BACKGROUND Androgen deprivation therapy improves the survival of castration-resistant prostate cancer (CRPC) patients, yet ultimately fails with debilitating side effects. Supraphysiological testosterone (SPT)-based therapy produces clinical responses with improved quality of life in a subset of patients. Currently, no information defines a durable response to SPT. OBJECTIVE To identify key molecular phenotypes underlying SPT response to improve patient selection and guide combination treatment to achieve a durable response. DESIGN, SETTING, AND PARTICIPANTS A patient-derived xenograft (PDX) preclinical trial was performed with 13 CRPC PDXs to identify molecular features associated with SPT response. Comprehensive intratumoral androgen, tumor growth, and integrated transcriptomic and protein analyses were performed in three PDXs resistant to the newer androgen receptor (AR) pathway inhibitor enzalutamide (ENZ) to define SPT response and resistance. INTERVENTION Testosterone cypionate. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS SPT efficacy was evaluated by PDX growth, prostate-specific antigen (PSA) change, and survival. Intratumoral androgens were analyzed using mass spectrometry. Global transcriptome analysis was performed using RNA sequencing, and confirmed by quantitative real-time polymerase chain reaction and immunohistochemistry. Log-rank and Mann-Whitney tests were used for survival and molecular analyses, respectively. RESULTS AND LIMITATIONS A durable SPT responder was identified, presenting robust repressions of ARv7 and E2F transcriptional outputs, and a DNA damage response (DDR) transcriptomic program that were altogether restored upon SPT resistance in the transient responder. ENZ rechallenge of SPT-relapsed PDXs resulted in PSA decreases but tumor progression. CONCLUSIONS SPT produces a durable response in AR-pathway inhibitor ENZ CRPC that is associated with sustained suppression of ARv7 and E2F transcriptional outputs, and the DDR transcriptome, highlighting the potential of combination treatments that maintain suppression of these programs to drive a durable response to SPT. PATIENT SUMMARY Patients with ENZ-resistant prostate cancer have very limited treatment options. Supraphysiological testosterone presents a prominent option for improved quality of life and a potential durable response in patients with sustained suppression on ARv7/E2F transcriptional outputs and DNA repair program.

中文翻译：

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耐恩杂鲁胺的前列腺癌对超生理性睾丸激素的持久反应与患者来源异种移植物中的多方面生长抑制和受损的DNA损伤反应转录组计划有关。

背景技术雄激素剥夺疗法改善了去势抵抗性前列腺癌（CRPC）患者的存活率，但最终以使人衰弱的副作用而失败。基于超生理性睾丸激素（SPT）的疗法可在部分患者中产生具有改善的生活质量的临床反应。当前，没有信息定义对SPT的持久响应。目的确定SPT反应的关键分子表型，以改善患者选择并指导联合治疗以获得持久的反应。设计，地点和参与者使用13个CRPC PDX进行了患者源异种移植（PDX）临床前试验，以鉴定与SPT反应相关的分子特征。全面的肿瘤内雄激素，肿瘤生长，并在三种对较新的雄激素受体（AR）途径抑制剂enzalutamide（ENZ）有抗性的PDX中进行了转录组和蛋白质组分析，以定义SPT反应和抗性。干预睾丸激素环磷酸酯。结果测量和统计分析SPT疗效通过PDX的生长，前列腺特异性抗原（PSA）的变化和存活率进行评估。使用质谱分析瘤内雄激素。使用RNA测序进行全局转录组分析，并通过实时定量聚合酶链反应和免疫组织化学证实。对数秩和Mann-Whitney检验分别用于生存率和分子分析。结果与局限性鉴定出一种持久的SPT应答者，表现出对ARv7和E2F转录输出的强大抑制作用，以及DNA损伤反应（DDR）转录组程序，该程序在瞬时应答器中因SPT抗性而完全恢复。ENZ对SPT复发的PDX的再攻击导致PSA降低，但肿瘤进展。结论SPT在AR途径抑制剂ENZ CRPC中产生持久应答，与ARv7和E2F转录输出以及DDR转录组的持续抑制有关，这突出了联合治疗可保持抑制这些程序的潜力，从而推动对SPT的持久应答。 。患者总结耐ENZ的前列腺癌患者的治疗选择非常有限。