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

摘要 前列腺癌(PCA)是美国男性癌症相关死亡的第二大原因。虽然男人有 欧洲血统(EA)仍然是前列腺癌患者中最大的群体，非洲血统(AA)的男性 不成比例地受到PCA的影响，患病率更高，结果更差。雄激素受体(AR) 配体依赖的核转录因子，在前列腺癌的发展中起着关键作用，并且有很好的- 在EA和AA男性之间，AR基因和相关通路的遗传差异已经确立。然而， 目前尚不清楚这些遗传差异如何改变AR与相关蛋白质的相互作用，以及它们的潜力 在前列腺癌的发展和AR靶向治疗的反应中的作用。在这项研究中，我们假设 AR信号转导导致AA组和EA组的PCA以及AA组的PCA之间的生物学差异 男性可能有明显的AR依赖，并且容易受到结合AR靶向治疗的治疗的影响 和其他目标特工的关系。为了验证这些假设，目标1将评估雄激素刺激对 AA和EA患者的PCa细胞，以及反映AR遗传差异的等基因细胞。目标2将 识别AA与EA PCA模型中针对AR靶向治疗所产生的漏洞。

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.