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：
10194413
负责人：
ANDREI GOGA
金额：
$ 36.94万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10194413
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/antagonist 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.

项目概要 MYC 癌基因在一些最具侵袭性和最难治疗的人类癌症中过度表达，包括受体三阴性乳腺癌 (TNBC)，以及高级别淋巴瘤和侵袭性淋巴瘤肝癌的亚型。 MYC 过度表达通过驱动增殖和诱导高度恶性状态改变肿瘤细胞内的各种代谢程序。我们最近发现 MYC 驱动的转基因乳腺癌模型已经重新编程了细胞代谢，有利于脂肪酸氧化（FAO）作为一种能源。这一发现也在 MYC 高 TNBC 中观察到，并且最近得到了一项研究的证实独立研究小组。在人类细胞系、MYC 驱动的转基因动物模型和乳腺癌患者来源的异种移植（PDX）模型导致肿瘤生长减少和细胞增加死亡。目前尚不清楚的是 MYC 重编程肿瘤的分子机制是什么新陈代谢有利于粮农组织。此外，我们试图了解为什么 MYC 高肿瘤依赖于粮农组织为其成长和生存提供途径。最后，我们寻求通过以下方式改进当前的 TNBC 疗法：在 PDX 模型中进行预先临床前研究，以确定是否单独或联合阻断FAO 与体内其他代谢途径的结合将提供改善的治疗反应。我们的学习将提高我们的了解 MYC 如何重新编程体内代谢，并将为难以治疗的疾病带来新的治疗方法治疗 MYC 过度表达的癌症。