Mechanistic studies of cancer cell adaptive response to PI3K/AKT inhibition

描述(申请人提供)：PI3K-AKT通路在许多人类癌症中被过度激活，包括肾细胞癌(RCC)，几种抑制该通路的药物目前正在各种临床前或临床试验中进行测试。然而，已有研究表明，PIK或AKT抑制导致反馈调节的解除和其他致癌信号通路的激活，这可能会限制这些抑制剂作为单一药物在癌症治疗中的临床应用。此外，只有一小部分癌症患者可能会对PI3K或AKT抑制剂产生积极反应，目前还不清楚哪些患者将受益最大。我们的长期目标是在药物反应的背景下理解PI3K-AKT信号，并将这些发现转化为有意义的临床应用。本应用程序的目标是 目的是研究我们发现的FoxO-Rictor信号轴在PI3K或AKT抑制治疗肾癌中的作用。我们广泛的初步数据支持我们提出的中心假设，即FoxO的激活通过上调Rictor表达和促进AKT Ser473磷酸化来介导PI3K或AKT抑制介导的AKT重新激活，这最终将限制PI3K或AKT抑制剂在肾癌治疗中的影响。在这个方案中，我们将采用多学科的方法，包括详细的生化机制研究，复杂的基因工程小鼠模型，以及肾癌患者样本的分析，以研究FoxO-Rictor信号轴在肾癌发生和治疗中的作用。这项研究的基本原理是，我们提出的研究将促进我们对PI3K-AKT抑制介导的反馈的理解，并将为开发针对PI3K-AKT途径的新的治疗策略或肾癌治疗的生物标志物提供重要的启示。我们的建议具有很高的创新性，因为它专注于一种以前未被探索的机制，填补了目前肾癌治疗的空白。我们提出的研究将对理解反馈调节的基本机制和在临床上操纵FoxO-Rictor通路在癌症患者的分层和治疗中具有重要意义。

DESCRIPTION (provided by applicant): The PI3K-AKT pathway is hyperactivated in many human cancers, including renal cell carcinoma (RCC), and several drugs to inhibit this pathway are currently tested in various pre-clinical or clinical trials. However, it has been shown that PIK or AKT inhibition results in the relief of feedback regulation and activation of other oncogenic signaling pathways, which likely will limit the clinical utilization of these inhibitors as a singl agent in cancer treatment. In addition, only a fraction of cancer patients will likely respond positively to PI3K or AKT inhibitors, and it is unclear which patients will benefit most. Our long-term goal is to understand the PI3K-AKT signaling in the context of drug response and to translate such discoveries into meaningful clinical applications. The objective of this application is to study the roles of FoxO-Rictor signaling axis we identified in renal cancer treatment by PI3K or AKT inhibition. Our extensive preliminary data support the central hypothesis of our proposal that activation of FoxO mediates PI3K or AKT inhibition-directed reactivation of AKT by upregulating Rictor expression and promoting AKT Ser473 phosphorylation, which eventually will limit the impact of the PI3K or AKT inhibitor in renal cancer treatment. In this proposal, we will employ multi-disciplinary approaches, including detailed biochemical mechanistic studies, sophisticated genetically engineered mouse models, and analysis of renal cancer patient samples, to study FoxO-Rictor signaling axis in renal cancer development and treatment. The rationale for the proposed research is that our proposed studies will advance our understanding of PI3K-AKT inhibition-mediated feedback, and will provide important insight for the development of novel therapeutic strategies or biomarkers targeting PI3K-AKT pathway in renal cancer treatment. Our proposal is highly innovative, because it focuses on a previously unexplored mechanism that fills in the current gap in renal cancer treatment. Our proposed studies will have significant impact on both understanding the fundamental mechanisms of feedback regulation and manipulating FoxO-Rictor pathway clinically in the stratification and treatment of cancer patients.