Akt Inhibitors to Treat Ewing's Sarcoma

描述(由申请人提供)：在对抗癌症的战争中，提高总体存活率并降低发病率的新药至关重要。Acenta Discovery Inc.已与隆巴迪癌症中心的托雷茨基实验室合作，创造并在临床前评估Akt蛋白的新型抑制剂。Akt抑制剂将在改善多种癌症患者的生活方面具有巨大价值，并导致成功的商业企业。 AKT调节的生存信号使肿瘤能够在细胞毒化疗中存活。抑制Akt信号转导会降低肿瘤存活率，从而通过增加细胞凋亡来提高细胞毒化疗的疗效。这种细胞毒性的增强可能是无病生存和微小残留疾病状态下复发之间的差异。由于磷脂酰肌醇将Akt重新聚集到细胞膜上是Akt发挥功能的关键，因此已开发出一些磷脂酰肌醇类似物来阻断Akt向细胞膜的运动，而不影响其他脂类依赖分子的功能。 我们有一个尤文氏肉瘤肿瘤家族(ESFT)的模型，该模型证明Akt对于化疗敏感性至关重要。此外，ESFT患者的临床存活率很低，特别是有转移性疾病的患者。众所周知，ESFT患者通常对最初的化疗反应良好，然而，复发发生在转移部位，这表明一批肿瘤细胞在最初的治疗周期中存活了下来。可以解释肿瘤细胞在化疗中存活的一个机制是IG F-I通过Akt激活生存途径并避免细胞死亡的能力。已知ESFT依赖于通过胰岛素样生长因子I型受体(IGF-IR)的信号来生存(通过Akt)和生长(通过MAP激酶)。我们以前的工作表明PI3-K和Akt是ESFT中重要的生存分子。在球形培养中生长的ESFT细胞表现出结构性激活的Akt。 我们假设Akt是ESFT患者的治疗靶点，特异性阻断Akt功能的临床分子的开发将提高患者的存活率。这项提案将评估一系列专门阻断Akt功能的分子，并确定这些分子是否在ESFT异种移植模型中发挥增强化疗效果的功能。我们在SUN第一阶段的发现有望导致一种关键化合物，该化合物可以在第二阶段STTR中进一步开发，最终导致在ESFT患者中进行临床试验。

DESCRIPTION (provided by applicant): Novel drugs that improve overall survival with decreased morbidity are critical in the war on cancer. Acenta Discovery Inc. has partnered with the Toretsky Lab of the Lombardi Cancer Center to create and preclinically evaluate novel inhibitors of the protein Akt. An Akt inhibitor would have tremendous value in improving the lives of patients with many types of cancer and lead to a successful commercial venture. Akt modulated survival signaling enables tumors to survive cytotoxic chemotherapy. Inhibition of Akt signaling will reduce tumor survival thereby enhancing the effectiveness of cytotoxic chemotherapy by increasing apoptosis. This augmentation of cytotoxicity could be the difference between disease-free survival and relapse following a state of minimal residual disease. Since the recruitment of Akt to the cell membrane with phosphatidylinositol is critical for Akt to function, analogues of phosphatidylinositol have been developed that block Akt movement to the membrane without affecting the function of other lipid dependent molecules. We have a model of Ewing's sarcoma family of tumors (ESFT) that demonstrates Akt as critical for sensitivity to chemotherapy. In addition, clinical survival rates for patients with ESFT are poor, especially for patients with metastatic disease. It is well established that patients with ESFT often respond well to initial chemotherapy, however, relapse occurs at metastatic sites indicating that a subpopulation of tumor cells survived the initial cycles of therapy. One mechanism that could explain tumor cells surviving chemotherapy is the ability for IG F-I to activate survival pathways through Akt and avoidance of cell death. ESFT are known to rely on signaling through the insulin-like growth factor type I receptor (IGF-IR) for their survival (via Akt) and growth (via MAP kinase). Our previous work implicates PI 3-K and Akt as important survival molecules in ESFT. ESFT cells growing in spheroid culture demonstrate constitutively activated Akt. We hypothesize that Akt is a therapeutic target in patients with ESFT and that the development of clinical molecules that specifically block Akt function will improve patient survival. This proposal~ will evaluate a series of molecules that specifically block Akt function and determine if these molecules function to enhance chemotherapy effects in xenograft models of ESFT. Our findings from this Phase I Sun will hopefully lead to a key compound that can be further developed in a Phase II STTR ultimately leading to clinical trials in patients with ESFT.