Prostate Cancer that is resistant to hormonal therapy is now thought to remain sensitive to hormonal manipulations that affect endocrine organs besides the testis. Multiple studies by Geller, Mohler and others have shown that androgens within “androgen resistant” prostate cancer remain well within the range capable of activating the androgen receptor.
There is a strong bias among the community that “castration resistant” prostate cancer (CRPC) utilizes adrenal androgens that it converts into testosterone and dihydrotestosterone (DHT) to drive tumor growth.
The efficacy of ketoconazole and estrogens such as diethylstilbestrol in some patients with CRPC has been ascribed to suppression of adrenal androgen production.
However there has been evidence that prostate cancer is also capable of synthesizing androgens de novo from cholesterol, and determining which pathway should be the primary target in human disease remains unclear.
This study used murine models, in which there are no adrenal androgens available for conversion by the tumor, and assessed whether estrogens inhibit tumoral androgen levels. If so, then the design of future therapies must consider the contribution which de novo steroidogenesis plays in tumor progression.
Our study showed that, indeed, estradiol inhibits tumor androgen levels in prostate cancers grown in castrate male mice. The data implicates de novo steroidogenesis as the primary driver of tissue androgen synthesis in this model.
The study highlights the fact that it is very difficult to achieve truly low tissue androgen levels, even with effective secondary manipulations. Lowering tissue androgens did not reverse, but only slowed tumor growth, supporting the idea that in this model there are other determinants of progression beyond androgens.
Overall the study suggests that effective agents should target both adrenal and de novo steroidogenesis in order to achieve optimal tissue androgen suppression.
Ongoing studies which examine tissue androgens in men treated with abiraterone and other CYP17 inhibitors will provide critical information about the true mechanism of action of these agents.
If these and the new generation of androgen receptor antagonists provide a greater margin of therapeutic benefit, it will spawn a new series of critical randomized studies to improve the treatment of men with this disease.
UroToday