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Uncovering Mechanisms of Regulation and Dependency on Fatty Acid Oxidation in MYC-Driven Tumors

揭示 MYC 驱动肿瘤中脂肪酸氧化的调节和依赖性机制

基本信息

批准号：
10436804
负责人：
ANDREI GOGA
金额：
$ 36.2万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2018-07-03 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10436804
关键词：
Acetyl Coenzyme A Acetyl-CoA Carboxylase Acyl Coenzyme A Adipocytes Adipose tissue Animal Model Automobile Driving Back Breast Breast Cancer Model Cancer Model Carnitine Carnitine Palmitoyltransferase I Catabolism Cell Death Cell membrane Cells Citric Acid Cycle Combined Modality Therapy Cytosol Dependence Development Distant Drug Targeting Energy-Generating Resources Enzymes Equilibrium Fatty Acids Growth Head Cancer Human Human Cell Line Lead Lipolysis Lymphoma MYC gene Maintenance Malignant Childhood Neoplasm Malignant Neoplasms Malignant neoplasm of liver Malonyl Coenzyme A Mediating Mediator of activation protein Metabolic Metabolic Pathway Metabolism Mitochondria Mitochondrial Matrix Molecular Neck Cancer Neoplasm Metastasis Outer Mitochondrial Membrane Pathway interactions Patient-derived xenograft models of breast cancer Process Production Regulation Research Site Testing Therapeutic Tissues Transgenic Animals Transgenic Model Transgenic Organisms acylcarnitine aggressive breast cancer base cancer type drug testing etomoxir fatty acid oxidation fatty acid transport fatty acid-binding proteins fatty acid-transport protein improved in vivo inhibitor innovation long chain fatty acid malignant breast neoplasm malignant state neoplastic cell new therapeutic target novel novel therapeutics overexpression oxidation patient derived xenograft model preclinical study programs receptor response small molecule small molecule inhibitor translocase treatment response triple-negative invasive breast carcinoma tumor tumor growth tumor metabolism tumor microenvironment

项目摘要

Project Summary The MYC oncogene is overexpressed in some of the most aggressive and difficult to treat human cancers, including receptor triple-negative breast cancers (TNBCs), as well as high-grade lymphomas and aggressive subtypes of liver cancers. MYC overexpression induces a highly malignant state by driving proliferation and altering various metabolic programs within tumor cells. We recently discovered that MYC-driven transgenic models of breast cancer have reprogramed cellular metabolism that favor fatty acid oxidation (FAO) as an energy source. This finding was also observed in MYC-high TNBCs and has recently been confirmed by an independent research group. Targeting FAO in human cell lines, MYC-driven transgenic animal models and patient-derived xenograft (PDX) models of breast cancer results in diminished tumor growth and increased cell death. What remains unknown is what are the molecular mechanisms through which MYC reprograms tumor metabolism to favor FAO. Furthermore, we seek to understand why MYC-high tumors are dependent on the FAO pathway for their growth and survival. Finally, we seek to improve upon current therapies for TNBCs by performing advance preclinical studies in PDX models to determine if blocking FAO alone or in combination with other metabolic pathways in vivo will provide improved therapeutic response. Our studies will improve our understanding of how MYC reprograms metabolism in vivo and will lead to novel therapeutics for difficult to treat MYC overexpressing cancers.

项目总结

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Deep whole genome sequencing identifies recurrent genomic alterations in commonly used breast cancer cell lines and patient-derived xenograft models.

DOI：
10.1186/s13058-022-01540-0
发表时间：
2022-09-24
期刊：
Breast cancer research : BCR
影响因子：
0
作者：
通讯作者：

In Vivo Optical Metabolic Imaging of Long-Chain Fatty Acid Uptake in Orthotopic Models of Triple-Negative Breast Cancer.

DOI：
10.3390/cancers13010148
发表时间：
2021-01-05
期刊：
Cancers
影响因子：
5.2
作者：
Madonna MC;Duer JE;Lee JV;Williams J;Avsaroglu B;Zhu C;Deutsch R;Wang R;Crouch BT;Hirschey MD;Goga A;Ramanujam N
通讯作者：
Ramanujam N