Androgen is essential for prostate cancer progression. Abiraterone and enzalutamide are the next generation of AR pathway inhibitors (ARPIs) for the treatment of castration resistant prostate cancer (CRPC). Currently, there is no approaches for ARPIs resistant prostate cancer and limited clues for further suppression on AR pathway.
In a study published in Cell Reports Medicine, a research team led by LI Zhenfei of the CAS Center for Excellence in Molecular Cell Science of the Chinese Academy of Sciences identify 3βHSD1 as a therapeutic target for abiraterone- and enzalutamide-resistant prostate cancer.
The researchers investigated the resistance mechanism of abiraterone and enzalutamide with various cell lines, mouse models and clinical specimens. Increasing of 3βHSD1 activity was found in drug resistant cell lines and patients. Inhibitors of 3βHSD1 successfully suppressed the development of abiraterone- and enzalutamide-resistant prostate cancer.
In a clinical trial (ChiCTRUE800015510) to regulate abiraterone metabolism in patients, they reveal a different drug metabolic feature between patients from China and the western countries. The SRD5A inhibitor, dutasteride, regulates abiraterone metabolism mildly in Chinese patients due to their intrinsic low SRD5A activity. The enzyme, 3βHSD1, is a more ideal target for Chinese patients for prostate cancer therapy.
Biochanin A (BCA) and its derivatives, including daidzein, are identified as 3βHSD1 inhibitors and rich in food and some Chinese traditional medicine. Patients with higher plasma daidzein respond better to abiraterone, shedding light on further dietary management and disease treatment. A related clinical trial is undergoing in Shanghai Tongji hospital (ChiCTR2000034019).
HUANG Shengsong’s team from Tongji University-affiliated Tongji hospital also participates in the study.