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一种。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激酶是一个引人注目的GBM靶点。mTOR复合物1在GBM中的作用得到了很好的认可; mTOR复合物2的作用知之甚少。我们提出了令人兴奋的初步数据，证明了GBM中mTORC 2信号传导在促进对雷帕霉素的治疗耐药性方面的关键作用，并证明了需要抑制两种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，该团队在GBM信号转导、mTORC 2生物化学和GBM体外和体内模型方面拥有专业知识，以阐明GBM中mTOR信号传导的分子电路，并开发和测试一种新型mTOR激酶抑制剂，该抑制剂可抑制两种mTOR信号复合物。我们将应用新的mTOR生化分析，以遗传定义的GBM在体外和体内模型和精心表征的临床样本，以阐明在GBM的mTORC 2信号的分子电路和功能的重要性。与Celgene合作，我们将开发和测试具有有效抗mTORC 1和mTORC 2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mTORC 2活性，并鉴定mTORC 2的上游激活物和下游效应物; 2）确定阻断肿瘤生长是否需要两种mTOR信号传导复合物的联合抑制，和确定新型mTOR激酶抑制剂用于治疗GBM患者的功效，包括鉴定最有可能从药物中获益的患者。

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.