Role of mTORC2 in GBM - development of a novel therapeutic mTOR kinase inhibitor

描述（由申请人提供）：胶质母细胞瘤（GBM）是成人最常见的恶性原发性脑肿瘤，也是所有癌症中最致命的肿瘤之一。需要新的治疗方法。基因组学、蛋白质组学和小鼠模型研究表明mTOR激酶是GBM的重要靶点。mTOR复合体1在GBM中的作用已得到充分认识；人们对mTOR复合体2的作用知之甚少。我们提供了令人兴奋的初步数据，证明mTORC2信号在GBM中促进对雷帕霉素的治疗性耐药的关键作用，并证明需要抑制这两种mTOR复合物才能有效诱导GBM肿瘤细胞死亡。该提案汇集了一个经验丰富的合作团队，具有GBM信号转导，mTORC2生物化学和GBM体外和体内模型的专业知识，以阐明GBM中mTOR信号传导的分子通路，并开发和测试一种抑制mTOR信号复合物的新型mTOR激酶抑制剂。我们将在体外和体内模型中对基因定义的GBM进行新的mTOR生化分析，并对临床样本进行细致的表征，以阐明mTORC2信号在GBM中的分子通路和功能重要性。我们将与Celgene合作，开发并测试一种具有强抗mtorc1和mTORC2活性的新型mTOR激酶抑制剂。我们将：1)直接测量遗传定义的GBM模型和临床样品中的mTORC2活性，并确定mTORC2的上游激活剂和下游效应剂；2)确定是否需要联合抑制两种mTOR信号复合物来阻断肿瘤生长；3)确定新型mTOR激酶抑制剂治疗GBM患者的疗效，包括确定最有可能从该药物中获益的患者。

DESCRIPTION (provided by applicant): Glioblastoma (GBM) is the most common malignant primary brain tumor of adults and one of the most lethal of all cancers. New therapeutic approaches are needed. Genomic, proteomic and mouse model studies implicate mTOR kinase as a compelling GBM target. The role of mTOR complex 1 in GBM is well recognized; the role of mTOR complex 2 is poorly understood. We present exciting preliminary data demonstrating a critical role for mTORC2 signaling in GBM in promoting therapeutic resistance to rapamycin and demonstrate that inhibition of both mTOR complexes is needed to potently induce GBM tumor cell death. This proposal brings together a highly experienced collaborative team with expertise in GBM signal transduction, mTORC2 biochemistry and GBM in vitro and in vivo models to illuminate the molecular circuitry of mTOR signaling in GBM and to develop and test a novel mTOR kinase inhibitor that inhibits both mTOR signaling complexes. We will apply novel mTOR biochemical assays to genetically defined GBM in vitro and in vivo models and meticulously characterized clinical samples to illuminate the molecular circuitry and functional importance of mTORC2 signaling in GBM. In partnership with Celgene, we will develop and test a novel mTOR kinase inhibitor with potent anti-mTORC1 and mTORC2 activity We will: 1) directly measure mTORC2 activity in genetically defined GBM models and clinical samples and identify upstream activators and downstream effectors of mTORC2; 2) determine whether combined inhibition of both mTOR signaling complexes is required to block tumor growth and 3) determine the efficacy of the novel mTOR kinase inhibitor for treatment of GBM patients including identifying patients most likely to benefit from the drug.