascade. Next, evaluate toxicity in vitro and in animals, measure effectiveness for inhibiting cutaneous as well as subcutaneous melanoma development and characterize mechanism leading to inhibition. Finally, lead compounds would be optimized for potency and bioavailability as injectable or dietary chemopreventive agents. Accomplishing these goals would be highly significant, providing novel insight into the chemopreventive potential of targeting a major signaling pathway promoting melanoma development, and provide solid rationale for initiating clinical trials in melanoma patients that target Akt3 signaling. We are prepared to undertake the proposed research, having demonstrated that the Akt3 pathways is a key target in melanoma and development of novel synthetic selenium based compounds derived from chemopreventive isothiocyanates that inhibit Akt3 signaling.