Gatenby Robert A, Anderson Alexander R A, Brown Joel S, Gallaher Jill, Krolick Jeffrey, Lemanne Dawn
Integrated Mathematical Oncology Department, Moffitt Cancer Center, Tampa, Florida, USA.
Cancer Biology and Evolution Program, Moffitt Cancer Center, Tampa, Florida, USA.
Prostate. 2025 Dec;85(16):1562-1567. doi: 10.1002/pros.70038. Epub 2025 Aug 28.
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.
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.
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.
This case suggests that evolution-informed strategies using population-based biomarkers to manipulate intra-tumoral evolution can restore castrate sensitivity in select patients.
几个世纪以来，人类一直利用定向进化来培育家畜的理想性状。我们推测，类似的策略或许可用于引导去势抵抗性前列腺癌细胞转变为去势敏感性表型，从而恢复雄激素剥夺疗法（ADT）并延长生存期。
我们的跨学科团队对一名转移性去势抵抗性前列腺癌患者进行了定向进化研究，以恢复其去势敏感性，该患者无法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，以PSA/睾酮比值作为肿瘤内种群动态的生物标志物，我们应用一系列睾酮注射作为进化选择力，以抑制雄激素受体上调的耐药克隆，并促进对ADT有反应的克隆的增殖。
当PSA/睾酮比值表明已成功转变为占主导地位的去势敏感群体时，重新采用适应性剂量的ADT已产生三个稳定周期。
该病例表明，利用基于种群的生物标志物来操纵肿瘤内进化的进化导向策略可恢复部分患者的去势敏感性。
