Treating the P13-Kinase/AKT

治疗 P13 激酶/AKT

• 批准号: 7742544
• 负责人: JAMES W MIER
• 金额: $ 14.79万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7742544
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adherent Culture; Affect; Apoptosis; Apoptotic; BAY 54-9085; Biological Markers; Biopsy; Carcinoma in Situ; Cell Line; Cell Survival; Cells; Clinical; Clinical Trials; Consensus; Dana-Farber Cancer Institute; Data; Databases; Development; Endothelium; Evaluation; Event; FDA approved; Failure; Feedback; Generations; Grant; Growth; In Vitro; Kidney; Lipids; Literature; MEKs; Malignant Epithelial Cell; Measurement; Mitogen-Activated Protein Kinases; Molecular; Molecular Target; Mus; Oncogenic; PTEN gene; Parents; Pathway interactions; Patients; Pericytes; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phosphorylation; Phosphotransferases; Platelet-Derived Growth Factor Receptor; Production; Progressive Disease; Protein Biosynthesis; Protein-Serine-Threonine Kinases; Proteins; Renal Cell Carcinoma; Renal carcinoma; Reporting; Reproduction spores; Research Design; Research Personnel; SDZ RAD; ST5 gene; Signal Pathway; Signal Transduction; Specimen; TP53 gene; Testing; Toxic effect; Tumor Angiogenesis; Tumor Cell Line; Tumor Tissue; Tyrosine Kinase Inhibitor; VHL gene; Variant; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Xenograft Model; Xenograft procedure; angiogenesis; antitumor agent; base; cell growth; clinical efficacy; density; design; drug development; drug efficacy; human FRAP1 protein; in vivo; inhibitor/antagonist; kinase inhibitor; mTOR Inhibitor; mTOR inhibition; neoplastic cell; novel; patient population; programs; research clinical testing; response; transcription factor; treatment effect; treatment response; tumor; tumor growth; vector

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.

项目4的主要目的是确定最近批准的mTOR抑制剂的疗效是否 通过阻断mTOR上游的信号传导事件，替西罗莫司在RCC中可以重现甚至超过 在P13-K通路中。PI 3-K抑制剂与常规mTOR相比具有许多理论优势 抑制剂，如替西罗莫司，其中最重要的是后者的倾向，激活PI 3-K，通过一个 涉及mTOR底物p70 '^'* 的反馈回路。我们最近开始研究 双重PI 3-K/mT 0 R抑制剂BEZ 235对细胞内信号传导和肿瘤生长的影响，并且已经观察到 在786-0异种移植物中的单一药剂抗肿瘤活性。我们现建议扩展这些研究， 比较BEZ 235与mTOR抑制剂依维莫司在异种移植物中的抗肿瘤活性 从RCC短期培养物（STC）中产生，这些培养物尚未作为单层培养物繁殖， 因此可能更能代表原位RCC。这些研究还将比较 在仅VHL状态或组成性Akt不同的成对肿瘤细胞系中用BEZ 235治疗 活性，这两者都已被证明会影响对mTOR抑制剂的反应。我们的一个提议 目的是在RCC患者中进行BEZ 235的11期试验。这项试验将包括寻找预测性的 生物标志物和药物对Akt，F0 X 03 a，p53和 肿瘤组织中的mTOR信号传导。BEZ 235诱导肾癌细胞系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它激酶（MEK， GSK-3P）。本申请的目的之一是确定BEZ 235和BZ 235之间的反式协同作用是否是有效的。 MEK或GSK-3 β的抑制剂可以在RCC异种移植模型中体内复制。我们建议的研究将 确定BEZ 235是否具有与PI 3-K抑制剂Ly 294002报告的类似的促血管生成作用， 同时给予VEGF受体拮抗剂是否可以阻断这种作用 舒尼替尼。最后，在该基金的最后一年，我们计划启动BEZ 235与 在上述异种移植物中显示出作为BEZ 235辅助药物的最大潜力的药物 问题研究总的来说，这些研究将评估BEZ 235作为单一药物和作为抗肿瘤药物的抗肿瘤活性。 与其他药物的组合，以及定义最有可能响应这种新型药物的患者群体。