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: 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
• 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

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）但不表达HER 2（ER+/HER 2-）的乳腺肿瘤占大多数。 复发和死于乳腺癌。在早期疾病患者中， 抑制ER活性可预防癌症复发，但约33%的患者（每年约30万名女性确诊） 最终会复发晚期/转移性乳腺癌通过进一步的抗- 雌激素治疗、靶向治疗和DNA损伤化疗。几乎所有转移性乳腺癌 癌症最终变得对这些疗法完全难治。在他莫昔芬获批之前， 雌激素常用于治疗乳腺癌。这似乎违反直觉，因为我们 现在依靠抗雌激素进行疾病管理，但对雌激素的反应率与 抗雌激素治疗晚期疾病大约1/3的抗雌激素耐药乳腺癌 对雌激素治疗有反应，转化为每年约100，000名新患者可能受益。同样地， 一些癌症对抗雌激素治疗的撤销有反应，这可能是由ER再激活引起的。乳腺 肿瘤对雌激素治疗的反应和抗雌激素药物的停药已经观察了70多年，但 缺乏A）对治疗机制的理解，和B）识别可能受益患者的标准 阻碍了临床应用。为了使这种廉价、广泛使用、经过时间考验、相对安全和 可耐受的治疗选择，并提供精确的医学基础，以限制其用于癌症患者 可能作出反应，需要解决以下关键问题：1）了解机制 抗雌激素耐药乳腺癌对雌激素治疗和抗雌激素治疗的潜在敏感性 退出; 2）鉴定预测从ER再激活治疗中获益的肿瘤标志物; 3）鉴定 增强反应的策略; 4）理解治疗反应/抗性的动力学。我们 假设在对抗雌激素和雌激素剥夺的适应过程中，ER+乳腺癌细胞获得 使雌激素依赖性ER再激活蛋白毒性和有害的分子变化。我们将测试 这一假说通过以下具体目的：1）确定是否ER转录的有限窗口 激活促进乳腺癌细胞的生长，以及这个窗口如何随着抗雌激素的获得而改变 2）确定ER再活化如何诱发蛋白毒性应激依赖性细胞死亡; 3）确定ER再活化如何诱导蛋白毒性应激依赖性细胞死亡。 抗雌激素抵抗乳腺癌患者17 b-雌二醇治疗的最佳剂量、持续时间和逃逸机制 4）确定预测对17 b-雌二醇治疗的反应的基线和药效学生物标志物， 抗雌激素抵抗乳腺癌患者。