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：调整内分泌疗法可有效治疗雌激素受体阳性（ER+） 乳腺癌，但耐药持久抗癌细胞（DTP）大约导致癌症复发 1/3的患者。那是针对DTP是一种有吸引力的治疗方法，但由于缺乏而受到阻碍 了解DTP生物学。我们的长期目标是发现DTP的脆弱性可能是 靶向。该项目的总体目的是确定脆弱性的后果和漏洞 由ER+乳腺癌细胞中的代谢重编程产生，可耐受雌激素剥夺。 我们的中心假设是，雌激素剥夺引起了产生能量代谢的重编程 ER+乳腺癌DTPS中的治疗脆弱性。该项目的理由是确定 DTP在ER+乳腺癌中的脆弱性将使治疗策略的合理发展得以发展 靶向DTP并防止癌症复发。中心假设将通过实现两个具体目标来检验： 1）确定雌激素剥夺对ER+乳腺癌能量代谢的影响； 2）阻止 - 在雌激素剥夺期间，ER+乳腺癌细胞持久性赋予的代谢脆弱性。 第一个目的将利用ER+乳腺癌细胞来衡量雌激素剥夺对生物效应的影响。 ICS和基本机制。在第二个目标中，我们将测量抑制线粒体的影响 ATP产生和量的氧化磷酸化以及内分泌敏感的细胞命运的氧化磷酸化 和内分泌抗ER+乳腺癌细胞系和肿瘤。这些研究的结果将提供 对代谢重编程如何在生物能依赖性中产生脆弱性的基本了解 - 并提供数据来指导代谢破坏者的临床测试，以诱导ER+诱导能量灾难 乳腺癌。获得这种知识对于改善治疗的发展至关重要 靶向内分泌症状的乳腺癌细胞的策略。拟议的研究具有创新性，因为它 将测试抑制Oxphos以引起能量灾难并阐明的治疗潜力 在内分泌疗法中存活的乳腺癌细胞中生物能转移的基础机制。专业人士 提出的研究很重要，因为这将使Oxphos依赖为DTPS的治疗脆弱性 并为代谢破坏者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的翻译研究的理想选择 CIAN科学家合作和癌症研究支持。集会的赞助团队成员的干部 - BERS将在研究和临床心理方面提供支持 ceptorship时间。加上概述的培训计划，拟议的工作将支持申请人的职业 计划成为一个专注于肿瘤学的独立，高产的身体科学家。