Bipolar Androgen Therapy for Progressive Castrate Resistant Prostate Cancer

双极雄激素治疗进行性去势抵抗性前列腺癌

• 批准号: 9262192
• 负责人: Samuel R Denmeade
• 金额: $ 26.15万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9262192
• 关键词: Acetates; Activities of Daily Living; Adrenal Glands; Agonist; Androgen Analogues; Androgen Antagonists; Androgen Receptor; Androgen Therapy; Androgens; Antibodies; Biological Assay; Biological Markers; Blood; CYP17A1 gene; Cancer Patient; Castration; Cell Cycle; Cells; Cessation of life; Chronic; Clinical; Clinical Data; Clinical Research; Clinical Trials; Custom; DNA; Data; Development; Dose; Down-Regulation; Effectiveness; Environment; Exons; Exposure to; Gene Amplification; Gene Mutation; Gene Rearrangement; Genes; Genetic Transcription; Goals; Growth; Homeostasis; Human; In Vitro; Injection of therapeutic agent; Length; Licensing; Licensing Factor; Ligands; Malignant neoplasm of prostate; Mediating; Messenger RNA; Metabolic syndrome; Metastatic Prostate Cancer; Monitor; Morbidity - disease rate; Mutation; Neoplasm Circulating Cells; Neoplasm Metastasis; Patients; Phase II Clinical Trials; Pilot Projects; Plasma; Play; Property; Quality of life; Randomized; Receptor Signaling; Recurrence; Research; Research Project Grants; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; Safety; Sampling; Serum; Sex Functioning; Site; Somatic Mutation; Stress; Surveys; Testing; Testosterone; Therapeutic; Time; Transcript; Variant; abiraterone; androgen deprivation therapy; androgen sensitive; base; burden of illness; cancer biomarkers; cancer cell; castration resistant prostate cancer; clinical material; cohort; digital; exome sequencing; falls; hormone therapy; improved; in vivo; individual patient; inhibitor/antagonist; men; metabolic abnormality assessment; objective response rate; older men; overexpression; palliative; pre-clinical; preclinical study; prostate cancer cell; prostate cancer cell line; public health relevance; research clinical testing; response; safety testing; therapy resistant; treatment response; treatment strategy; tumor DNA; tumor heterogeneity

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.

描述（由申请人提供）：该研究项目的重点是对具有“双极雄激素治疗”（BAT）的临床评估对具有casttratiation castration的抗cast割前列腺癌（CRPC）的新治疗策略进行临床评估（BAT），该策略由每月注射足够的注射足够的注射剂，可诱导高速静脉体的静态疗法，从而在高度静脉内降低了近距离疾病，以迅速升高，从而迅速降低了近距离的培训。在当前的复发性CRPC治疗范式中，男性接受了越来越有效的雄激素剥夺疗法（ADT）的治疗。长期暴露于ADT会导致治疗性抗性，降低的生活质量以及由于cast割引起的代谢综合征的发展而导致的发病率过多。治疗性耐药性是由于前列腺癌细胞适应自动调节雄激素受体（AR）的能力及其变体在慢性低雄激素微环境中维持AR信号传导的能力。除了其在转录中的作用外，AR已被证明是在复制中起关键作用的DNA许可因素，并且在细胞通过周期时必须降解。由于超生理睾丸激素过度稳定而缺乏AR降解会抑制DNA重新许可，从而导致随后的细胞周期死亡。因此，蝙蝠治疗的基本原理是，CRPC细胞对AR的自适应过表达成为一种治疗责任，可以通过给予睾丸激素的超生理学剂量来利用这种责任。该项目提出的蝙蝠方法的意义在于有可能破坏对ADT的阻力。更重要的是，BAT还可以提高生活质量和功能能力，并最大程度地减少慢性ADT产生的代谢综合征的发病率。该项目中提出的BAT策略得到了临床前机械研究和试点临床研究的数据的支持。这项研究表明，可以将BAT安全地施用给在慢性ADT上发展的中度转移负担至中度负担最小至中度的男性。 BAT诱导的大多数治疗患者的PSA下降。为了进一步评估BAT作为CRPC的新治疗范式，该项目提出了以下特定目标：（1）执行II期临床试验，以测试BAT在渐进式CRPC男性中的安全性和功效。该试验将在较大的患者队列中确认试验研究的结果，并测试BAT的量化，以使CRPC细胞对ADT和二线激素治疗阿比里特酮和乙酰氨酰胺。 （2）通过定量循环肿瘤细胞中的AR转录本来评估BAT期间AR的适应性自动调节。该目标的目的是评估循环肿瘤细胞中AR和AR变体的水平，以支持BAT破坏AR的自适应自动调节的假设。 （3）开发血浆DNA生物标志物来评估对BAT的反应。该目的的目的是使用血浆中循环肿瘤DNA的整个外显子组测序和液滴数字PCR来鉴定单个患者癌症中的体细胞突变，以产生一组个性化的生物标志物，这些个性化生物标志物可能有可能用于预测和/或监测对BAT的反应。