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.

项目摘要：辅助内分泌治疗对雌激素受体阳性(ER+)有效 乳腺癌，但耐药的周围癌细胞(DTP)在大约 1/3的患者。因此，靶向DTPs是一种有吸引力的治疗方法，但由于缺乏，它一直受到阻碍。 对DTP生物学的理解。我们的长期目标是发现DTP的漏洞，这些漏洞可能是 有的放矢。该项目的总体目标是确定和漏洞的后果 由ER+乳腺癌细胞的代谢重新编程产生，使人能够耐受雌激素剥夺。 我们的中心假设是，雌激素缺乏会导致能量代谢的重新编程，从而产生 ER+乳腺癌DTP的治疗脆弱性。该项目基本原理是确定 ER+乳腺癌DTP的脆弱性将使合理发展治疗策略成为可能 靶向DTP，防止癌症复发。核心假设将通过追求两个具体目标来检验： 1)确定雌激素缺乏对ER阳性乳腺癌能量代谢的影响；2)阻止雌激素缺乏对ER+乳腺癌能量代谢的影响。 挖掘雌激素缺乏期间ER+乳腺癌细胞持续存在所带来的代谢脆弱性。 第一个目标是利用ER+乳腺癌细胞来测量雌激素剥夺对生物能量的影响。 ICS和基本机制。在第二个目标中，我们将测量线粒体抑制的效果 氧化磷酸化对内分泌敏感型三磷酸腺苷产生的来源和数量以及细胞命运的影响 以及内分泌持久性ER+乳腺癌细胞株和肿瘤。这些研究的结果将提供一个 对代谢重新编程如何在生物能量依赖中造成脆弱性的基本理解- 并提供数据以指导临床测试代谢干扰物以诱导ER+的能量灾难 乳腺癌。获得这样的知识对于改进治疗的发展是必不可少的。 针对内分泌持久型乳腺癌细胞的策略。这项拟议的研究具有创新性，因为它 将测试抑制OXPHOS引发能量灾难的治疗潜力，并阐明 在内分泌治疗中存活的乳腺癌细胞发生生物能量转移的机制。支持- 提出的研究具有重要意义，因为它将表明对氧磷脂的依赖是DTP的一种治疗脆弱性 并为新陈代谢干扰物的临床测试提供理由。达特茅斯学院的环境和 达特茅斯癌症中心是拟议中的转译研究的理想选择，具有悠久的临床历史- 中国科学家合作和癌症研究支持。集结的赞助队干部-- BERS将在研究和临床指导方面提供支持，提供专业知识、材料和专门的预 开船时间到了。连同概述的培训计划，拟议的工作将支持申请者的职业生涯 计划成为一名独立、高效的内科医生兼科学家，专注于肿瘤学。