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。需要靶向组合治疗来抑制导致黑色素瘤的蛋白质或途径。遗憾的是，已经确定的目标相对较少，或者没有可用的治疗药物来抑制它们。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。功能上，活性Akt3降低了黑色素瘤对通常会通过细胞凋亡杀死的药物的反应性，从而促进肿瘤的发生和化疗耐药性的发展。不幸的是，目前还没有药物可以抑制黑色素瘤中的这一重要途径。此外，目前尚不清楚靶向Akt3信号是否足以治疗，或者靶向其他黑色素瘤引起蛋白（如V600E B-Raf）的组合方法是否需要有效治疗。基于这些重要的未解问题，本提案的中心假设是单独靶向Akt3信号或联合抑制V600E B-Raf将是抑制黑色素瘤的有效靶向方法。该假设将通过以下方式得到验证：(1)表征新型合成异硫氰酸酯和异硒氰酸酯衍生物抑制Akt3信号以减少黑色素瘤的肿瘤发生和转移的效用；(2)确定靶向Akt3和V600E B-Raf信号的组合方法在黑色素瘤中的治疗潜力。我们已经证明Akt3和V600EB-Raf通路是黑色素瘤的关键治疗靶点，并且开发了从化学预防异硫氰酸酯衍生的新型合成化合物来抑制Akt3信号传导，我们准备进行拟议的研究。实现这些目标将是非常重要的，为靶向黑色素瘤主要信号通路的治疗意义提供新的见解，并为靶向Akt3信号通路的黑色素瘤患者启动临床试验提供坚实的理论基础。对于黑色素瘤患者来说，这些发现可能最终导致改进治疗方法的发展，从而延长患有这种疾病的个体的寿命和生活质量。从长远来看，发现抑制Akt3信号通路的治疗方法和有效途径，预计将对目前晚期黑色素瘤患者面临的不良预后产生显著的积极影响。具体来说，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，本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.