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

开发转移性雄激素受体阳性三阴性乳腺癌的新型联合疗法

基本信息

  • 批准号:
    9898144
  • 负责人:
  • 金额:
    $ 3.82万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-12-01 至 2021-11-30
  • 项目状态:
    已结题

项目摘要

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.
项目总结/摘要 尽管过去在乳腺癌患者的诊断、治疗和预后方面取得了重大进展, 几十年来,对于转移性疾病的改进的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,并且通常难以接受标准治疗。 治疗,包括雌激素受体(ER)阳性和人表皮生长因子的靶向治疗 受体2(HER 2)阳性疾病和三阴性乳腺癌(TNBC)的化疗。TNBC是一种 特别是侵袭性亚型,具有转移到重要器官的倾向,包括脑、肝和 肺,治疗仅限于毒性化疗药物,这些药物通常对减缓疾病无效 预防复发或复发。为了改善这些患者的结局,必须开发更多 有效的、毒性较小的治疗方案,包括靶向治疗。雄激素受体(AR), 目前转移性前列腺癌的治疗靶点,在乳腺肿瘤的显著百分比中表达 并且在几个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,在这方面, 考虑到单一药物方案导致治疗耐药性和复发的趋势, 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 特征鲜明的拟议的研究将使用临床相关的患者来源的异种移植物(PDX)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之外, 并筛选与AR抑制有效组合的FDA批准的药物。初步研究 已经表明恩杂鲁胺(一种FDA批准的AR抑制剂)在体外对AR阳性TNBC细胞具有细胞毒性。 临床基因表达数据集的初步分析显示,AR表达基于内在的 AR表达水平与无转移呈显著负相关 ER阴性疾病的生存率。这些研究表明,AR靶向治疗可能适用于一个子集, TNBC患者中,目前仅限于化疗。拟议研究的目的 目的是:1)评估AR抑制对体外AR阳性TNBC细胞活力的影响; 2)鉴定AR抑制对TNBC细胞活力的影响。 FDA批准的化合物与AR靶向疗法组合有效;和3)测试功效 在治疗乳腺肿瘤和脑转移瘤中包括体内AR抑制的联合方案, 肝和肺。使用患者肿瘤的有效药物组合靶向的途径的后续分析 基因表达数据集将有助于确定哪种联合方案适合进一步的研究。 临床前开发和最终的临床试验。从这些研究中产生的数据可能具有 对晚期AR阳性TNBC患者的治疗决策和结局产生重大影响。

项目成果

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Tia H. Turner其他文献

Tia H. Turner的其他文献

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{{ truncateString('Tia H. Turner', 18)}}的其他基金

Development of novel combination treatments for metastatic androgen receptor-positive triple-negative breast cancer
开发转移性雄激素受体阳性三阴性乳腺癌的新型联合疗法
  • 批准号:
    10055959
  • 财政年份:
    2018
  • 资助金额:
    $ 3.82万
  • 项目类别:

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