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，是典型的快速增殖肿瘤，对化疗干预具有抗性。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（mTOR）激酶靶点已成为胶质瘤治疗干预的一个有吸引力的靶点。存在两种含有mTOR的多亚基复合物，mTORC1和mTORC2，它们的调控亚基组成不同，分别含有Raptor和Rictor。虽然过度活跃的mTORC1活性已被靶向治疗许多癌症，包括胶质瘤，但成功程度有限，但mTORC2功能失调直到最近才开始被研究。在这个应用中，我们建议：1)剖析Rictor在胶质瘤中的过表达机制；2)阐明最近发现的Rictor介导的胶质瘤形成的基因修饰物，该基因修饰物可能连接mTORC2和Hippo肿瘤抑制信号通路；3)在基因工程小鼠（GEM）疾病模型中评估一种新的mTORC2特异性小分子抑制剂。我们还建议研究和化学修饰抑制剂，以建立针对mTORC2激酶和耐药胶质瘤的额外活性。

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.