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

基本信息

批准号：
10598612
负责人：
Todd W Miller
金额：
$ 24.26万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10598612
关键词：
Affect Anabolism Apoptosis Aromatase Inhibitors Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment Cell Fate Control Cell Line Cells Clinic Clinical Clinical Trials DNA Damage DNA Repair Data Development Diagnosis Disease Management Disease Progression ERBB2 gene ESR1 gene Endocrine Engineering Estradiol Estrogen Antagonists Estrogen Receptor alpha Estrogen Receptors Estrogen Therapy Estrogens Fertilizers Fulvestrant Genes Genetic Engineering Genetic Transcription Goals Growth Heterozygote Investigation Kinetics Ligand Binding Domain Mammary Neoplasms Measurement Measures Mediating Metastatic breast cancer Mission Modeling Morbidity - disease rate Mutation Outcome Patients Persons Poly(ADP-ribose) Polymerases Public Health Recurrent Malignant Neoplasm Recurrent disease Research Resistance Role Shapes Tamoxifen Testing Therapeutic Time Translating Treatment Efficacy Woman adjuvant endocrine therapy advanced breast cancer anti-cancer cancer cell cancer recurrence clinical implementation cytotoxic cytotoxicity deprivation effective therapy genetic profiling homologous recombination hormone therapy improved innovation malignant breast neoplasm mortality mutant overexpression patient derived xenograft model patient subsets pharmacologic precision medicine prevent promoter research clinical testing response spatiotemporal therapy development treatment response treatment strategy tumor tumor growth

项目摘要

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：尚不清楚为什么某些雌激素受体α（ER）阳性乳腺癌是对雌激素疗法敏感，而其他人则具有抗性，并有效地利用雌激素治疗的策略没有建立的。这种调查的长期目标是最大化用于治疗ER+乳腺癌的内分泌疗法。该项目的总体目的是定义响应雌激素17b-雌二醇控制ER+乳腺癌中细胞命运的机制。这中心假设是基底雌激素与ER扩增引起的转录活性，过表达或突变使乳腺癌细胞对17b-雌二醇/ER诱导的细胞毒性作用敏感 DNA损伤。该项目的理由是（i）治疗基础机制的定义对17b-雌二醇和（ii）决定对17b-雌二醇反应的肿瘤特征的反应将提供精度医学基础使用并提供增强反应的策略。中心假设将通过追求三个特定目标：（1）确定17b-雌二醇/ER诱导的DNA损伤和响应控制细胞命运；（2）确定抑制DNA损伤反应如何影响对17b-雌二醇的敏感性；（3）定义ER（ESR1）突变在决定乳腺癌对17B-雌二醇的反应中的作用。在第一个目标中 17b-雌二醇/ER诱导的转录活性，DNA损伤的动力学和时空关系并将在基因设计和雌激素独立的ER+乳腺癌细胞中测量反应。这些研究将为17b-雌二醇的细胞毒性作用提供机械基础。第二个目标使用细胞系和患者衍生的异种移植物来测量17b-雌二醇在聚（ADP-核糖）聚合酶1/2（PARP）以及同源重组的药理抑制不足。这些研究将提供治疗策略，以增强对17b-雌二醇的反应。在第三个目标中工程细胞和ESR1突变的患者衍生异种移植物将用于测量17b-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ESR1突变如何塑造癌细胞对17B-雌二醇的反应并提供机械基础来告知其临床用途。拟议的研究具有创新性，因为它暗示了ER诱导的DNA 17b-雌二醇治疗引起的细胞毒性机制的损害，使能够发展针对晚期ER+乳腺癌的DNA损伤反应的策略。根据我们的临床试验调查结果，该项目将测试ER突变使ER+乳腺癌细胞敏感的创新概念 17b-雌二醇。拟议的研究很重要，因为它将揭示17b-雌二醇的根本原因诱导ER+乳腺癌的细胞毒性，并解释细胞适应如何转化17B-雌二醇增长抑制剂的增长促进剂。这项研究还将为临床提供强大的科学原理在可识别的患者亚群中测试17B-雌二醇治疗。