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

描述(申请人提供)：胶质母细胞瘤(GBM)是成人最常见的恶性原发脑瘤，也是所有癌症中最致命的癌症之一。需要新的治疗方法。基因组、蛋白质组和小鼠模型研究表明，mTOR激酶是一个引人注目的GBM靶点。MTOR复合体1在GBM中的作用已得到很好的认识，但对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，证明了mTORC2信号在GBM中在促进雷帕霉素治疗耐药中的关键作用，并证明了需要抑制这两个mTOR复合体才能有效地诱导GBM肿瘤细胞死亡。这项建议汇集了一支经验丰富的合作团队，他们在GBM信号转导、mTORC2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信号的分子电路，并开发和测试一种新型的mTOR激酶抑制剂，该抑制剂可以抑制这两种mTOR信号复合体。我们将把新的mTOR生化分析应用于基因定义的GBM的体外和体内模型以及精心表征的临床样本，以阐明mTORC2信号在GBM中的分子回路和功能重要性。我们将与Celgene合作，开发和测试一种新型的mTOR激酶抑制剂，具有强大的抗mTORC1和mTORC2活性。我们将：1)直接测量基因定义的GBM模型和临床样本中的mTORC2活性，并确定mTORC2的上游激活剂和下游效应物；2)确定是否需要联合抑制这两种mTOR信号复合体来阻止肿瘤生长；3)确定新型mTOR激酶抑制剂用于治疗GBM患者的疗效，包括确定最有可能从该药物中受益的患者。

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.