Targeted Chemoprevention Through Inhibition of Akt3 Signaling

描述（由申请人提供）： 恶性黑色素瘤是最具侵袭性和致命性的皮肤癌，没有有效的治疗方法来治疗晚期疾病，导致生存率低。需要靶向化学预防，重点是抑制导致黑色素瘤发展的蛋白质或途径。令人遗憾的是，相对较少的目标已被确定，涉及绝大多数散发性黑色素瘤或没有化学预防剂可用于抑制它们。最近，我们发现与正常细胞相比，约70%的散发性黑色素瘤中Akt3活性升高。在功能上，活性Akt3降低早期恶性前黑素瘤细胞对通常通过凋亡杀死的药剂的反应性，从而促进黑素瘤发展。不幸的是，没有化学预防剂可用于抑制早期黑素瘤细胞中的Akt3信号级联。本申请的中心假设是靶向Akt3信号传导将是抑制黑色素瘤发展的有效化学预防方法。将通过表征新型合成异硒氰酸酯衍生物的化学预防效用来测试该假设，所述异硒氰酸酯衍生物在黑素瘤的临床前小鼠模型中抑制Akt3信号传导。所使用的方法涉及开发新的合成含硒化合物，该化合物来源于异硫氰酸酯，其通过靶向Akt3信号级联抑制黑色素瘤的发展。接下来，评价体外和动物毒性，测量抑制皮肤和皮下黑色素瘤发展的有效性，并表征导致抑制的机制。最后，将优化先导化合物作为可注射或膳食化学预防剂的效力和生物利用度。实现这些目标将是非常重要的，为靶向促进黑色素瘤发展的主要信号传导途径的化学预防潜力提供了新的见解，并为在黑色素瘤患者中启动靶向Akt3信号传导的临床试验提供了坚实的理论基础。我们准备进行拟议的研究，已经证明Akt3途径是黑色素瘤的关键靶标，并开发了新型合成硒基化合物，这些化合物来源于抑制Akt3信号传导的化学预防性异硫氰酸酯。

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.