Maximal Targeted Inhibition of Androgen Signaling for Prostate Cancer Therapy

临床和实验室证据继续表明，雄激素和雄激素受体 (AR)是治疗/预防早期和晚期前列腺癌的最佳可用靶点。 已经设计了许多临床试验来干扰AR通路，但实际上很少有 通过展示最大靶点干扰来评估治疗的有效性。这项建议 旨在使用新辅助临床试验形式严格评估MAXAL的有效性 通过测量前列腺内雄激素水平来抑制雄激素，并以最大 将DHT水平抑制为零。这种方法的临床益处将通过以下方式进行评估 肿瘤分级、分期、切缘、肿瘤细胞凋亡及雄激素调节基因的检测 表情。目标是： 目的1.确定获得特定(低)前列腺内雄激素水平和 通过直接评估肿瘤的存活率、凋亡、增殖和 雄激素调控的基因表达。 目的2.评估和比较能够维持雄激素活性的替代机制。 原发癌和转移性前列腺癌的去势环境：(I)肾上腺雄激素的利用； (Ii)主动的雄激素转运；(Iii)肿瘤前列腺上皮对雄激素的生物合成。 目的3.评价新靶向疗法活性的临床前疗效及作用机制(S) 旨在抑制睾丸、肾上腺和前列腺雄激素代谢和/或AR信号。 这项研究项目的完成将：1)证明努力的有效性(或缺乏) 去除组织雄激素；2)测量肿瘤对特定雄激素水平和AR抑制的反应；以及 3)为针对AR而设计的其他方法提供背景。

Clinical and laboratory evidence continues to demonstrate that androgens and the androgen receptor (AR) are the best available targets for treating/preventing both early and advanced prostate cancer. Numerous clinical trials have been designed to interfere with the AR pathway, but few have actually assessed the effectiveness of the therapy by demonstrating maximal target interference. This proposal aims to use a neoadjuvant clinical trial format to rigorously evaluate the effectiveness of maximal androgen suppression through measurements of intraprostatic androgen levels, and to target a maximal suppression of DHT levels to zero. The clinical benefit of this approach will be evaluated through measurements of tumor grade, stage, margin, tumor cell apoptosis and androgen-regulated gene expression. The aims are: Aim 1. To determine the anti-tumor efficacy of achieving specific (low) intraprostatic androgen levels and inhibition of AR-signaling through direct assessments of tumor viability, apoptosis, proliferation, and androgen-regulated gene expression. Aim 2. To evaluate and compare alternative mechanisms capable of maintaining androgen-activity in a 'castrate' environment in both primary and metastatic prostate cancer: (i) utilization of adrenal androgens; (ii) active androgen transport; (iii) cfenovo biosynthesis of androgens by neoplastic prostate epithelium. Aim 3. To evaluate the pre-clinical efficacy and mechanism(s) of activity of new targeted therapies designed to inhibit testicular, adrenal, and prostatic androgen metabolism and/or AR signaling. The completion of this research project will: 1) demonstrate the efficacy (or lack thereof) of efforts to ablate tissue androgens; 2) measure tumor responses to specific androgen levels and AR inhibition; and 3) provide a context for additional approaches designed to target the AR.