Directed Evolution Restored Castrate Sensitivity in a Patient With Castrate Resistant Metastatic Prostate Cancer.

IF 2.5 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Prostate Pub Date : 2025-08-28 DOI:10.1002/pros.70038

Robert A Gatenby, Alexander R A Anderson, Joel S Brown, Jill Gallaher, Jeffrey Krolick, Dawn Lemanne

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引用次数: 0

Abstract

Objective: For centuries, humans have used directed evolution to promote desired traits in domesticated animals. We hypothesized similar strategies may be employed to steer castrate resistant prostate cancer cells to a castrate sensitive phenotype allowing resumption of Androgen Deprivation therapy (ADT) and prolonging survival.

Methods: Our interdisciplinary team investigated directed evolution to restore castrate sensitivity in a patient with metastatic castrate resistant prostate cancer who could not tolerate available therapeutic agents for castrate resistant disease. Guided by an evolutionary mathematical model and using the PSA/testosterone ratio as a biomarker for intra-tumoral population dynamics, we applied a sequence of testosterone injections as evolutionary selection forces to suppress resistant androgen receptor-upregulated clones and promote proliferation of ADT-responsive clones.

Results: When the PSA/testosterone ratio indicated successful transition to dominant castrate sensitive population, reinstitution of adaptive dosing of ADT has resulted in three stable cycles.

Conclusion: This case suggests that evolution-informed strategies using population-based biomarkers to manipulate intra-tumoral evolution can restore castrate sensitivity in select patients.

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定向进化恢复了去势抵抗性转移性前列腺癌患者的去势敏感性。

目的：几个世纪以来，人类一直使用定向进化来促进家养动物的理想特征。我们假设可以采用类似的策略将去势抵抗性前列腺癌细胞转向去势敏感表型，允许恢复雄激素剥夺治疗（ADT）并延长生存期。方法：我们的跨学科团队研究了定向进化以恢复转移性去势抵抗性前列腺癌患者的去势敏感性，这些患者不能耐受现有的去势抵抗性疾病治疗药物。在进化数学模型的指导下，利用PSA/睾酮比率作为肿瘤内种群动态的生物标志物，我们将一系列睾酮注射作为进化选择力来抑制抗性雄激素受体上调的克隆，并促进adt反应性克隆的增殖。结果：当PSA/睾酮比值表明成功过渡到优势阉割敏感人群时，重新开始适应性给药ADT导致了三个稳定的周期。结论：该病例表明，使用基于群体的生物标志物来操纵肿瘤内进化的进化知情策略可以恢复特定患者的去势敏感性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Prostate 医学-泌尿学与肾脏学

CiteScore

5.10

自引率

3.60%

发文量

180

审稿时长

1.5 months

期刊介绍： The Prostate is a peer-reviewed journal dedicated to original studies of this organ and the male accessory glands. It serves as an international medium for these studies, presenting comprehensive coverage of clinical, anatomic, embryologic, physiologic, endocrinologic, and biochemical studies.