Therapeutically leveraging metabolic vulnerabilities in breast cancer

利用乳腺癌代谢脆弱性进行治疗

• 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
• 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

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.

项目摘要：抗癌药物治疗通常不会完全放射体内所有癌细胞， 留下“耐药持久性”癌细胞（DTP），最终可以发展出耐药性 引起肿瘤复发。这种调查的长期目标是确定历史上的目标 DTP中的脆弱性推动人类恶性肿瘤的治疗策略。在雌激素中 受体α阳性（ER+）乳腺癌，DTP可以持续多年的目的地内分泌疗法 直接或通过雌激素剥夺抑制ER活性，导致肿瘤在20年内的回报。这 该项目的总体目的是确定ER+乳腺癌细胞如何利用代谢重编程 耐受并最终克服内分泌疗法。中心假设是ER+乳腺癌细胞 通过可逆的代谢开关来生存内分泌疗法，从而增加脂肪酸代谢， 线粒体呼吸和受保护的氧化应激反应。这个项目的理由是 DTP在ER+乳腺癌中的代谢脆弱性的定义将使合理发展 抑制或放射性DTP并防止癌症复发的治疗策略。中心假设 将通过追求三个具体目标来测试：（1）确定脂肪酸代谢和呼吸的漏洞 在ER+乳腺癌中幸存的内分泌疗法的DTP中； （2）定义氧化应激反应的作用 在ER+乳腺癌中DTP的持久性； （3）确定代谢的可塑性程度 从内分泌耐受到抗性的疾病进展过程中，在ER+乳腺癌中重新编程。在 首先，将在ER+中测量内分泌治疗引起的呼吸和脂肪酸代谢的变化 乳腺癌细胞在体外和体内作为原位细胞系和患者衍生的Xenographtics产生 自发转移。使用关键代谢信号节点的药物抑制剂，这些研究将 确定脂肪酸代谢和呼吸对DTP存活的贡献。第二个目标将确定 氧化应激的时间和贡献以及对乳腺癌细胞的氧化应激反应 内分泌治疗期间的持久性。在第三个目标中，我们将分析代谢适应在 获得和维持人类肿瘤组织中雌激素剥夺的抵抗力和临床前的耐药性 型号。本应用程序中提出的研究具有创新性，因为它专注于（a）识别 DTP中的漏洞将被热探索，（b）确定DTP中的适应如何启用 耐药性，这将推动药物的合理发展以预防和管理复发。 拟议的研究很重要，因为它将为发展和 在ER+乳腺癌中利用代谢脆弱性并产生的治疗策略的未来临床试验 对癌细胞代谢可塑性的机械洞察力。