Therapeutically leveraging metabolic vulnerabilities in breast cancer

利用乳腺癌代谢脆弱性进行治疗

• 批准号: 10908068
• 负责人: Todd W Miller
• 金额: $ 51.62万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-04 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10908068
• 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

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.

项目概要：抗癌药物治疗往往不能完全消灭体内所有癌细胞， 留下“耐药持久性”癌细胞（DTP），这些细胞最终会产生耐药性 该研究的长期目标是确定可治疗的靶点。 DTP 中的漏洞可推动人类恶性肿瘤治疗策略的发展。 对于受体 α 阳性 (ER+) 乳腺癌，DTP 可以持续数年，尽管内分泌治疗 直接或通过雌激素剥夺抑制 ER 活性，导致肿瘤在 20 年以上的时间内复发。 该项目的总体目标是确定 ER+ 乳腺癌细胞如何利用代谢重编程来 耐受并最终克服内分泌治疗的中心假设是 ER+ 乳腺癌细胞。 通过增加脂肪酸代谢的可逆代谢开关在内分泌治疗中存活下来， 线粒体呼吸和保护性氧化应激反应该项目的基本原理是： ER+乳腺癌中 DTP 代谢脆弱性的定义将有助于合理开发 抑制或根除 DTP 并预防癌症复发的治疗策略。 将通过追求三个具体目标进行测试：（1）确定脂肪酸代谢和呼吸的脆弱性 在 ER+ 乳腺癌内分泌治疗中存活的 DTP 中；(2) 定义氧化应激反应的作用； ER+乳腺癌中DTP的持久性；（3）确定代谢的可塑性程度； ER+乳腺癌从内分泌耐受到耐药的疾病进展过程中的重编程。 第一个目标是在 ER+ 中测量内分泌治疗引起的呼吸和脂肪酸代谢变化 乳腺癌细胞作为原位细胞系和患者来源的异种移植物在体外和体内生长，产生 这些研究将使用关键代谢信号节点的自发转移。 确定脂肪酸代谢和呼吸对 DTP 存活的贡献。 氧化应激的发生时间和贡献以及氧化应激对乳腺癌细胞的反应 在第三个目标中，我们将分析代谢适应在内分泌治疗过程中的作用。 人类肿瘤组织和临床前对雌激素剥夺的抵抗力的获得和维持 本申请中提出的研究具有创新性，因为它侧重于 (a) 识别。 DTP 中的漏洞可用于治疗，以及 (b) 确定 DTP 中的适应如何能够实现 耐药性，这将推动药物的合理开发，以预防和控制复发。 拟议的研究意义重大，因为它将为开发和利用提供强有力的科学依据。 利用 ER+ 乳腺癌代谢脆弱性的治疗策略的未来临床试验和产量 对癌细胞代谢可塑性的机制洞察。