OESTROGENS IN CASTRATION- RESISTANT PROSTATE CANCER: BACK TO THE FUTURE?
The world of castration-resistant prostate cancer (CRPC) is evolving rapidly; data from novel agents are now being presented at a dizzying pace. Why are articles on an ancient drug like diethylstilbestrol (DES) still relevant today?
Despite years of work, we remain uncertain how DES and other oestrogens cause responses in CRPC. In this case, ignorance leads to interesting questions. We have long been able to improve upon agents once a clear mechanism of action is demonstrated; the androgen receptor was targeted by flutamide long before envisioning MDV3100 and ketoconazole inhibition of androgen synthesis long preceded abiraterone. Despite DES activity in CRPC being well-known for decades, we have yet to develop a truly better oestrogen-based CRPC therapy. In part this may be because we still debate the mechanism(s) of action for oestrogens for this disease state.
The authors of the present paper on DES note a plethora of potential actions explaining DES activity in CRPC, including changes in adrenal steroids, microtubules and cell-cycle regulation. Despite these investigators being among the best in their field, it is not clear which (if any) of these potential mechanisms of action are relevant.
Several observations on oestrogenic mechanistic studies in CRPC are not mentioned by the authors, including reports that oestrogens can significantly suppress testosterone and dihydrotestosterone levels in tumour tissue in an oestrogen-receptor-independent manner . These results imply that oestrogens might directly or indirectly inhibit synthesis of intratumoural androgens. From studies on patients with CRPC, oestrogen treatments are known to cause significant declines in serum testosterone despite marked increases in sex-hormone binding globulin (SHBG) . Whether oestrogens directly inhibit intratumoural androgen synthesis or decrease access for ‘free’ serum androgens (or precursors) via SHBG increases is not clear. More work is needed to clarify these issues. These explorations may point the way to better CRPC therapy.