Androgen Receptor Action in Castration Resistant Prostate Cancer

这是一个修改后的竞争性更新申请，我们的P01题为“雄激素受体作用在去势 前列腺癌的治疗方法在过去的几年里，前列腺癌（PCa）发生了范式转变。 治疗，因为现在很清楚雄激素受体（AR）保持活性，是PCa的治疗靶点 手术或药物去势后复发的前列腺癌（去势抵抗性前列腺癌，CRPC）。以前的基本， 研究者在P01提案中进行的转化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， 患者的抵抗力。CYP 17 A1抑制剂阿比特龙和AR拮抗剂恩杂鲁胺，现在是 标准二线激素治疗的男性谁复发后阉割。不幸的是，大多数男人 对这些治疗有效的患者将在1-2年内复发。值得注意的是，虽然阿比特龙或 Enzalutamide耐药PCa可能成为AR独立性，研究者在P01和P02中的最新结果显示， 其他研究表明，大多数继续表达高水平的AR，其似乎是转录活性的。 因此，该提案中的一个主要假设是AR活性仍然存在，并且有助于肿瘤的发生。 阿比特龙和恩杂鲁胺耐药PCa的生长。此外，我们假设， PCa细胞对AR靶向治疗的反应产生了可以在治疗上利用的漏洞。 因此，总体计划目标是阐明有助于CRPC的临床相关机制， 阿比特龙/恩杂鲁胺耐药性，以确定可以克服这些耐药性的治疗方法 机制和/或利用新的弱点，并评估这些治疗方法在临床前 可以为临床试验奠定基础的模型。本课题的研究内容如下：1）确定和开发 AR介导的细胞抑制机制，2）驱动AR全长和剪接变体的机制 活性和拮抗剂抗性，3）影响去势抵抗的雄激素受体的蛋白激酶 前列腺癌，4）在拮抗剂抗性CRPC中作为AR活性基础的必需基因的鉴定。

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.