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，导致存活率很低。需要有针对性的化学预防，重点是抑制导致黑色素瘤发展的蛋白质或途径。遗憾的是，与绝大多数散发性黑色素瘤相关的靶点相对较少，或者没有化学预防药物可用来抑制它们。最近，我们发现，与正常细胞相比，散发性黑色素瘤中约70%的AKT3活性升高。在功能上，激活的AKT3降低了早期恶性前黑色素瘤细胞对通常会通过凋亡杀死的药物的反应性，从而促进了黑色素瘤的发展。不幸的是，目前还没有有效的化学预防药物来抑制早期黑色素瘤细胞中AKT3信号级联反应。这一应用的中心假设是，靶向AKT3信号将是抑制黑色素瘤发展的有效化学预防方法。这一假说将通过表征新型合成异硫氰酸酯衍生物在临床前黑色素瘤小鼠模型中抑制AKT3信号的化学预防效用来检验。将使用的方法包括开发从异硫氰酸酯衍生的新型合成含硒化合物，该化合物通过靶向AKT3信号级联来抑制黑色素瘤的发展。接下来，评估体外和动物的毒性，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，作为注射或饮食化学预防药物，先导化合物的效力和生物利用度将得到优化。实现这些目标将具有非常重要的意义，为靶向促进黑色素瘤发展的主要信号通路的化学预防潜力提供了新的见解，并为启动针对AKT3信号通路的黑色素瘤患者临床试验提供了坚实的理论基础。我们准备开展这项拟议的研究，因为我们已经证明AKT3通路是黑色素瘤和开发新型合成硒化合物的关键靶点，这些化合物来自于抑制AKT3信号转导的化学预防异硫氰酸酯。

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.