Therapeutically leveraging metabolic vulnerabilities in breast cancer

项目概述：抗癌药物治疗往往不能完全根除体内所有癌细胞， 留下的“耐药持续”癌细胞（DTP）最终会产生耐药性， 导致肿瘤复发。这项研究的长期目标是确定治疗靶向 DTP的脆弱性，以推动人类恶性肿瘤治疗策略的发展。雌激素 受体α阳性（ER+）乳腺癌，DTP可以持续多年，尽管内分泌治疗， 直接或通过雌激素剥夺抑制ER活性，导致肿瘤复发超过20年。的 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， 耐受并最终克服内分泌治疗。核心假设是ER+乳腺癌细胞 通过增加脂肪酸代谢的可逆代谢转换， 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使合理开发 抑制或根除DTP和预防癌症复发的治疗策略。核心假设 将通过追求三个具体目标进行测试：（1）识别脂肪酸代谢和呼吸的脆弱性 ER+乳腺癌中内分泌治疗存活的DTP;（2）定义氧化应激反应的作用 在ER+乳腺癌中DTP的持续性;（3）确定代谢的可塑性程度， 在疾病从内分泌耐受进展到耐药期间，ER+乳腺癌中的重编程。在 第一个目标是，将在ER+中测量内分泌治疗诱导的呼吸和脂肪酸代谢变化。 乳腺癌细胞在体外和体内作为原位细胞系和患者来源的异种移植物生长， 自发转移使用关键代谢信号节点的药理学抑制剂，这些研究将 确定脂肪酸代谢和呼吸对DTP存活的贡献。第二个目标是确定 乳腺癌细胞氧化应激反应的时间和作用 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 在人肿瘤组织中获得和维持对雌激素剥夺的抗性以及临床前 模型本申请中提出的研究是创新的，因为它侧重于（a）识别 DTP中的脆弱性将被利用治疗，以及（B）确定DTP中的适应如何使 耐药性，这将推动药物的合理开发，以预防和管理复发。的 拟议的研究是重要的，因为它将提供强有力的科学理由的发展， 利用ER+乳腺癌代谢脆弱性的治疗策略的未来临床试验， 对癌细胞代谢可塑性的机理性洞察。

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.