Active DHEA uptake in the prostate gland correlates with aggressive prostate cancer.

Strategies for patient stratification and early intervention are required to improve clinical benefits for patients with prostate cancer. Here, we found that active DHEA utilization in the prostate gland correlated with tumor aggressiveness at early disease stages, and 3ßHSD1 inhibitors were promising for early intervention. [3H]-labeled DHEA consumption was traced in fresh prostatic biopsies ex vivo. Active DHEA utilization was more frequently found in patients with metastatic disease or therapy-resistant disease. Genetic and transcriptomic features associated with the potency of prostatic DHEA utilization were analyzed to generate clinically accessible approaches for patient stratification. UBE3D, by regulating 3ßHSD1 homeostasis, was discovered to be a regulator of patient metabolic heterogeneity. Equilin suppressed DHEA utilization and inhibited tumor growth as a potent 3ßHSD1 antagonist, providing a promising strategy for the early treatment of aggressive prostate cancer. Overall, our findings indicate that patients with active prostatic DHEA utilization might benefit from 3ßHSD1 inhibitors as early intervention.

Management of prostate cancer by targeting 3ßHSD1 after enzalutamide and abiraterone treatment.

Novel strategies for prostate cancer therapy are required to overcome resistance to abiraterone and enzalutamide. Here, we show that increasing 3ßHSD1 after abiraterone and enzalutamide treatment is essential for drug resistance, and biochanin A (BCA), as an inhibitor of 3ßHSD1, overcomes drug resistance. 3ßHSD1 activity increases in cell lines, biopsy samples, and patients after long-term treatment with enzalutamide or abiraterone. Enhanced steroidogenesis, mediated by 3ßHSD1, is sufficient to impair enzalutamide function. In patients, accelerated abiraterone metabolism results in a decline of plasma abiraterone as disease progresses. BCA inhibits 3ßHSD1 and suppresses prostate cancer development alone or together with abiraterone and enzalutamide. Daidzein, a BCA analog of dietary origin, is associated with higher plasma abiraterone concentrations and prevented prostate-specific antigen (PSA) increases in abiraterone-resistant patients. Overall, our results show that 3ßHSD1 is a promising target to overcome drug resistance, and BCA suppresses disease progression as a 3ßHSD1 inhibitor even after abiraterone and enzalutamide resistance.