Dysregulation of mTORC2 in gliomas

胶质瘤中 mTORC2 的失调

• 批准号: 8341292
• 负责人: JOSEPH F GERA
• 金额: $ 22.97万
• 依托单位: BRENTWOOD BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-17 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8341292
• 关键词: Biochemical; Cell Line; Cell Proliferation; Cell Survival; Cells; Complex; Data; Development; Disease; Drug resistance; Enhancers; Evaluation; Event; Feedback; Genetic; Genetically Engineered Mouse; Glial Fibrillary Acidic Protein; Glioblastoma; Glioma; Gliomagenesis; Growth; Human; In Vitro; Intervention; Link; Malignant Neoplasms; Mediating; Modeling; Molecular Chaperones; Mus; NDRG1 gene; Nature; Neuraxis; Neuroglia; Oncogenic; Pathway interactions; Patients; Phosphotransferases; Polyadenylation Pathway; Pre-Clinical Model; Principal Investigator; Process; Proliferating; Property; Proteins; Proto-Oncogene Proteins c-akt; Raptors; Resistance; Role; Signal Pathway; Signal Transduction; Structure-Activity Relationship; Substrate Specificity; Testing; Therapeutic Intervention; Tumor Cell Line; Tumor Suppressor Proteins; Yeasts; base; cell growth; clinically relevant; in vivo; inhibitor/antagonist; mRNA Stability; mTOR protein; migration; mouse model; neoplastic cell; novel; outcome forecast; overexpression; pre-clinical; premature; programs; promoter; research clinical testing; research study; small molecule; success; tumor

DESCRIPTION (provided by applicant): Gliomas 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 has emerged as an attractive target for therapeutic intervention in gliomas. 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 glioma with limited success, dysregulated mTORC2 function has only recently begun to be investigated. In this application we propose to 1). dissect the mechanism(s) of Rictor overexpression in gliomas, 2). clarify a recently identified genetic modifier of Rictor-mediated gliomagenesis potentially linking the mTORC2 and Hippo tumor suppressor signaling pathways and 3.) evaluate a novel mTORC2 specific small molecule inhibitor in genetically engineered mouse (GEM) models of the disease. We also propose to investigate and chemically modify the inhibitor to build in additional activitie against both the mTORC2 kinase and drug resistant gliomas. PUBLIC HEALTH RELEVANCE: Successful completion of this project will substantiate a preclinical rationale for the continued development of mTORC2 specific inhibitors for trials in patients with glioma. Additionally, this study will provide information as to the operative mechanism(s) contributing to gliomagenesis as a result of aberrant mTORC2 activities.

描述（由申请人提供）：神经胶质瘤是中枢神经系统最常见的原发性恶性肿瘤，并且通常是对化疗干预具有抵抗力的快速增殖肿瘤。它们的复杂性和异质性阻碍了成功疗法的开发。哺乳动物雷帕霉素靶点 (mTOR) 激酶已成为神经胶质瘤治疗干预的一个有吸引力的靶点。存在两种含有 mTOR 的多亚基复合物，即 mTORC1 和 mTORC2，它们的不同之处在于分别含有 Raptor 和 Rictor 的调节亚基组成。虽然 mTORC1 活性过度活跃已成为许多癌症（包括神经胶质瘤）治疗的目标，但成效有限，但 mTORC2 功能失调的研究最近才开始。在此应用中，我们建议 1)。剖析 Rictor 在神经胶质瘤中过度表达的机制，2)。阐明最近发现的 Rictor 介导的神经胶质瘤发生的遗传修饰剂，可能与 mTORC2 和 Hippo 肿瘤抑制信号通路相关；3.) 在该疾病的基因工程小鼠 (GEM) 模型中评估一种新型 mTORC2 特异性小分子抑制剂。我们还建议对抑制剂进行研究和化学修饰，以增强针对 mTORC2 激酶和耐药神经胶质瘤的额外活性。 公共健康相关性：该项目的成功完成将证实继续开发 mTORC2 特异性抑制剂用于神经胶质瘤患者试验的临床前基本原理。此外，本研究将提供有关 mTORC2 活性异常导致神经胶质瘤发生的操作机制的信息。