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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.

项目总结

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.

DOI：
10.18632/aging.202462
发表时间：
2021-01-07
期刊：
Aging
影响因子：
0
作者：
Morales-Martinez M;Lichtenstein A;Vega MI
通讯作者：
Vega MI

Turnover of the mTOR inhibitor, DEPTOR, and downstream AKT phosphorylation in multiple myeloma cells, is dependent on ERK1-mediated phosphorylation.

DOI：
10.1016/j.jbc.2022.101750
发表时间：
2022-04
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Vega M;Chen Y;Shi Y;Gera J;Lichtenstein A
通讯作者：
Lichtenstein A

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

DOI：
10.1007/s11060-021-03699-6
发表时间：
2021-04
期刊：
Journal of neuro-oncology
影响因子：
3.9
作者：
Saunders JT;Holmes B;Benavides-Serrato A;Kumar S;Nishimura RN;Gera J
通讯作者：
Gera J

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

DOI：
10.1007/s11060-023-04331-5
发表时间：
2023-05
期刊：
JOURNAL OF NEURO-ONCOLOGY
影响因子：
3.9
作者：
Saunders, Jacquelyn T. T.;Kumar, Sunil;Benavides-Serrato, Angelica;Holmes, Brent;Benavides, Kennedy E. E.;Bashir, Muhammad T. T.;Nishimura, Robert N. N.;Gera, Joseph
通讯作者：
Gera, Joseph

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