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

基本信息

批准号：
10353728
负责人：
Corey W. Speers
金额：
$ 18.23万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10353728
关键词：
Address Aftercare Androgen Antagonists Androgen Receptor Antiandrogen Therapy Biological Assay Biological Markers Breast Cancer Model Breast Cancer Patient Breast Cancer cell line Bromouridine sequencing Cell Line ChIP-seq Clinical Clinical Management Clinical Trials DNA Binding DNA Damage DNA Repair Gene Data Development Estrogen receptor positive Generations Genes Genetic Transcription Genomics Goals In Vitro Ionizing radiation Knowledge Malignant Neoplasms Mediating Mediator of activation protein Modeling Molecular Nonhomologous DNA End Joining Nonmetastatic Outcome Pathway interactions Patients Pharmacology Phase I/II Clinical Trial Phase I/II Trial Play Radiation Radiation Tolerance Radiation therapy Radiosensitization Receptor Inhibition Receptor Signaling Recurrence Regulation Research Resistance Role Subgroup Testing Transcriptional Activation Translating Woman aggressive breast cancer cancer radiation therapy cancer subtypes cohort efficacy testing enzalutamide experimental study high risk homologous recombination improved in vivo ineffective therapies malignant breast neoplasm patient derived xenograft model patient population pre-clinical radiation resistance rational design receptor binding receptor expression response targeted agent therapeutic target therapy design transcriptomics treatment strategy triple-negative invasive breast carcinoma tumor

项目摘要

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.

阐明雄激素受体（AR）在介导AR阳性乳腺癌中介导的辐射抗性中的作用如何使治疗对患有侵略性乳腺癌的女性更有效疗法无效；理性设计的治疗强化放射疗法（RT）仍然是当前乳腺癌临床管理的主要手段，但最少对三阴性乳腺癌（TNBC）的女性有效。另外，TNBC是最致命的形式乳腺癌，但是这种放射线的分子驱动因素目前尚不清楚。鉴于基本缺乏有关抗辐射抗性介体的知识和进一步的缺乏目标药物的知识 TNBC，很明显，开发其他放射性敏感的目标代表了一个关键临床需求。我们先前确定雄激素受体（AR）在介导中起着重要作用 AR阳性TNBC中的放射线，尽管这种放射线的确切机制尚不清楚。尽管抗雄激素治疗可有效地使AR+ TNBC敏感，但尚不清楚抗雄激素是否是否 AR+雌激素受体阳性（ER+）乳腺癌的治疗同样有效。最多70％的ER+ 肿瘤还表达AR，有效靶向AR进行放射敏化具有改善局部控制的潜力在所有AR+乳腺癌中，不仅是AR+ TNBC。拟议的研究的目的是制定更有效的放射敏化处理策略具有侵略性形式的乳腺癌形式的女性，包括AR+ TNBC和AR+ Luminal B癌症。我们假设AR介导了所有AR+乳腺癌中的放射性，而不仅仅是AR+ TNBC。我们进一步假设AR表达通过控制AR介导电离辐射后DNA修复基因的转录和激活，并且这种放射线存在可以使用第二代抗雄激素抑制AR信号来逆转。测试这些假设，我们将使用AR+/ER+患者的RT使用enzalutamide来确定放射敏的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变化辐射后，发生抗雄激素处理，以确定AR和AR介导的DNA结合辐射处理后的转录变化并用抗雄激素抑制AR使用RT处理。