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Updated: Sep 9, 2025
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Published on: March 6, 2018
Directed Evolution Restored Castrate Sensitivity in a Patient With Castrate Resistant Metastatic Prostate Cancer
Robert A Gatenby1,2, Alexander R A Anderson1,2, Joel S Brown1,2
1Integrated Mathematical Oncology Department, Moffitt Cancer Center, Tampa, Florida, USA.
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.
