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: 8669473
• 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/8669473
• 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; Evaluation; Exons; Exposure to; Gene Amplification; Gene Rearrangement; Genes; Genetic Transcription; Goals; Growth; Heterogeneity; Homeostasis; Human; In Vitro; Individual; 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; PC3 cell line; Patients; Phase II Clinical Trials; Pilot Projects; Plasma; Play; Property; Quality of life; Randomized; Receptor Gene; Receptor Signaling; Recurrence; Regulation; 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; base; burden of illness; castration resistant prostate cancer; clinical material; cohort; deprivation; digital; exome sequencing; falls; hormone therapy; improved; in vivo; inhibitor/antagonist; men; metabolic abnormality assessment; older men; overexpression; palliative; pre-clinical; preclinical study; prostate cancer cell; public health relevance; research clinical testing; response; safety testing; therapy development; treatment strategy; tumor

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通过每月注射一次的“双极雄激素疗法”（BAT）对患有去势抵抗性前列腺癌（CRPC）男性的新治疗策略进行临床评估足够的睾酮以诱导血清睾酮在一个治疗周期内从超生理水平快速上升然后下降到接近阉割水平。在当前复发性 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)。长期接触 ADT 会导致治疗抵抗、生活质量下降以及由于阉割引起的代谢综合征的发生而导致发病率过高。治疗抵抗是由于前列腺癌细胞能够适应性地自动调节雄激素受体（AR）及其变体的表达至足够的水平，以在长期低雄激素微环境中维持AR信号传导。除了在转录中的作用外，AR 还被证明是一种 DNA 许可因子，在复制中发挥着关键作用，并且必须在细胞周期过程中被降解。由于超生理睾酮的过度稳定而导致 AR 降解不足，会抑制 DNA 重新许可​​，导致随后的细胞周期死亡。因此，BAT 疗法的基本原理是，CRPC 细胞对 AR 的适应性过度表达成为一种治疗责任，可以通过施用超生理剂量的睾酮来利用。本项目提出的 BAT 方法的意义在于它有可能打破 ADT 的阻力。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 BAT 策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度至中度转移负担且正在接受慢性 ADT 治疗的男性。 BAT 导致大多数接受治疗的患者 PSA 下降。为了进一步评估 BAT 作为 CRPC 的新治疗范例，本项目提出以下具体目标： (1) 进行 II 期临床试验，测试 BAT 对进展性 CRPC 男性的安全性和有效性。该试验将证实在更大范围的患者中进行的试点研究的结果，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) 通过量化循环肿瘤细胞中的 AR 转录本来评估 BAT 期间 AR 的适应性自动调节。该目标的目标是评估循环肿瘤细胞中 AR 和 AR 变异的水平，以支持 BAT 破坏 AR 适应性自动调节的假设。 (3) 开发血浆 DNA 生物标志物来评估对 BAT 的反应。该目标的目标是使用全外显子组测序和血浆中循环肿瘤 DNA 的液滴数字 PCR 来识别个体患者癌症内的体细胞突变，从而产生一组个性化生物标志物，可用于预测和/或监测对癌症的反应。蝙蝠。