P4 - Treating the P13-Kinase/AKT

项目4的主要目标是确定最近批准的mTOR抑制剂的疗效 替西罗莫司可以通过阻断mTOR上游的信号事件在RCC中复制甚至超过 在P13-K途径中。与传统的mTOR相比，PI3-K抑制剂有许多理论上的优势 抑制剂，如替西罗莫司，其中最重要的是后者的趋势是激活PI3-K 涉及mTOR底物p70‘^’*的反馈环。我们最近已经开始研究这些因素的影响 双重PI3-K/mT0R抑制剂BEZ235对细胞内信号转导和肿瘤生长的影响 单药对786-0移植瘤的抗肿瘤活性。我们现在建议通过以下方式延长这些研究 BEZ235与mTOR抑制剂伊波利莫斯在异种移植瘤中的抗肿瘤活性比较 由尚未作为单层培养物繁殖的RCC短期培养物(STC)生成，并且 因此可能更能代表原位碾压混凝土。这些研究还将比较 BEZ235对仅在VHL状态或构成Akt方面存在差异的成对肿瘤细胞系的治疗 活性，这两者都已被证明影响对mTOR抑制剂的反应。我们建议的其中一项 AIMS涉及在肾癌患者中使用BEZ235的11期试验。该试验将包括对预测性的搜索 生物标志物及其对Akt、F0X03a、P53和AKT影响的综合药效学分析 肿瘤组织中的mTOR信号转导。BEZ235诱导肾癌细胞生长停滞及其抗增殖作用 通过同时抑制与细胞存活相关的其他激酶(MEK， 葛兰素史克-3P)。本申请的目标之一是确定BEZ235和BEZ235之间的输入/输出协同 MEK或GSK-3的抑制剂(3)可在肾细胞癌异种移植模型中体内复制。我们建议的研究将 确定BEZ235是否具有与报道的PI3-K抑制剂Ly294002类似的促血管生成作用 血管内皮生长因子受体拮抗剂能否阻断这一作用 舒尼替尼。最后，在这笔赠款的最后一年，我们建议启动BEZ235的联合临床试验 在上述异种移植中，该药物显示出作为BEZ235辅助药物的最大潜力 学习。总的来说，这些研究将评估BEZ235作为单一药物和在 与其他药物的结合，以及确定最有可能对这种新型药物做出反应的患者群体。

The primary objective of Project 4 is to determine if the efficacy of the recently approved mTOR inhibitor temsirolimus can be reproduced or even surpassed in RCC by blocking signaling events upstream of mTOR in the P13-K pathway. PI3-K inhibitors have numerous theoretical advantages over conventional mTOR inhibitors such as temsirolimus, not the least of which is the tendency of the latter to activate PI3-K through a feedback loop involving the mTOR substrate p70'^'*. We have recently begun studies ofthe effects ofthe dual PI3-K/mT0R inhibitor BEZ235 on intracellular signaling and tumor growth and have already observed single agent antitumor activity in 786-0 xenografts. We are now proposing to extend these studies by comparing the antitumor activities of BEZ235 with those ofthe mTOR inhibitor everolimus in xenografts generated from RCC short term cultures (STCs) that have not been propagated as monolayer cultures and therefore may be more representative of RCC in situ. These studies will also compare the effects of treatment with BEZ235 in paired tumor cell lines that differ only with respect to VHL status or constitutive Akt activity, both of which have been shown to affect the response to mTOR inhibitors. One of our proposed Aims involves a Phase 11 trial with BEZ235 in RCC patients. This trial will include a search for predictive biomarkers and a comprehensive pharmacodynamic analysis of the drug's effect on Akt, F0X03a, p53 and mTOR signaling in tumor tissue. BEZ235 induces growth arrest in RCC cell lines and its antiproliferative effects can be enhanced by the concurrent inhibition of other kinases associated with cell survival (MEK, GSK-3P). One of the objectives of this application is to determine if the in v/fro synergy between BEZ235 and inhibitors of MEK or GSK-3(3 can be duplicated in vivo in RCC xenograft models. Our proposed studies will determine if BEZ235 has pro-angiogenic effects similar to that reported for the PI3-K inhibitor Ly294002 and whether this effect can be blocked with the concurrent administration ofthe VEGF receptor antagonist sunitinib. Finally, in the final year ofthis grant, we propose to initiate a clinical trial of BEZ235 in combination with the drug that showed the greatest potential as an adjunct to BEZ235 in the aforementioned xenograft studies. Collectively, these studies will assess the antitumor activity of BEZ235 both as a single agent and in combination with other drugs as well as define the patient population most likely to respond this novel agent.