Dysregulation of mTORC2 in gliomas

描述（由申请人提供）：胶质瘤是中枢神经系统最常见的原发性恶性肿瘤，通常是对化疗干预具有抗性的快速增殖肿瘤。它们的复杂性和异质性阻碍了成功疗法的发展。哺乳动物雷帕霉素靶蛋白（mTOR）激酶已成为神经胶质瘤治疗干预的有吸引力的靶点。存在两种含有mTOR的多亚基复合物，mTORC 1和mTORC 2，它们分别在含有Raptor和Rictor的调节亚基组成上不同。虽然过度活跃的mTORC 1活性已在许多癌症中被靶向，包括成功有限的胶质瘤，但失调的mTORC 2功能最近才开始研究。在本申请中，我们提出1）。剖析神经胶质瘤中Rictor过度表达的机制，2）。澄清最近鉴定的Rictor介导的胶质瘤发生的遗传修饰剂，其可能连接mTORC 2和Hippo肿瘤抑制信号传导途径;和3.）在该疾病的遗传工程小鼠（GEM）模型中评估新型mTORC 2特异性小分子抑制剂。我们还建议研究和化学修饰抑制剂，以建立对mTORC 2激酶和耐药胶质瘤的额外活性。 公共卫生相关性：该项目的成功完成将证实继续开发用于神经胶质瘤患者试验的mTORC 2特异性抑制剂的临床前原理。此外，本研究将提供有关mTORC 2活性异常导致胶质瘤形成的操作机制的信息。

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.