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

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.