Co-targeting mTOR and YAP signaling in glioblastoma

项目摘要 胶质母细胞瘤是中枢神经系统最常见的原发恶性肿瘤，典型的 对化疗干预耐药的快速增殖的肿瘤。它们的复杂性和异质性 自然界阻碍了成功治疗方法的发展。哺乳动物的目标是 雷帕霉素(MTOR)激酶和YAP癌蛋白最近成为一个有吸引力的靶点 胶质母细胞瘤的治疗干预。 存在两个含有mTOR的多亚基复合体，mTORC1和mTORC2具有不同的性质 分别含有Raptor和Rictor的调节亚基组合物。而过度活跃的mTORC1 活性在许多癌症中被作为靶点，包括胶质母细胞瘤，但效果有限，调节失调 MTORC2函数是最近才开始研究的。 YAP是河马级联反应的下游效应因子，已被发现在脑癌中过度表达 最近，实验证据支持串扰机制协调这些活动 级联反应促进胶质母细胞瘤的增殖、运动和侵袭性。 在本申请中，我们建议1)。鉴定和鉴定与胶质母细胞瘤相关的激活突变 在使该癌蛋白具有结构性活性的YAP中，2)。澄清最近发现的信号串扰 MTORC2和河马信号级联组分之间的相互作用评估一个新的YAP-TEAD 特异性小分子抑制剂单独和与mTORC2特异性抑制剂联合应用于异种移植和 基因工程小鼠(GEM)的疾病模型。我们还建议调查和化学研究 修改YAP抑制剂以构建所需的抗胶质母细胞瘤效果。

Project Summary Glioblastomas 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 and the YAP oncoprotein have recently emerged as an attractive targets for therapeutic intervention in glioblastoma. 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 glioblastoma with limited success, dysregulated mTORC2 function has only recently begun to be investigated. The downstream effector of the Hippo cascade, YAP has been found to be overexpressed in brain cancers and recently, experimental evidence has supported crosstalk mechanisms coordinating the activities of these cascades to promote glioblastoma proliferation, motility and invasiveness. In this application we propose to 1). identify and characterize glioblastoma-associated activating mutations in YAP which render this oncoprotein constitutively active, 2). clarify recently identified signaling crosstalk interactions between mTORC2 and Hippo signaling cascade components and 3.) evaluate a novel YAP-TEAD specific small molecule inhibitor alone and in combination with mTORC2 specific inhibitors in xenografts and genetically engineered mouse (GEM) models of the disease. We also propose to investigate and chemically modify the YAP inhibitor to build in desired anti-glioblastoma effects.