A precision medicine basis for estrogen therapy for advanced breast cancer

晚期乳腺癌雌激素治疗的精准医学基础

• 批准号: 10930779
• 负责人: Todd W Miller
• 金额: $ 14.27万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-10-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10930779
• 关键词: precision; medicine; basis; estrogen; therapy

Project Summary: It remains unknown why some estrogen receptor alpha (ER)-positive breast cancers are sensitive to estrogen therapy while others are resistant, and strategies for effectively utilizing estrogen therapy are not well-established. The long-term goal of this line of investigation is to maximize the clinical potential of endocrine therapies for the management of ER+ breast cancer. The overall objective of this project is to define the mechanism that controls cell fate in ER+ breast cancer in response to the estrogen 17b-estradiol. The central hypothesis is that basal estrogen-independent ER transcriptional activity caused by ER amplification, overexpression, or mutation sensitizes breast cancer cells to the cytotoxic effects of 17b-estradiol/ER-induced DNA damage. The rationale for this project is that definition of (i) the mechanism underlying therapeutic response to 17b-estradiol and (ii) tumor features that dictate response to 17b-estradiol will provide a precision medicine basis for its use and offer strategies to enhance response. The central hypothesis will be tested by pursuing three specific aims: (1) Determine how 17b-estradiol/ER-induced DNA damage and response control cell fate; (2) Determine how inhibition of the DNA damage response affects sensitivity to 17b-estradiol; (3) Define the role of ER (ESR1) mutations in dictating breast cancer response to 17b-estradiol. In the first aim, the kinetics and spatiotemporal relationship of 17b-estradiol/ER-induced transcriptional activity, DNA damage, and response will be measured in genetically engineered and estrogen-independent ER+ breast cancer cells. These studies will provide a mechanistic basis for the cytotoxic effects of 17b-estradiol. The second aim will use cell lines and patient-derived xenografts for measurement of the effects of 17b-estradiol in the context of pharmacological inhibition of poly(ADP-ribose) polymerases 1/2 (PARP) as well as homologous recombination deficiency. These studies will offer treatment strategies to enhance response to 17b-estradiol. In the third aim, engineered cells and ESR1-mutant patient-derived xenografts will be used for measurement of 17b-estradiol- induced changes in cell fate, tumor growth, and ER transcriptional activity. These studies will provide understanding of how ESR1 mutations shape cancer cell response to 17b-estradiol and provide a mechanistic basis to inform its clinical use. The proposed research is innovative because it implicates ER-induced DNA damage in the mechanism of cytotoxicity induced by 17b-estradiol therapy, enabling the development of strategies that target the DNA damage response for advanced ER+ breast cancer. Based on our clinical trial findings, this project will test the innovative concept that ER mutations sensitize ER+ breast cancer cells to 17b-estradiol. The proposed research is significant because it will reveal the root cause of 17b-estradiol- induced cytotoxicity in ER+ breast cancer, as well as explain how cell adaptations convert 17b-estradiol from a growth promoter to a growth suppressor. This research will also provide strong scientific rationale for clinical testing of 17b-estradiol therapy in genetically identifiable patient subpopulations.

项目摘要：目前还不清楚为什么一些雌激素受体α（ER）阳性的乳腺癌， 对雌激素治疗敏感，而另一些则耐药，以及有效利用雌激素治疗的策略 并不完善。该研究的长期目标是最大限度地发挥 内分泌疗法用于ER+乳腺癌的管理。本项目的总体目标是确定 雌激素17 b-雌二醇对ER+乳腺癌细胞命运的控制机制。的 中心假设是基础雌激素非依赖性ER转录活性由ER扩增引起， 过表达或突变使乳腺癌细胞对17 b-雌二醇/ER诱导的细胞毒性作用敏感 DNA损伤。该项目的基本原理是定义（i）治疗的潜在机制 对17 b-雌二醇的反应和（ii）决定对17 b-雌二醇反应的肿瘤特征将提供精确的 药物使用的基础，并提供战略，以加强反应。中心假设将通过以下方式进行检验： 本研究的目的有三：（1）确定17 b-雌二醇/ER如何诱导DNA损伤和反应控制 细胞命运;（2）确定DNA损伤反应的抑制如何影响对17 b-雌二醇的敏感性;（3） 确定ER（ESR 1）突变在决定乳腺癌对17 b-雌二醇反应中的作用。在第一个目标中， 17 b-雌二醇/ER诱导的转录活性，DNA损伤， 并将在基因工程和雌激素非依赖性ER+乳腺癌细胞中测量反应。 这些研究将为17 b-雌二醇的细胞毒性作用提供机制基础。第二个目标将 使用细胞系和患者来源的异种移植物来测量17 β-雌二醇在 聚（ADP-核糖）聚合酶1/2（PARP）以及同源重组的药理学抑制 缺陷这些研究将提供治疗策略，以增强对17 b-雌二醇的反应。第三个目标， 工程化细胞和ESR 1突变患者来源的异种移植物将用于测量17 b-雌二醇， 诱导细胞命运、肿瘤生长和ER转录活性的变化。这些研究将提供 了解ESR 1突变如何塑造癌细胞对17 b-雌二醇的反应，并提供一种机制， 为临床使用提供依据。这项研究具有创新性，因为它涉及ER诱导的DNA 17 b-雌二醇治疗诱导的细胞毒性机制中的损伤，使得 针对晚期ER+乳腺癌的DNA损伤反应的策略。根据我们的临床试验 研究结果，该项目将测试ER突变使ER+乳腺癌细胞敏感的创新概念， 17 b-雌二醇。这项拟议的研究意义重大，因为它将揭示17 b-雌二醇的根本原因， 在ER+乳腺癌中诱导的细胞毒性，以及解释细胞适应如何将17 b-雌二醇从 生长促进剂到生长抑制剂。这项研究也将为临床研究提供强有力的科学依据。 在遗传可识别的患者亚群中测试17 β-雌二醇治疗。