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：
9311512
负责人：
Todd W Miller
金额：
$ 37.06万
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 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9311512
关键词：
Address Adjuvant Therapy Anabolism Apoptosis Aromatase Inhibitors Biological Markers Biology Biopsy Specimen Blood specimen Breast Cancer Cell Breast Cancer Treatment Cancer Cell Growth Cell Death Cells Cessation of life Clinical Clinical Management Clinical Research Clinical Trials DNA Damage Diagnosis Disease Disease Management Disease Progression Dose Down-Regulation Drug Targeting ERBB2 gene Endocrine Estradiol Estrogen Antagonists Estrogen Receptor alpha Estrogen Receptors Estrogen Therapy Estrogens Exhibits Genetic Transcription Growth Hormones Hypersensitivity Malignant Neoplasms Mammary Neoplasms Metastatic breast cancer Molecular Outcome Patients Phase Proteins Recurrence Recurrent disease Refractory Resistance SDZ RAD Stress Tamoxifen Testing Therapeutic Therapeutic Effect Time Transcriptional Activation Translating Treatment Protocols Tumor Markers Withdrawal Woman advanced disease cancer recurrence chemotherapy deprivation drug candidate effective therapy insight malignant breast neoplasm molecular marker mortality multicatalytic endopeptidase complex pharmacodynamic biomarker precision medicine predicting response predictive marker prevent proteotoxicity response restoration targeted treatment therapy duration treatment response tumor

项目摘要

Breast tumors expressing estrogen receptor alpha (ER) but not HER2 (ER+/HER2-) account for the majority of recurrences and deaths from breast cancer. In patients with early-stage disease, anti-estrogen therapies that suppress ER activity prevent cancer recurrence, but ~33% of patients (~300,000 women diagnosed each year) eventually develop recurrent disease. Advanced/metastatic breast cancer is managed with further anti- estrogen therapies, targeted therapies, and DNA-damaging chemotherapies. Nearly all metastatic breast cancers eventually become completely refractory to these therapies. Prior to the approval of tamoxifen, estrogens were frequently used for the treatment of breast cancer. This may seem counterintuitive since we now rely on anti-estrogens for disease management, but response rates to estrogens are similar to those of anti-estrogens in the setting of advanced disease. Approximately 1/3 of anti-estrogen-resistant breast cancers respond to estrogen therapy, translating into ~100,000 new patients each year who could benefit. Similarly, some cancers respond to withdrawal of anti-estrogen therapy, which may be caused by ER reactivation. Breast tumor responses to estrogen therapies and anti-estrogen withdrawal have been observed for >70 years, but the lack of A) understanding of therapeutic mechanism(s), and B) criteria to identify patients likely to benefit have hindered clinical use. To legitimize this inexpensive, widely accessible, time-tested, relatively safe and tolerable treatment option, and to provide a precision medicine basis to limit its use to patients with cancers likely to respond, the following critical issues need to be addressed: 1) understanding the mechanism(s) underlying sensitivity of anti-estrogen-resistant breast cancers to estrogen therapy and anti-estrogen withdrawal; 2) identifying tumor markers that predict benefit from ER reactivation therapy; 3) identifying strategies to enhance response; 4) understanding the dynamics of therapeutic response/resistance. We hypothesize that during adaptation to anti-estrogens and estrogen deprivation, ER+ breast cancer cells acquire molecular changes that render estrogen-dependent ER reactivation proteotoxic and deleterious. We will test this hypothesis through the following Specific Aims: 1) Determine whether a finite window of ER transcriptional activation promotes growth of breast cancer cells, and how this window shifts with acquisition of anti-estrogen resistance; 2) Determine how ER reactivation elicits proteotoxic stress-dependent cell death; 3) Determine the optimal dose, duration, and mechanisms of escape from 17b-estradiol therapy in anti-estrogen-resistant breast tumors; 4) Identify baseline and pharmacodynamic biomarkers that predict response to 17b-estradiol therapy in patients with anti-estrogen-resistant breast cancer.

表达雌激素受体α（ER）的乳腺肿瘤（ER+/HER2-）占多数乳腺癌的复发和死亡。在早期疾病的患者中，抗雌激素疗法抑制ER活性可预防癌症复发，但约33％的患者（每年被诊断出约30万名女性）最终患上复发性疾病。先进/转移性乳腺癌通过进一步的抗雌激素疗法，靶向疗法和DNA损害化学疗法。几乎所有转移性乳房癌症最终对这些疗法完全难治性。在批准他莫昔芬之前，雌激素经常用于治疗乳腺癌。这似乎是违反直觉的，因为我们现在依靠抗雌激素进行疾病管理，但是对雌激素的反应率与晚期疾病的抗雌激素。大约1/3的抗雌激素耐药性乳腺癌对雌激素疗法的反应，每年转化为约有100,000名新患者，可以受益。相似地，一些癌症对抗雌激素疗法的戒断有何反应，这可能是由ER重新激活引起的。胸部已经观察到肿瘤对雌激素疗法和抗雌激素戒断的反应已有70年了，但是缺乏a）对治疗机制的理解和b）确定可能受益的患者的标准阻碍了临床用途。合法化这种廉价，广泛访问，经过时间测试，相对安全和可耐受的治疗选择，并提供精确的医学基础以将其用于癌症患者的使用可能需要解决以下关键问题：1）了解机制抗雌激素的乳腺癌对雌激素治疗和抗雌激素的潜在敏感性撤离； 2）确定预测ER重新激活疗法的肿瘤标记； 3）识别增强反应的策略； 4）了解治疗反应/抗性的动力学。我们假设在适应抗雌激素和雌激素剥夺期间，ER+乳腺癌细胞获得分子变化，使雌激素依赖性ER重新激活蛋白毒性和有害。我们将测试通过以下特定目的这一假设：1）确定是否有限的ER转录窗口激活促进乳腺癌细胞的生长，以及该窗口如何通过抗雌激素的获取而移动反抗; 2）确定ER重新激活如何引起蛋白毒性应激依赖性细胞死亡； 3）确定从17b-雌二醇治疗抗雌激素的乳房中逃脱的最佳剂量，持续时间和机制肿瘤； 4）确定预测对17B-雌二醇治疗的反应的基线和药效生物标志物患有抗雌激素的乳腺癌患者。