Development of novel combination treatments for metastatic androgen receptor-positive triple-negative breast cancer

项目摘要/摘要 尽管过去乳腺癌患者在诊断、治疗和预后方面取得了重大进展 几十年来，对转移性疾病改进治疗策略的需要是至关重要的。转移性 疾病占所有乳腺癌相关死亡的99%以上，而且往往难以达到标准 治疗，包括针对雌激素受体(ER)阳性和人表皮生长因子的靶向治疗 受体2(HER2)阳性疾病和三阴性乳腺癌的化疗。TNBC是一种 特别是侵袭性亚型，有转移到重要器官的倾向，包括大脑，肝脏和 肺部，治疗仅限于有毒的化疗药物，这些药物在减缓疾病方面往往无效 进展或防止复发。为了改善这些患者的预后，必须开发更多的 结合靶向治疗的有效、毒性较低的治疗方案。雄激素受体(AR)是 目前转移性前列腺癌的治疗靶点是在相当大比例的乳腺肿瘤中表达 并在几项临床前和临床乳腺癌研究中显示出作为治疗靶点的前景。然而， 鉴于单一药物方案有导致治疗耐药和复发的趋势，重要的是 开发治疗晚期TNBC的联合方案。此外，AR在转移性疾病中的作用不是 刻画得很好。拟议的研究将使用临床相关的患者来源的异种移植模型 除了研究AR作为治疗转移性乳腺癌的靶点的乳腺癌细胞系外， 并筛选FDA批准的与AR抑制联合有效的药物。初步研究 研究表明，FDA批准的AR抑制剂苯扎鲁胺在体外对AR阳性的TNBC细胞具有细胞毒作用。 对临床基因表达数据的初步分析表明，AR的表达基于内在的不同而不同 AR表达水平与无转移呈显著负相关。 ER阴性疾病的存活率。这些研究表明，AR靶向治疗可能适用于某一亚型 目前在药物方面仅限于化疗的TNBC患者。拟议研究的目的 目的：1)评价AR抑制对AR阳性的TNBC细胞活性的影响；2)鉴定 FDA批准的与AR靶向治疗相结合有效的化合物；以及3)测试疗效 包括体内AR抑制治疗乳腺肿瘤和脑转移瘤的联合方案， 肝和肺。使用患者肿瘤的有效药物组合靶向通路的后续分析 基因表达数据集将有助于确定哪种联合方案适合进一步 临床前开发和最终的临床测试。从这些研究中产生的数据可能具有 对AR阳性的晚期TNBC患者的治疗决策和结果有重大影响。

PROJECT SUMMARY/ABSTRACT Despite major advances in diagnosis, treatment, and prognosis for patients with breast cancer over the past several decades, the need for improved therapeutic strategies for metastatic disease is critical. Metastatic disease accounts for greater than 99% of all breast cancer-related deaths, and is often refractory to standard therapies, including targeted therapies for estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) positive disease and chemotherapy for triple-negative breast cancer (TNBC). TNBC is a particularly aggressive subtype with a propensity to metastasize to vital organs including the brain, liver, and lung, and treatment is limited to toxic chemotherapeutics which are often ineffective in slowing disease progression or preventing recurrence. To improve outcomes for these patients, it is imperative to develop more effective, less toxic treatment regimens that incorporate targeted therapies. The androgen receptor (AR), a current therapeutic target in metastatic prostate cancer, is expressed in a significant percentage of breast tumors and has shown promise as a therapeutic target in several preclinical and clinical breast cancer studies. However, given the tendency of single-drug regimens to result in therapeutic resistance and relapse, it is important to develop combination regimens to treat advanced TNBC. Furthermore, the role of AR in metastatic disease is not well-characterized. The proposed studies will use clinically-relevant patient-derived xenograft (PDX) models in addition to breast cancer cell lines to investigate AR as a target for the treatment of metastatic breast cancer, and to screen for FDA-approved drugs that are effective in combination with AR inhibition. Preliminary studies have indicated that enzalutamide, an FDA-approved AR inhibitor, is cytotoxic to AR-positive TNBC cells in vitro. Preliminary analyses of clinical gene expression datasets revealed that AR expression varies based on intrinsic subtype, and that there is a significant negative correlation between AR expression level and metastasis-free survival in ER-negative disease. These studies suggest that AR-targeted therapy may be suitable for a subset of TNBC patients, who currently are pharmacologically limited to chemotherapy. The aims of the proposed study are: 1) to evaluate the effects of AR inhibition on the viability of AR-positive TNBC cells in vitro; 2) to identify FDA-approved compounds that are effective in combination with AR-targeted therapy; and 3) to test the efficacy of combination regimens including AR inhibition in vivo in treating mammary tumors and metastases in the brain, liver and lung. Subsequent analysis of the pathways targeted by effective drug combinations using patient tumor gene expression datasets will help determine which combination regimens would be suitable for further preclinical development and eventual clinical testing. The data generated from these studies can potentially have a major impact on treatment decisions and outcomes for patients with advanced AR-positive TNBC.