Project 2: Therapeutic targeting of estrogen receptor beta in triple negative breast cancer

项目2：三阴性乳腺癌中雌激素受体β的治疗靶向

• 批准号: 10017908
• 负责人: John R. Hawse
• 金额: $ 28.3万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-22 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017908
• 关键词: Address; Agonist; Androgen Receptor; Biological Markers; Biopsy; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; Cell Proliferation; Characteristics; Chemotherapy-Oncologic Procedure; Clinic; Clinical; Cystatins; Data; Development; Diagnosis; Disease; Disease Management; ERBB2 gene; Endocrine; Epidermal Growth Factor Receptor; Estradiol; Estradiol Receptors; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Therapy; Event; Expression Profiling; Goals; In Vitro; Individual; Lead; Mediating; Messenger RNA; MicroRNAs; Modeling; Neoadjuvant Therapy; Neoplasm Metastasis; Nonmetastatic; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase II Clinical Trials; Progesterone Receptors; Protein Family; Proteins; Residual Tumors; Resistance; Role; Series; Signal Transduction; Testing; Therapeutic; Transforming Growth Factor beta; Treatment Efficacy; Woman; Xenograft procedure; anti-cancer; base; cancer therapy; chemotherapy; cohort; genetic signature; improved; improved outcome; in vivo; malignant breast neoplasm; migration; mortality; new therapeutic target; patient population; patient response; receptor; response; side effect; targeted treatment; therapeutic biomarker; therapeutic target; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor progression

PROJECT SUMMARY/ABSTRACT: In 2015 it is estimated that more than 1.6 million women will develop breast cancer world-wide, of which nearly 20% will be diagnosed with a form of the disease referred to as triple negative breast cancer (TNBC) that lacks expression of estrogen receptor alpha (ERα), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2). For these reasons, targeted therapies are currently limited for this patient population. While chemotherapy improves the survival of TNBC patients, 5 year mortality rates approach 50% for individuals with residual disease after neoadjuvant treatment. It is therefore paramount to identify new drug targets and therapeutic strategies for women with TNBC. We and others have recently demonstrated that 30% of TNBCs express ERβ and have shown that ERβ expression is associated with improved survival in TNBC patients. Additionally, the large majority of ERβ+ TNBCs do not express the androgen receptor allowing for the potential expansion of endocrine related therapies into an additional subset of TNBC patients. To identify therapies that may have utility for the treatment of ERβ+ TNBC, we have developed ERβ expressing TNBC cell lines and have generated ERβ+ and ERβ- patient derived xenografts (PDX) from women with non-metastatic locally advanced TNBC. We show that activation of ERβ with estradiol significantly reduces cell proliferation and tumor growth, effects that appear to be mediated in part by a family of proteins known as the cystatins which are highly induced by ERβ in TNBC cells. Elevated cystatin levels lead to suppression of canonical TGFβ signaling, a pathway known to drive tumor progression, metastasis, and resistance to chemotherapy regimens. We have also shown that these same anti-cancer effects can be achieved with drugs such as LY500307 that specifically target ERβ allowing for the opportunity to develop cancer therapies that could avoid the negative side effects associated with estradiol. Based on these preliminary data, our central hypothesis is that therapeutic activation of ERβ will result in clinical benefit for patients with ERβ+ TNBC by regulating a series of events that involves the induction of cystatins and suppression of canonical TGFβ signaling. To test this hypothesis, the following Specific Aims are proposed: 1). Determine the role of cystatins, and their impact on TGFβ signaling, in mediating the anti-cancer effects of ERβ in TNBC and characterize the expression of these biomarkers in a large cohort of TNBC patients; 2). Characterize the in vivo effects of estradiol and LY500307 on ERβ+ TNBC PDXs; 3). Elucidate the therapeutic efficacy of estradiol in ERβ+ TNBC. To address these Specific Aims, we will employ multiple in vitro and in vivo approaches to fully characterize the mechanisms of action and anti-tumor activity of estradiol and ERβ specific agonists for the treatment of ERβ+ TNBC. Given the extremely poor outcomes in women with TNBC and the lack of targeted therapies for this group of patients, the proposed studies are of critical importance towards the goal of indentifying novel drug targets and therapeutic strategies to more effectively treat and manage this disease.

项目摘要/摘要： 2015年，估计全球将有超过160万女性罹患乳腺癌，其中近 20% 的人将被诊断出患有一种称为三阴性乳腺癌 (TNBC) 的疾病，这种疾病缺乏 雌激素受体α（ERα）、孕激素受体（PR）和表皮生长因子受体的表达 2 (HER2) 由于这些原因，目前针对该患者群体的靶向治疗受到限制。 化疗可提高 TNBC 患者的生存率，患有此类疾病的患者 5 年死亡率接近 50% 因此，确定新的药物靶点和新辅助治疗后的残留疾病至关重要。 我们和其他人最近证明，30% 的 TNBC 患者的治疗策略。 表达 ERβ，并表明 ERβ 表达与 TNBC 患者生存率的提高相关。 此外，绝大多数 ERβ+ TNBC 不表达雄激素受体，因此具有潜在的潜力 将内分泌相关疗法扩展到另一类 TNBC 患者中，以确定能够治疗的疗法。 可能对治疗 ERβ+ TNBC 有用，我们开发了表达 ERβ 的 TNBC 细胞系 已从局部非转移性女性身上产生了 ERβ+ 和 ERβ- 患者来源的异种移植物 (PDX) 我们发现雌二醇激活 ERβ 会显着降低细胞增殖和 肿瘤生长的影响似乎部分是由称为半胱氨酸蛋白酶抑制剂的蛋白质家族介导的， TNBC 细胞中 ERβ 高度诱导，胱抑素水平升高导致经典 TGFβ 受到抑制。 信号传导，一种已知可驱动肿瘤进展、转移和化疗方案耐药性的途径。 我们还表明，使用 LY500307 等药物也可以实现这些相同的抗癌效果， 专门针对 ERβ，从而有机会开发可以避免负面影响的癌症疗法 根据这些初步数据，我们的中心假设是与雌二醇相关的副作用。 ERβ 的治疗激活将通过调节 ERβ+ TNBC 患者带来临床获益。 涉及半胱氨酸蛋白酶抑制剂的诱导和经典 TGFβ 信号传导抑制的一系列事件。 为了检验这一假设，提出了以下具体目标： 1) 确定半胱氨酸蛋白酶抑制剂的作用及其作用。 对 TGFβ 信号传导的影响，介导 TNBC 中 ERβ 的抗癌作用并表征 这些生物标志物在一大群 TNBC 患者中的表达；表征 2) 的体内效应。 雌二醇和 LY500307 对 ERβ+ TNBC PDX 的疗效；阐明雌二醇对 ERβ+ 的治疗效果； 为了实现这些具体目标，我们将采用多种体外和体内方法来充分实现 表征雌二醇和 ERβ 特异性激动剂的作用机制和抗肿瘤活性 鉴于女性 TNBC 的治疗效果极差且缺乏针对性。 对于这组患者的治疗，拟议的研究对于实现这一目标至关重要 确定新的药物靶点和治疗策略，以更有效地治疗和管理这种疾病。