Androgen Receptor Action in Castration Resistant Prostate Cancer

这是我们P01的修订后的竞争续订申请，标题为“雄激素受体在去势中的作用 耐药前列腺癌“。在过去的几年里，前列腺癌(PCa)的治疗模式发生了转变 治疗，因为现在很清楚雄激素受体(AR)仍然活跃，是PCa的治疗靶点 手术或药物去势(去势抵抗型前列腺癌，CRPC)后复发。以前的基础知识， 本P01提案中研究人员进行的翻译和临床研究对以下方面做出了重大贡献 通过阐明AR作用的基本机制和去势机制，这种范式转变- 患者的耐药性。CYP17A1抑制剂阿比特龙和AR拮抗剂苯扎鲁胺现在正在 标准的二线激素疗法，用于去势后复发的男性。不幸的是，大多数男人 对这些疗法的反应将在1-2年内复发。值得注意的是，阿比特龙或阿比特龙的子集 对苯扎鲁胺耐药的PCA可能变得不依赖AR，这是P01和P01研究人员的最新结果 其他研究表明，大多数继续表达高水平的AR，似乎在转录上是活跃的。 因此，这一建议中的一个主要假设是AR活性仍然持续存在，并对肿瘤起作用 阿比特龙和苯扎鲁胺耐药前列腺癌的生长。此外，我们假设，由 前列腺癌细胞对AR靶向治疗的反应造成了可用于治疗的漏洞。 因此，总体规划目标是阐明与CRPC和CRPC相关的临床机制。 阿比特龙/苯扎鲁胺耐药，以确定可以克服这些耐药的治疗方法 机制和/或利用新的脆弱性，并评估这些治疗方法在临床前 可以构成临床试验基础的模型。项目内容如下：1)确定和开发 AR介导的细胞抑制机制，2)AR全长和剪接变异体的驱动机制 活性与拮抗剂抗性；3)去势抗性中影响雄激素受体的蛋白激酶 前列腺癌，4)识别在拮抗剂耐药的CRPC中影响AR活性的基本基因。

This is a revised competitive renewal application for our P01 entitled “Androgen Receptor Action In Castration Resistant Prostate Cancer”. The past several years have seen a paradigm shift in prostate cancer (PCa) therapy, as it is now clear that the androgen receptor (AR) remains active and is a therapeutic target in PCa that relapses after surgical or medical castration (castration-resistant prostate cancer, CRPC). Previous basic, translational and clinical research conducted by investigators in this P01 proposal made major contributions to this paradigm shift by elucidating fundamental mechanisms of AR action and mechanisms of castration- resistance in patients. The CYP17A1 inhibitor abiraterone, and the AR antagonist enzalutamide, are now standard second line hormonal therapies for men who relapse after castration. Unfortunately, most men who respond to these therapies will relapse within 1-2 years. Significantly, while a subset of abiraterone or enzalutamide-resistant PCa may become AR independent, recent results from investigators in this P01 and others indicate that most continue to express high levels of AR that appears to be transcriptionally active. Therefore, a major hypothesis in this proposal is that AR activity still persists and is contributing to tumor growth in abiraterone and enzalutamide-resistant PCa. Moreover, we hypothesize that adaptations made by PCa cells in response to AR targeted therapies create vulnerabilities that can be exploited therapeutically. Hence, overall program goals are to elucidate clinically relevant mechanisms that contribute to CRPC and abiraterone/enzalutamide-resistance, to identify therapeutic approaches that can overcome these resistance mechanisms and/or exploit new vulnerabilities, and to assess these therapeutic approaches in preclinical models that can form foundations for clinical trials. The Projects are as follows: 1) Determining and Exploiting Mechanisms of AR-Mediated Suppression of Cell, 2) Mechanisms Driving AR Full Length and Splice Variant Activities and Antagonist Resistance, 3) Protein Kinases Influencing Androgen Receptor in Castrate Resistant Prostate Cancer, 4) Identification of Essential Genes Underlying AR Activity in Antagonist-Resistant CRPC.