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Dysregulation of mTORC2 in gliomas

胶质瘤中 mTORC2 的失调

基本信息

批准号：
8512676
负责人：
JOSEPH F GERA
金额：
$ 21.59万
依托单位：
BRENTWOOD BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
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/8512676
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

项目摘要

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.

描述（由申请人提供）：胶质瘤是中枢神经系统最常见的原发性恶性肿瘤，通常是对化疗干预具有抗性的快速增殖肿瘤。它们的复杂性和异质性阻碍了成功疗法的发展。哺乳动物雷帕霉素靶蛋白（mTOR）激酶已成为神经胶质瘤治疗干预的有吸引力的靶点。存在两种含有mTOR的多亚基复合物，mTORC 1和mTORC 2，它们分别在含有Raptor和Rictor的调节亚基组成上不同。虽然过度活跃的mTORC 1活性已在许多癌症中被靶向，包括成功有限的胶质瘤，但失调的mTORC 2功能最近才开始研究。在本申请中，我们提出1）。剖析神经胶质瘤中Rictor过度表达的机制，2）。澄清最近鉴定的Rictor介导的胶质瘤发生的遗传修饰剂，其可能连接mTORC 2和Hippo肿瘤抑制信号传导途径;和3.）在该疾病的遗传工程小鼠（GEM）模型中评估新型mTORC 2特异性小分子抑制剂。我们还建议研究和化学修饰抑制剂，以建立对mTORC 2激酶和耐药胶质瘤的额外活性。