Dysregulation of mTORC2 in gliomas

描述(申请人提供)：胶质瘤是最常见的中枢神经系统原发恶性肿瘤，是典型的快速增殖的肿瘤，对化疗干预具有抵抗力。它们的复杂性和异质性阻碍了成功治疗方法的发展。哺乳动物靶点雷帕霉素(MTOR)激酶已成为胶质瘤治疗干预的一个有吸引力的靶点。存在两个含有mTOR的多亚基复合体，mTORC1和mTORC2，它们的调节亚基组成不同，分别含有Raptor和Rictor。虽然高度活跃的mTORC2活性在许多癌症中被作为靶点，包括成功的胶质瘤，但mTORC2功能失调的研究直到最近才开始。在本申请中，我们建议1)。剖析Rictor在胶质瘤中过表达的机制(S)，2)。阐明最近发现的Rictor介导的胶质瘤发生的遗传修饰物，可能将mTORC2和河马肿瘤抑制信号通路联系起来。在遗传工程小鼠(GEM)的疾病模型中评估一种新的mTORC2特异性小分子抑制剂。我们还建议对该抑制剂进行研究和化学修饰，以增加针对mTORC2激酶和耐药胶质瘤的活性。 公共卫生相关性：该项目的成功完成将证实继续开发mTORC2特异性抑制剂用于脑胶质瘤患者试验的临床前理论基础。此外，这项研究将提供关于mTORC2活性异常导致胶质瘤形成的操作机制(S)的信息。

DESCRIPTION (provided by applicant): Gliomas are the most common primary malignancy of the central nervous system and are typically rapidly proliferating tumors resistant to chemotherapeutic intervention. Their complex and heterogeneous nature has hampered progress towards the development of successful therapies. The mammalian target of rapamycin (mTOR) kinase has emerged as an attractive target for therapeutic intervention in gliomas. Two multisubunit complexes containing mTOR exist, mTORC1 and mTORC2 which differ in their regulatory subunit compositions containing Raptor and Rictor, respectively. While hyperactive mTORC1 activity has been targeted in many cancers, including glioma with limited success, dysregulated mTORC2 function has only recently begun to be investigated. In this application we propose to 1). dissect the mechanism(s) of Rictor overexpression in gliomas, 2). clarify a recently identified genetic modifier of Rictor-mediated gliomagenesis potentially linking the mTORC2 and Hippo tumor suppressor signaling pathways and 3.) evaluate a novel mTORC2 specific small molecule inhibitor in genetically engineered mouse (GEM) models of the disease. We also propose to investigate and chemically modify the inhibitor to build in additional activitie against both the mTORC2 kinase and drug resistant gliomas. PUBLIC HEALTH RELEVANCE: Successful completion of this project will substantiate a preclinical rationale for the continued development of mTORC2 specific inhibitors for trials in patients with glioma. Additionally, this study will provide information as to the operative mechanism(s) contributing to gliomagenesis as a result of aberrant mTORC2 activities.