权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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AR阳性乳腺癌放射耐药中的作用