Akt3 Signaling as a Therapeutic Target

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。需要靶向组合疗法来抑制引起黑色素瘤的蛋白质或途径。令人遗憾的是，相对较少的目标已被确定或没有治疗剂可用于抑制它们。最近，我们发现与正常细胞相比，约70%的散发性黑色素瘤中Akt 3活性升高。在功能上，活性Akt 3降低黑素瘤对通常通过凋亡杀死的药剂的响应性，从而促进肿瘤发生和化学抗性的发展。不幸的是，没有药物可用于抑制黑色素瘤中的这一重要途径。此外，靶向Akt 3信号传导是否在治疗上是足够的，或者靶向其他引起黑色素瘤的蛋白质如V600 E B-Raf的组合方法是否是有效治疗所必需的，这是未知的。基于这些重要的未回答的问题，该提议的中心假设是单独靶向Akt 3信号传导或与V600 E B-Raf抑制组合将是抑制黑素瘤的有效靶向方法。该假设将通过以下来检验：（1）表征抑制Akt 3信号传导以减少黑素瘤肿瘤发生和转移的新型合成异硫氰酸酯和异硒氰酸酯衍生物的效用;和（2）确定靶向黑素瘤中的Akt 3和V600 E B-Raf信号传导的组合方法的治疗潜力。我们准备进行拟议的研究，已经证明Akt 3和V600 EB-Raf途径是黑色素瘤的关键治疗靶点，并开发了来自化学预防性异硫氰酸酯的新型合成化合物来抑制Akt 3信号传导。实现这些目标将是非常重要的，为靶向黑色素瘤中主要信号传导途径的治疗意义提供了新的见解，并为在黑色素瘤患者中启动靶向Akt 3信号传导的临床试验提供了坚实的理论基础。对于黑色素瘤患者，这些发现最终可能导致开发改进的治疗方法，从而增加患有这种疾病的个体的生命长度和质量。从长远来看，抑制Akt 3信号通路的治疗方法和有效方法的发现预计将对晚期黑色素瘤患者目前面临的不良预后产生显着的积极影响。具体而言，这些药物将有助于获得更有效的治疗方法，这将增加黑色素瘤患者的寿命和生活质量。因此，这项研究对黑色素瘤治疗领域的积极影响将是显著的。

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 combinatorial therapeutics is needed that inhibit proteins or pathways causing melanoma. Regrettably, relatively few targets have been identified or no therapeutic 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 melanomas to agents that would normally kill via apoptosis, thereby promoting tumorigenesis and development of chemoresistance. Unfortunately, no agents are available to inhibit this important pathway in melanomas. Furthermore, it is unknown whether targeting Akt3 signaling would be therapeutically sufficient or whether a combinatorial approach targeting other melanoma causing proteins, such as V600E B-Raf, would be necessary for an effective therapeutic. Based on these important unanswered questions, the central hypothesis for this proposal is that targeting Akt3 signaling alone or in combination with V600E B-Raf inhibition would be an effective targeted approach for inhibiting melanoma. The hypothesis will be tested by: (1) characterizing the utility of novel synthetic isothiocyanate and isoselenocyanate derivatives that inhibit Akt3 signaling to reduce melanoma tumorigenesis and metastasis; and (2) determining the therapeutic potential of a combinatorial approach targeting Akt3 and V600E B-Raf signaling in melanomas. We are prepared to undertake the proposed research, having demonstrated that the Akt3 and V600EB-Raf pathways are key therapeutic targets in melanoma and development of novel synthetic compounds derived from chemopreventive isothiocyanates to inhibit Akt3 signaling. Accomplishing these goals would be highly significant, providing novel insight into the therapeutic implications of targeting a major signaling pathway in melanoma, and provide solid rationale for initiating clinical trials in melanoma patients targeting Akt3 signaling. For melanoma patients, these discoveries could ultimately lead to development of improved therapeutics that would increase length and quality of life for individuals suffering from this disease. Over the long-term, discovery of therapeutics and effective approaches to inhibit the Akt3 signaling pathway are predicted to have a significantly positive impact on the currently poor prognosis faced by advanced-stage melanoma patients. Specifically these agents would contribute to the availability of more effective therapies, which would increase the length and quality of life for melanoma patients. Therefore, the positive impact of this study on the melanoma therapeutics field will be significant.