Bipolar Androgen Therapy for Progressive Castrate Resistant Prostate Cancer

描述（由申请人提供）：本研究项目的重点是对去势抵抗性前列腺癌（CRPC）男性患者的新治疗策略进行临床评价，该策略通过给予“双极雄激素治疗”（BAT），包括每月注射足够的睾酮，以诱导血清睾酮在治疗周期内从超生理水平快速升高，然后下降至接近去势水平。在目前复发性CRPC的治疗模式中，男性接受越来越有效的雄激素剥夺疗法（ADT）治疗。ADT的长期暴露导致治疗耐药性、生活质量降低和去势诱导的代谢综合征的发病率过高。治疗抗性是由于前列腺癌细胞适应性地自动调节雄激素受体（AR）及其变体的表达至足以在长期低雄激素微环境中维持AR信号传导的水平的能力。除了在转录中的作用外，AR已被证明是一种DNA许可因子，在复制中起关键作用，并且必须随着细胞周期的进行而降解。由于超生理睾酮的过度稳定而导致的AR降解的缺乏抑制了DNA再许可，导致随后的细胞周期中的死亡。因此，BAT治疗的基本原理是CRPC细胞对AR的适应性过表达成为一种治疗倾向，可以通过给予超生理剂量的睾酮来利用。本项目中提出的最佳可得技术方法的意义在于，它有可能打破对ADT的抵抗。更重要的是，BAT还可以改善生活质量和功能能力，并最大限度地减少慢性ADT产生的代谢综合征的发病率。该项目中提出的最佳可得技术战略得到了临床前机制研究和试点临床研究数据的支持。这项研究表明，BAT可以安全地用于患有轻微至中度转移性负荷的男性，这些男性在长期ADT治疗中进展。BAT在大多数接受治疗的患者中诱导PSA下降。为了进一步评估BAT作为CRPC的新治疗模式，本项目提出了以下具体目标：（1）进行II期临床试验，测试BAT在男性进展性CRPC中的安全性和有效性。本试验将证实在较大患者队列中进行的初步研究的结果，并测试BAT使CRPC细胞对ADT和二线激素疗法阿比特龙和恩杂鲁胺重新敏感的能力。(2)通过定量循环肿瘤细胞中的AR转录本，评价BAT期间AR的适应性自动调节。本目标的目的是评价循环肿瘤细胞中AR和AR变体的水平，以支持BAT破坏AR的适应性自动调节的假设。(3)开发血浆DNA生物标志物，以评价对BAT的反应。该目标的目的是使用血浆中循环肿瘤DNA的全外显子组测序和液滴数字PCR来鉴定个体患者癌症内的体细胞突变，以产生一组个性化生物标志物，其可以潜在地用于预测和/或监测对BAT的响应。

DESCRIPTION (provided by applicant): The focus of this research project is to perform a clinical evaluation of a new treatment strategy for men with castration resistant prostate cancer (CRPC) through the administration of "Bipolar Androgen Therapy" (BAT) consisting of monthly injections of sufficient testosterone to induce a rapid rise and then fall in serum testosterone from supraphysiologic to near-castrate levels over a treatment cycle. In the current treatment paradigm for recurrent CRPC, men are treated with increasingly more potent androgen deprivation therapies (ADT). The chronic exposure to ADT leads to therapeutic resistance, reduced quality of life and excess morbidity due to development of a castration-induced metabolic syndrome. Therapeutic resistance is due to the ability of prostate cancer cells to adaptively auto-regulate the expression of the androgen receptor (AR) and its variants to sufficient levels to maintain AR signaling in a chronically low androgen microenvironment. Besides its role in transcription, AR has been demonstrated to be a DNA licensing factor that plays a critical role in replication and must be degraded as the cell goes through cycle. Lack of AR degradation due to over- stabilization by supraphysiologic testosterone inhibits DNA re-licensing resulting in death in the subsequent cell cycle. Thus, the rationale for BAT therapy is that adaptive overexpression of AR by CRPC cells becomes a therapeutic liability that can be exploited through the administration of supraphysiologic doses of testosterone. The significance of the BAT approach proposed in this Project is that is has the potential to break resistance to ADT. Of further importance, BAT may also improve quality of life and functional capacity and minimize the morbidity from the metabolic syndrome produced by chronic ADT. The BAT strategy proposed in the project is supported by preclinical mechanistic studies and data from a pilot clinical study. This study demonstrated that BAT could be safely administered to men with minimal to moderate metastatic burden that were progressing on chronic ADT. BAT induced PSA declines in the majority of treated patients. To further evaluate BAT as a new treatment paradigm for CRPC the following Specific Aims are proposed in this Project: (1) Perform a Phase II clinical trial testing the safety and efficacy of BAT in men with progressive CRPC. This trial will confirm the results from the pilot study in a larger cohort of patients and test the abiity of BAT to re- sensitize CRPC cells to ADT and second-line hormone therapies abiraterone and enzalutamide. (2) Evaluate adaptive autoregulation of AR during BAT through quantification of AR transcripts in circulating tumor cells. The goal of this Aim is to evaluate levels of AR and AR variants in circulating tumor cells to support the hypothesis that BAT disrupts adaptive auto-regulation of AR. (3) Develop plasma DNA biomarkers to evaluate response to BAT. The goal of this Aim is to use whole exome sequencing and droplet digital PCR of circulating tumor DNA in plasma to identify somatic mutations within an individual patient's cancer to produce a set of personalized biomarker that can potentially be used to predict and/or monitor response to BAT.