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Therapeutically leveraging metabolic vulnerabilities in breast cancer

利用乳腺癌代谢脆弱性进行治疗

基本信息

批准号：
10659058
负责人：
Todd W Miller
金额：
$ 3.43万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-04 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10659058
关键词：
Antineoplastic Agents Aromatase Inhibitors Blood Bone Marrow Breast Cancer Cell Breast Cancer Patient Catabolism Cell Line Cell Survival Clinical Clinical Trials Data Dependence Development Disease Disease Progression Drug Tolerance Drug resistance ERBB2 gene Endocrine Estrogen Receptor alpha Estrogens Excision Exhibits Fatty Acids Future Goals Human In Vitro Investigation Maintenance Malignant Neoplasms Measures Metabolic Metabolism Mission Mitochondria Morbidity - disease rate Neoplasm Metastasis Operative Surgical Procedures Outcome Oxidative Phosphorylation Oxidative Stress Patients Pharmacotherapy Phase Pre-Clinical Model Production Prognosis Public Health Recurrence Recurrent Malignant Neoplasm Recurrent disease Recurrent tumor Research Resistance Respiration Role Signal Transduction Testing Therapeutic Therapeutically Targetable Time Tissue Model Tumor Tissue Woman adjuvant endocrine therapy anticancer treatment biological adaptation to stress cancer cell cancer recurrence cancer therapy cancer type deprivation drug development drug resistance development experience fatty acid metabolism hormone therapy improved in vivo inhibitor innovation insight lipid metabolism malignant breast neoplasm mortality oxidation patient derived xenograft model pharmacologic preservation prevent therapeutic development therapy development treatment strategy tumor

项目摘要

Project Summary: Anti-cancer drug treatments often do not completely eradicate all cancer cells in the body, leaving behind “drug-tolerant persister” cancer cells (DTPs) that can ultimately develop drug resistance to cause tumor recurrence. The long-term goal of this line of investigation is to identify therapeutically targetable vulnerabilities in DTPs to drive the development of treatment strategies for human malignancies. In estrogen receptor alpha-positive (ER+) breast cancer, DTPs can persist for years despite endocrine therapies that inhibit ER activity directly or via estrogen deprivation, causing tumor recurrences over a >20-year period. The overall objective of this project is to determine how ER+ breast cancer cells utilize metabolic reprogramming to tolerate and eventually overcome endocrine therapy. The central hypothesis is that ER+ breast cancer cells survive endocrine therapy through a reversible metabolic switch that increases fatty acid metabolism, mitochondrial respiration, and a protective oxidative stress response. The rationale for this project is that definition of the metabolic vulnerabilities of DTPs in ER+ breast cancer will enable the rational development of therapeutic strategies to suppress or eradicate DTPs and prevent cancer recurrence. The central hypothesis will be tested by pursuing three specific aims: (1) Identify vulnerabilities in fatty acid metabolism and respiration in DTPs surviving endocrine therapy in ER+ breast cancer; (2) Define the role of the oxidative stress response in the persistence of DTPs in ER+ breast cancer; (3) Determine the degree of plasticity of metabolic reprogramming in ER+ breast cancer during disease progression from endocrine tolerance to resistance. In the first aim, endocrine therapy-induced changes in respiration and fatty acid metabolism will be measured in ER+ breast cancer cells grown in vitro and in vivo as orthotopic cell line- and patient-derived xenografts that yield spontaneous metastases. Using pharmacological inhibitors of key metabolic signaling nodes, these studies will determine contributions of fatty acid metabolism and respiration to DTP survival. The second aim will identify the timing and contributions of oxidative stress and the oxidative stress response to breast cancer cell persistence during endocrine therapy. In the third aim, we will analyze the role of metabolic adaptation in the acquisition and maintenance of resistance to estrogen deprivation in human tumor tissues and preclinical models. The research proposed in this application is innovative because it focuses on (a) identifying vulnerabilities in DTPs to be exploited therapeutically, and (b) determining how adaptations in DTPs enable drug resistance, which will drive the rational development of drugs to prevent and manage recurrence. The proposed research is significant because it will provide strong scientific rationale for the development and future clinical trials of treatment strategies leveraging metabolic vulnerabilities in ER+ breast cancer, and yield mechanistic insight into the metabolic plasticity of cancer cells.

项目总结：抗癌药物治疗往往不能完全根除体内所有癌细胞，