Targeting androgen receptor signaling in prostate cancer in men with African ancestry

靶向非洲血统男性前列腺癌中的雄激素受体信号传导

基本信息

批准号：
10704700
负责人：
Changmeng Cai
金额：
$ 14.73万
依托单位：
UNIVERSITY OF MASSACHUSETTS BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-28 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10704700
关键词：
AR gene Address Affect African American population African ancestry American Androgen Receptor Androgen Therapy Androgens Apoptotic Basic Science Biological Boston CAG repeat Cancer Center Cancer Etiology Cancer Patient Cells Cessation of life Clinical Combined Modality Therapy Critical Pathways DNA Damage DNA Sequence Rearrangement Dana-Farber Cancer Institute Dependence Development Dose European ancestry Genetic Genetic Polymorphism Genetic Transcription Genomics Glutamine Grant High Prevalence KDM1A gene Lead Length Ligands Malignant neoplasm of prostate Massachusetts Modeling Molecular Target Mutation N-terminal Nuclear Outcome Pathway interactions Patients Play Population Proteins Receptor Signaling Research Risk Factors Role Testing Therapeutic Translational Research Universities cancer health disparity cancer initiation men polyglutamine programs prostate cancer cell prostate cancer cell line prostate cancer model racial disparity repaired response targeted agent targeted treatment transcription factor tumor progression

项目摘要

ABSTRACT Prostate cancer (PCa) is the second leading cause of cancer-related death in American men. Although men with European ancestry (EA) still represent the largest population of PCa patients, men with African ancestry (AA) are disproportionately affected by PCa with higher prevalence and worse outcomes. Androgen receptor (AR), a ligand-dependent nuclear transcription factor, plays a pivotal role in PCa development, and there are well- established genetic differences in the AR gene and associated pathways between EA versus AA men. However, it remains unclear how these genetic differences alter AR interaction with associated proteins, and their potential role in PCa development and response to AR targeted therapies. In this study, we hypothesize that differences in AR signaling contribute to the biological differences between PCa in AA versus EA men, and that PCa in AA men may have distinct AR-dependencies and be vulnerable to therapies that combine AR-targeted therapies with other targeted agents. To test these hypotheses, Aim 1 will assess the effect of androgen stimulation on PCa cells from AA versus EA patients, and in isogenic cells reflecting the genetic difference of AR. Aim 2 will identify vulnerabilities generated in response to AR-targeted therapies in AA versus EA PCa models.

抽象的前列腺癌（PCA）是美国男性与癌症相关死亡的第二大原因。虽然有男人欧洲血统（EA）仍然是PCA患者的最大人口，非洲血统的男性（AA）受PCA的影响不成比例，患病率较高，结果较差。雄激素受体（AR），A 配体依赖性核转录因子，在PCA发育中起关键作用，并且有很好的作用在AR基因和AA男性之间建立了遗传差异以及相关的途径。然而，尚不清楚这些遗传差异如何改变与相关蛋白的相互作用，它们的潜力在PCA开发和对AR靶向疗法的反应中的作用。在这项研究中，我们假设差异在AR信号中，AA与EA的PCA和AA中的PCA有助于PCA之间的生物学差异男性可能具有不同的AR依赖性，并且容易受到结合AR靶向疗法的疗法与其他目标代理。为了检验这些假设，AIM 1将评估雄激素刺激对来自AA与EA患者的PCA细胞以及反映AR遗传差异的同基因细胞。 AIM 2意志确定响应于AA与EA PCA模型中AR靶向疗法产生的漏洞。