P4 - Treating the P13-Kinase/AKT

P4 - 治疗 P13 激酶/AKT

基本信息

批准号：
8079680
负责人：
JAMES W MIER
金额：
$ 14.74万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8079680
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 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 Reporting Research Design 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 research clinical testing response transcription factor treatment effect treatment response tumor tumor growth vector

项目摘要

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抑制剂的功效是否是否 Temsirolimus可以通过阻止MTOR上游的信号事件在RCC中复制甚至超过在P13-K途径中。 PI3-K抑制剂比常规MTOR具有许多理论上的优势抑制剂，例如temsirolimus，其中最少的是后者通过A激活PI3-K的趋势反馈循环涉及MTOR基板p70'^'*。我们最近开始研究双PI3-K/MT0R抑制剂BEZ235在细胞内信号传导和肿瘤生长上，已经观察到 786-0异种移植物中的单药抗肿瘤活性。我们现在建议通过将BEZ235与异种移植物中的MTOR抑制剂Everolimus的抗肿瘤活性进行比较由RCC短期文化（STC）产生的，这些文化尚未传播为单层文化和因此，可能更代表RCC的原位。这些研究还将比较在成对的肿瘤细胞系中用BEZ235处理仅在VHL状态或本构AKT方面有所不同活性，两者都已证明会影响对MTOR抑制剂的反应。我们提议的之一 AIMS涉及在RCC患者中对BEZ235进行11期试验。该试验将包括搜索预测生物标志物以及对药物对AKT的影响，F0X03A，p53和 MTOR信号在肿瘤组织中。 BEZ235诱导RCC细胞系及其抗增殖性的生长停滞通过同时抑制与细胞存活相关的其他激酶（MEK，，MEK， GSK-3P）。本应用程序的目标之一是确定bez235和 MEK或GSK-3的抑制剂（可以在RCC异种移植模型中复制3个。我们提出的研究将确定BEZ235是否具有类似于PI3-K抑制剂LY294002和 VEGF受体拮抗剂的并发施用是否可以阻止这种效果 Sunitinib。最后，在此赠款的最后一年，我们建议启动BEZ235的临床试验在上述异种移植物中显示出最大潜力作为BEZ235的辅助药物的药物研究。总的来说，这些研究将评估Bez235的抗肿瘤活性，既是单一药物，又结合其他药物，并定义最有可能反应这种新型药物的患者人群。