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）：神经胶质瘤是中枢神经系统中最常见的原发性恶性肿瘤，通常会迅速增殖的肿瘤对化学疗法干预具有抗性。他们复杂而异质的性质阻碍了成功疗法发展的进步。雷帕霉素（MTOR）激酶的哺乳动物靶标已成为治疗干预神经胶质瘤的有吸引力的靶标。存在两个包含MTOR的多育种复合物，分别在其含有猛禽和rictor的调节亚基组合物中有所不同。虽然许多癌症（包括成功的胶质瘤）已针对多活跃的MTORC1活性，但MTORC2功能失调的功能直到最近才开始研究。在此应用程序中，我们建议1）。剖析神经胶质瘤中Rictor过表达的机制，2）。阐明了最近确定的Rictor介导的胶质作用的遗传学修饰剂，可能将MTORC2和HIPPO肿瘤抑制器信号传导途径和3.）评估。我们还建议研究并化学修改抑制剂，以在其他激活中对MTORC2激酶和耐药性神经胶质瘤构建。