Prostatic cancer and hormones

MDV3100

Medivation Inc and Astellas Pharma Inc., announced positive Phase I/II results for MDV3100, an androgen receptor antagonist, for the treatment of castration-resistant prostate cancer (http://www.prnewswire.com/news-releases/medivation-and-astellas-announce-publication-in-the-lancet-of-positive-efficacy-data-from-phase-1-2-trial-of-mdv3100-in-advanced-prostate-cancer-patients-90883649.html).

The failure of previously employed androgen receptor antagonists over time is thought to occur due to a robust upregulation of the androgen receptor in response to tonic inhibition (a common homeostatic response)(Chen et al., 2004, Nat. Med., 10:33–39), resulting in a subsequent revelation of a weak partial agonist action of these anti-androgen receptor compounds. Thus, androgen action by the very agents used to initially block it may end up supporting the prostate cancer. This latter phenomenon may be responsible for the notion of androgen-independent (a.k.a. castration-resistant or hormone-refractory) prostate cancer. MDV3100 appears to have virtually no agonist effects (Jung et al., 2010, J. Med. Chem., 53:2779–2796, http://pubs.acs.org/doi/abs/10.1021/jm901488g ) at the level of the androgen receptor, and is apparently clinically effective in treating so-called androgen-independent prostatic cancer.

So, what is the source of androgen for post-castration patients? The adrenal glands! The adrenal cortex produces androgens which can interact with androgen receptors directly or via peripheral conversion to testosterone and dihydrotestosterone. Adrenal androgen output is independent of the hypothalamo-pituitary-gonadal axis, and thus is not influenced by physical castration or by treatment with LHRH super-agonists (pharmacological shut down the hypothalamo-pituitary axis at the level of the pituitary by LHRH receptor desensitization). Adrenal androgen output is physiologically significant, as it is responsible for pubic hair development, which precedes true pubertal gonadal activation (Auchus and Rainy, 2004, Clin Endocrinol (Oxf) 60:288–296), and is sufficient to affect, and may be responsible for, the timing the onset of puberty in primates (Remer et al., 2010, J Clin Endocrinol Metab. 2010 Apr 6. ; Fraser et al., 2005, Pediatr Res., 57:141-8).

Thus, the adrenals as a source of androgen may indeed be sufficient to support long term prostate cancer growth in the absence of the testes, hence the need for a continued, and complete, androgen receptor antagonism. MDV3100, a full androgen receptor antagonist, is promising in this regard, and further provides us with a better understanding of the nature of the hormone-dependent cancers, and therefore how to approach them therapeutically.

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