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性恶性肿瘤， 快速增殖的肿瘤对化疗干预具有抗性。它们的复杂性和多样性 大自然阻碍了成功疗法的发展。的哺乳动物靶标 雷帕霉素（mTOR）激酶和雅普癌蛋白最近已经成为治疗肿瘤的有吸引力的靶点。 胶质母细胞瘤的治疗干预。 存在两种含有mTOR的多亚基复合物，mTORC 1和mTORC 2，它们在其结构上不同。 分别含有Raptor和Rictor的调节亚基组合物。当mTORC 1过度活跃时 活性已经在许多癌症中被靶向，包括成功有限的胶质母细胞瘤， mTORC 2功能最近才开始研究。 Hippo级联反应的下游效应物雅普已被发现在脑癌中过表达 最近，实验证据支持协调这些活动的串扰机制， 级联促进胶质母细胞瘤增殖、运动和侵袭。 在本申请中，我们提出1）。胶质母细胞瘤相关激活突变鉴定和表征 在使这种癌蛋白具有组成性活性雅普中，2）。澄清最近发现的信令串扰 mT 0 RC 2和Hippo信号级联组分之间的相互作用和3.）评价一种新的YAP-TEAD 在异种移植物中单独使用特异性小分子抑制剂和与mTORC 2特异性抑制剂组合使用， 基因工程小鼠（GEM）模型的疾病。我们还建议研究和化学 修饰所述雅普抑制剂以建立所需的抗胶质母细胞瘤作用。

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.