Targeting Metabolic Reprogramming in ER+ Breast Cancer

针对 ER 乳腺癌的代谢重编程

• 批准号: 10751676
• 负责人: Steven Tau
• 金额: $ 4.77万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751676
• 关键词: Adjuvant Therapy; Aromatase Inhibitors; Award; Bioenergetics; Blood; Bone Marrow; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; Cancer Biology; Cancer Center; Cancer Research Project; Cancer Survivorship; Cell Line; Cell Survival; Cells; Cellular biology; Clinical; Collaborations; Complex; Data; Dedications; Dependence; Development; Disease; Disease Outcome; Down-Regulation; Drug Targeting; Drug Tolerance; Endocrine; Energy Metabolism; Environment; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen Therapy; Estrogen receptor positive; Estrogens; Gene Silencing; Glycolysis; Goals; Knock-out; Knowledge; Laboratories; Left; MYC gene; Measures; Mediating; Mentorship; Metabolic; Metabolism; Mission; Mitochondria; Morbidity - disease rate; Neoplasm Circulating Cells; Oncology; Outcome; Oxidative Phosphorylation; Patients; Persons; Physicians; Positioning Attribute; Production; Productivity; Public Health; Recording of previous events; Recurrence; Recurrent Malignant Neoplasm; Recurrent disease; Recurrent tumor; Refractory; Reporting; Research; Research Personnel; Research Support; Role; Scientist; Source; Testing; Therapeutic; Time; Training; Translational Research; Withdrawal; Work; adjuvant endocrine therapy; anticancer research; cancer cell; cancer prevention; cancer recurrence; career; college; deprivation; genome-wide; hormone therapy; improved; inhibitor therapy; innovation; malignant breast neoplasm; member; mitochondrial dysfunction; mortality; mouse model; neoplastic cell; pharmacologic; prevent; prognostic; research clinical testing; therapeutic development; therapeutic evaluation; therapeutic target; therapy development; translational cancer research; tumor; tumor progression

Project Summary: Adjuvant endocrine therapies are effective in treating estrogen receptor-positive (ER+) breast cancer, but drug-tolerant persister cancer cells (DTPs) contribute to cancer recurrence in approximately 1/3 of patients. Thus, targeting DTPs is an attractive therapeutic approach, but it has been hampered by a lack of understanding of DTP biology. Our long-term goal is to discover vulnerabilities of DTPs that can be thera- peutically targeted. The overall objective of this project is to determine the consequences of, and vulnerabilities created by, metabolic reprogramming in ER+ breast cancer cells that enable tolerance of estrogen deprivation. Our central hypothesis is that estrogen deprivation induces reprogramming of energy metabolism that creates therapeutic vulnerabilities in ER+ breast cancer DTPs. The rationale for this project is that identification of the vulnerabilities of DTPs in ER+ breast cancer will enable the rational development of therapeutic strategies to target DTPs and prevent cancer recurrence. The central hypothesis will be tested by pursing two specific aims: 1) Determine the effects of estrogen deprivation on energy metabolism in ER+ breast cancer; and 2) Deter- mine the metabolic vulnerabilities conferred by ER+ breast cancer cell persistence during estrogen deprivation. The first aim will utilize ER+ breast cancer cells to measure the effects of estrogen deprivation on bioenerget- ics and underlying mechanisms. In the second aim, we will measure the effects of inhibition of mitochondrial oxidative phosphorylation on the source and amount of ATP production, and on cell fate in endocrine-sensitive and endocrine-persistent ER+ breast cancer cell lines and tumors. Results from these studies will provide a fundamental understanding of how metabolic reprogramming creates vulnerabilities in bioenergetic depend- ence, and provide data to guide clinical testing of metabolic disruptors to induce energetic catastrophe in ER+ breast cancer. The acquisition of such knowledge is essential to the development of improved therapeutic strategies to target endocrine-persistent breast cancer cells. The proposed research is innovative because it will test the therapeutic potential of suppressing OXPHOS to elicit energetic catastrophe as well as elucidate the mechanism underlying bioenergetic shifts in breast cancer cells that survive endocrine therapy. The pro- posed research is significant because it will implicate OXPHOS reliance as a therapeutic vulnerability in DTPs and provide justification for clinical testing of metabolic disruptors. The environment at Dartmouth College and Dartmouth Cancer Center is ideal for the proposed translational research with a long-standing history of clini- cian-scientist collaborations and cancer research support. The cadre of assembled Sponsoring Team mem- bers will provide support in both research and clinical mentorship with expertise, materials, and dedicated pre- ceptorship time. Together with the outlined training plan, the proposed work will support the Applicant’s career plan to become an independent, highly productive physician-scientist focused on oncology.

项目概述：辅助内分泌疗法可有效治疗雌激素受体阳性（ER+） 乳腺癌，但耐药持续癌细胞（DTP）有助于癌症复发， 1/3的患者。因此，靶向DTP是一种有吸引力的治疗方法，但由于缺乏有效的治疗方法， 对DTP生物学的理解。我们的长期目标是发现DTP的漏洞， 目标明确。该项目的总体目标是确定其后果和脆弱性 由ER+乳腺癌细胞中的代谢重编程产生，使其能够耐受雌激素剥夺。 我们的中心假设是，雌激素剥夺诱导能量代谢的重新编程， ER+乳腺癌DTP的治疗漏洞。该项目的基本原理是， DTP在ER+乳腺癌中的脆弱性将使治疗策略的合理发展成为可能， 靶向DTP和预防癌症复发。中心假设将通过追求两个具体目标来检验： 1)确定雌激素剥夺对ER+乳腺癌中能量代谢的影响;和2）阻止- 在雌激素缺乏期间，挖掘ER+乳腺癌细胞持久性所赋予的代谢脆弱性。 第一个目标将利用ER+乳腺癌细胞来测量雌激素剥夺对生物能量的影响。 ICS和潜在机制。在第二个目标中，我们将测量抑制线粒体的影响， 氧化磷酸化对ATP产生的来源和数量，以及对内分泌敏感细胞的细胞命运的影响。 和内分泌持续性ER+乳腺癌细胞系和肿瘤。这些研究的结果将提供 对代谢重编程如何造成生物能量脆弱性的基本理解取决于- 并提供数据来指导代谢干扰物的临床试验，以诱导ER+中的能量灾难。 乳腺癌这些知识的获得对于开发改进的治疗药物是必不可少的。 针对内分泌持续性乳腺癌细胞的策略。这项研究是创新的，因为它 将测试抑制OXPHOS的治疗潜力，以引发能量灾难，并阐明 乳腺癌细胞在内分泌治疗中存活的生物能量转换的潜在机制。亲- 提出的研究是重要的，因为它将涉及OXPHOS依赖作为DTP的治疗漏洞 并为代谢干扰物的临床试验提供依据。达特茅斯学院的环境和 达特茅斯癌症中心是理想的建议转化研究与长期的临床历史， 科学家合作和癌症研究支持。主办单位的干部们聚集在一起， bers将在研究和临床指导方面提供专业知识，材料和专门的预 时间到了。连同概述的培训计划，建议的工作将支持申请人的职业生涯 计划成为一个独立的，高生产力的医生，科学家专注于肿瘤学。