Co-targeting mTOR and YAP signaling in glioblastoma

胶质母细胞瘤中 mTOR 和 YAP 信号的共同靶向

基本信息

批准号：
10382229
负责人：
JOSEPH F GERA
金额：
$ 32.01万
依托单位：
GREATER LOS ANGELES VETERANS RESEARCH AND EDUCATION FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10382229
关键词：
AMOT gene Affect Apoptosis Biochemical Brain Neoplasms Catalogs Cell Count Cell Line Cell Proliferation Cell Survival Cells Chemicals Complex Data Development Disease model FRAP1 gene Gene Amplification Genetically Engineered Mouse Glial Fibrillary Acidic Protein Glioblastoma Glioma Gliomagenesis Glomerular basement membrane antibody Growth Growth Factor Human Hydrophobicity Hyperactivity Intervention Knock-in Mouse Lead Malignant Neoplasms Malignant neoplasm of brain Mus Mutation NDRG1 gene Nature Neuraxis Nutrient Oncoproteins Organ Size PRKCA gene Pathway interactions Patients Phosphotransferases Pre-Clinical Model Preclinical Testing Proliferating Property Raptors Regulation Resistance Role Signal Pathway Signal Transduction Signal Transduction Pathway Structure-Activity Relationship Substrate Specificity Testing Therapeutic Intervention Transactivation Transcription Coactivator Tumor Suppressor Proteins Ubiquitination Xenograft Model Xenograft procedure Yeasts base cell growth cell motility clinically relevant drug sensitivity experimental study inhibitor inhibitor therapy migration mutant neoplastic cell novel overexpression patient prognosis patient stratification pre-clinical protein degradation research clinical testing small molecule inhibitor success targeted treatment tumor

项目摘要

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.

项目概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，通常是快速增殖的肿瘤对化疗干预有抵抗力。它们的复杂性和异质性大自然阻碍了成功疗法的开发。哺乳动物的目标雷帕霉素 (mTOR) 激酶和 YAP 癌蛋白最近已成为有吸引力的靶标胶质母细胞瘤的治疗干预。存在两个含有 mTOR 的多亚基复合物：mTORC1 和 mTORC2，它们的不同之处在于分别含有 Raptor 和 Rictor 的调节亚基组合物。 mTORC1 过度活跃时活性已针对许多癌症，包括胶质母细胞瘤，但成功有限，失调 mTORC2 功能最近才开始研究。 Hippo 级联的下游效应子 YAP 被发现在脑癌中过度表达最近，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。在此应用中，我们建议 1)。识别和表征胶质母细胞瘤相关的激活突变在 YAP 中，这使得该癌蛋白具有组成型活性，2)。澄清最近发现的信号串扰 mTORC2 和 Hippo 信号级联组件之间的相互作用，以及 3.) 评估新型 YAP-TEAD 单独使用特异性小分子抑制剂以及与异种移植物中的 mTORC2 特异性抑制剂联合使用该疾病的基因工程小鼠（GEM）模型。我们还建议进行调查和化学研究修改 YAP 抑制剂以产生所需的抗胶质母细胞瘤效果。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Function of Deptor and its roles in hematological malignancies.

Deptor 的功能及其在血液恶性肿瘤中的作用。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Morales;Lichtenstein, Alan;Vega, Mario I
通讯作者：
Vega, Mario I

Translation of circHGF RNA encodes an HGF protein variant promoting glioblastoma growth through stimulation of c-MET.

circHGF RNA 的翻译编码 HGF 蛋白变体，通过刺激 c-MET 促进胶质母细胞瘤生长。

DOI：
发表时间：
2023-05
期刊：
影响因子：
3.9
作者：
Saunders, Jacquelyn T;Kumar, Sunil;Benavides;Holmes, Brent;Benavides, Kennedy E;Bashir, Muhammad T;Nishimura, Robert N;Gera, Joseph
通讯作者：
Gera, Joseph

mTORC2-mediated direct phosphorylation regulates YAP activity promoting glioblastoma growth and invasive characteristics.

mTORC2 介导的直接磷酸化调节 YAP 活性，促进胶质母细胞瘤生长和侵袭特征。

DOI：
发表时间：
2021-09
期刊：
影响因子：
0
作者：
Holmes, Brent;Benavides;Saunders, Jacquelyn T;Kumar, Sunil;Nishimura, Robert N;Gera, Joseph
通讯作者：
Gera, Joseph

The protein arginine methyltransferase PRMT5 confers therapeutic resistance to mTOR inhibition in glioblastoma.

蛋白质精氨酸甲基转移酶 PRMT5 赋予胶质母细胞瘤对 mTOR 抑制的治疗抗性。

DOI：
发表时间：
2019-10
期刊：
影响因子：
3.9
作者：
Holmes, Brent;Benavides;Saunders, Jacquelyn T;Landon, Kenna A;Schreck, Adam J;Nishimura, Robert N;Gera, Joseph
通讯作者：
Gera, Joseph

Targeting the YAP-TEAD interaction interface for therapeutic intervention in glioblastoma.

针对胶质母细胞瘤治疗干预的 YAP-TEAD 相互作用界面。