Elucidating The Role Of Androgen Receptor (AR) In Mediating Radioresistance In AR-Positive Breast Cancer

阐明雄激素受体 (AR) 在介导 AR 阳性乳腺癌放射抗性中的作用

• 批准号: 10746200
• 负责人: Corey W. Speers
• 金额: $ 22.13万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10746200
• 关键词: Elucidating; Role; Androgen; Receptor; AR

Elucidating the role of androgen receptor (AR) in mediating radioresistance in AR-positive breast cancer How to make treatment more effective for the women with aggressive breast cancers for whom standard therapies are ineffective; rationally designed treatment intensification Radiation therapy (RT) remains a mainstay of current clinical management of breast cancer but is least effective in women with triple-negative breast cancer (TNBC). Additionally, TNBC is the most lethal form of breast cancer, but the molecular drivers of this radioresistance are currently unknown. Given the fundamental lack of knowledge regarding the mediators of radiation resistance and a furthered lack of targeted agents for TNBC, it is clear that the development of additional targets for radiosensitization represents a critical unmet clinical need. We previously identified that the androgen receptor (AR) plays an important role in mediating radioresistance in AR-positive TNBC, though the exact mechanism of this radioresistance remains unclear. Although antiandrogen therapy is effective in radiosensitizing AR+ TNBC, it is unclear whether antiandrogen treatment in AR+ estrogen receptor-positive (ER+) breast cancer is similarly effective. As up to 70% of ER+ tumors also express AR, effective targeting of AR for radiosensitization has the potential to improve local control in all AR+ breast cancer, not just AR+ TNBC. The goal of the proposed research is to develop more effective radiosensitizing treatment strategies for woman with aggressive forms of breast cancer-including AR+ TNBC and AR+ Luminal B cancers that are ER+. We hypothesize that AR mediates radioresistance in all AR+ breast cancer, and not just AR+ TNBC. We further hypothesize that AR expression confers this radioresistance by controlling AR-mediated transcription and activation of DNA repair genes after ionizing radiation and that this radioresistance can be reversed by inhibition of AR-signaling using second generation anti-androgens. To test these hypotheses, we will determine the degree of radiosensitization using enzalutamide with RT in AR+/ER+ patient derived xenograft (PDX) cell lines and PDX models. We will also determine the gene transcription changes that occur with anti-androgen treatment after radiation to determine how DNA binding of AR and AR-mediated transcription changes after radiation treatment and inhibition of AR with antiandrogens with RT treatment.

雄激素受体（AR）在AR阳性乳腺癌放射抵抗中的作用 如何使治疗更有效的妇女与侵略性乳腺癌的标准 治疗无效;合理设计的治疗强化 放射治疗（RT）仍然是目前乳腺癌临床治疗的主要手段， 对三阴性乳腺癌（TNBC）女性有效。此外，TNBC是最致命的形式， 乳腺癌，但这种放射抗性的分子驱动因素目前尚不清楚。鉴于基本的 缺乏关于辐射抗性介体的知识，并且进一步缺乏针对辐射抗性的靶向剂。 TNBC，很明显，放射增敏的额外靶点的开发代表了一个关键的未满足的问题。 临床需要我们以前发现雄激素受体（AR）在介导 在AR-阳性TNBC中，放射抗性是一个重要的特征，尽管这种放射抗性的确切机制仍不清楚。 尽管抗雄激素治疗对AR+ TNBC的放射增敏有效，但目前尚不清楚抗雄激素治疗是否 AR+雌激素受体阳性（ER+）乳腺癌的治疗同样有效。高达70%的ER+ 肿瘤也表达AR，有效靶向AR用于放射增敏具有改善局部控制的潜力 在所有AR+乳腺癌中，而不仅仅是AR+ TNBC。 这项研究的目的是开发更有效的放射增敏治疗策略， 患有侵袭性形式的乳腺癌的女性-包括ER+的AR+ TNBC和AR+管腔B癌。 我们假设AR介导所有AR+乳腺癌的放射抗性，而不仅仅是AR+ TNBC。我们 我进一步假设AR表达通过控制AR介导的 电离辐射后DNA修复基因的转录和激活， 可以通过使用第二代抗雄激素抑制AR信号传导来逆转。测试这些 假设，我们将在AR+/ER+患者中确定Enzalutamide联合RT的放射增敏程度 衍生的异种移植（PDX）细胞系和PDX模型。我们还将确定基因转录的变化， 发生与抗雄激素治疗后辐射，以确定如何DNA结合的AR和AR介导的 辐射处理后的转录变化和用RT处理用抗雄激素抑制AR。