Akt3 Signaling as a Therapeutic Target

描述(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。需要有针对性的组合疗法来抑制引起黑色素瘤的蛋白质或途径。遗憾的是，确定的靶点相对较少，或者没有可用的治疗剂来抑制它们。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降低了黑色素瘤对通常通过细胞凋亡而致死的药物的反应性，从而促进了肿瘤的发生和化疗耐药的发展。不幸的是，没有任何药物可以抑制黑色素瘤的这一重要途径。此外，目前尚不清楚靶向AKT3信号转导是否在治疗上就足够了，或者是否需要针对其他导致黑色素瘤的蛋白质，如V600E B-Raf，来进行有效的治疗。基于这些重要的悬而未决的问题，这一提议的中心假设是，单独靶向AKT3信号转导或联合抑制V600E B-Raf将是抑制黑色素瘤的有效靶向方法。这一假设将通过以下几个方面得到验证：(1)鉴定新型合成异硫氰酸酯和异硫氰酸酯衍生物的有效性，这些衍生物抑制AKT3信号转导以减少黑色素瘤的发生和转移；(2)确定针对AKT3和V600E B-Raf信号的组合方法在黑色素瘤中的治疗潜力。我们准备开展这项拟议的研究，因为我们已经证明AKT3和V600EB-Raf通路是黑色素瘤的关键治疗靶点，并开发从化学预防性异硫氰酸酯衍生的新型合成化合物来抑制AKT3信号转导。实现这些目标将具有非常重要的意义，为靶向黑色素瘤主要信号通路的治疗意义提供了新的见解，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。对于黑色素瘤患者来说，这些发现最终可能导致改进治疗方法的发展，从而延长患有这种疾病的患者的时间和生活质量。从长远来看，抑制AKT3信号通路的治疗方法和有效方法的发现，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。具体地说，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生活时间和质量。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.