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 HER2 (ER+/​​HER2-) 的乳腺肿瘤占大多数 乳腺癌复发和死亡。对于早期疾病患者，抗雌激素疗法 抑制 ER 活性可防止癌症复发，但约 33% 的患者（每年约 300,000 名女性被诊断） 最终发展为复发性疾病。晚期/转移性乳腺癌可通过进一步抗肿瘤治疗来治疗 雌激素疗法、靶向疗法和 DNA 损伤化疗。几乎所有转移性乳房 癌症最终对这些疗法完全无效。在他莫昔芬获批之前， 雌激素经常用于治疗乳腺癌。这可能看起来违反直觉，因为我们 现在依靠抗雌激素来进行疾病管理，但对雌激素的反应率与 在晚期疾病中使用抗雌激素。大约 1/3 的抗雌激素耐药乳腺癌 对雌激素治疗有反应，每年约有 100,000 名新患者可以受益。相似地， 一些癌症对停止抗雌激素治疗有反应，这可能是由 ER 重新激活引起的。胸部 肿瘤对雌激素治疗和抗雌激素戒断反应的观察已超过 70 年，但 缺乏 A) 对治疗机制的了解，以及 B) 识别可能受益的患者的标准 阻碍了临床应用。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，并提供精准医学基础以限制其在癌症患者中的使用 为了可能做出回应，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药物的潜在敏感性 撤回； 2) 识别预测 ER 再激活治疗获益的肿瘤标志物； 3）识别 加强应对的战略； 4）了解治疗反应/抵抗的动态。我们 假设在适应抗雌激素和雌激素剥夺过程中，ER+乳腺癌细胞获得 使雌激素依赖性 ER 重新激活具有蛋白质毒性和有害性的分子变化。我们将测试 该假设通过以下具体目标：1）确定 ER 转录的有限窗口是否存在 激活促进乳腺癌细胞的生长，以及该窗口如何随着抗雌激素的获得而变化 反抗; 2) 确定 ER 重新激活如何引发蛋白毒性应激依赖性细胞死亡； 3）确定 抗雌激素耐药乳腺中 17b-雌二醇治疗的最佳剂量、持续时间和逃避机制 肿瘤； 4) 确定预测 17b-雌二醇治疗反应的基线和药效生物标志物 抗雌激素耐药乳腺癌患者。