CYP11A1 inhibition as a therapeutic approach for the treatment of castration resistant prostate cancer.

Abstract

340 Background: Castration-resistant prostate cancer (CRPC) is a major cause of cancer mortality worldwide. The mechanisms behind the development of resistance are complex and not fully understood; altered androgen synthesis, androgen receptor (AR) overexpression or gene amplification, and mutations have been indentified. However, tumor growth may still be responsive to therapies that can further suppress de novo intratumoral steroid synthesis upstream of CYP17A1. ODM-208 is an oral, non-steroidal and selective inhibitor of CYP11A1 enzyme that suppresses the synthesis of all steroid hormones and their precursors. Methods: The inhibition of CYP11A1 was measured in vitro by the formation of radiolabelled isocapronic acid in a human adrenal cortex cell line (H295R), and further analysing pregnenolone (Preg) and testosterone (T) formation by ELISA. The tumor growth inhibition of ODM-208 alone or in combination with prednisone (Pred) was studied in VCaP CRPC xenograft where also concentrations of main steroid hormones progesterone (P), corticosterone (CORT) and T in tumors and adrenals were analysed. In addition, plasma ACTH and LH levels were measured at the end of the xenograft study. In dogs an ACTH stimulation test was done. Toxicity studies were conducted in rats and dogs. Results: ODM-208 potently inhibits CYP11A1 and synthesis of Preg and T with nM concentrations in vitro. In the VCaP CRPC xenograft ODM-208 alone and in combination with Pred significantly inhibited tumor growth. Concentrations of T, P and CORT were significantly decreased in the adrenals, indicating strong CYP11A1 inhibition. Also, significantly decreased steroid levels in tumors was observedhe Pred combination increased plasma ACTH levels less than ODM-208 alone, whereas no difference was seen in the LH. In dogs ACTH-stimulated cortisol production was significantly inhibited after single oral dose of ODM-208. In toxicological studies ODM-208 showed expected reversible findings in target tissues, mainly related to the pharmacology. Conclusions: ODM-208 shows promising antitumor activity in preclinical CRPC models with favorable toxicological profile. Thus, ODM-208 might have potential for treating the patients with CRPC.

Contribution of Adrenal Glands to Intratumor Androgens and Growth of Castration-Resistant Prostate Cancer

“…This suggests a reduction in adrenally-derived androgens beyond those achieved by ABI may have clinical benefit in men with CRPC, and is consistent with our observation that tissue androgens and tumor growth were suppressed more strongly by surgical ADX in this study than in previously reported studies using ABI. This suggests that proof-of-concept studies testing agents capable of achieving true ‘non-surgical ADX’ are warranted (such as the recently reported CYP11A inhibitor ODM-208),(69) and that optimal clinical efficacy may be obtained by a combination of CYP11A and CYP17A inhibition. While beyond the scope of the current work, PDX studies testing CYP11A inhibition are planned.…”

Hijacking Sexual Immuno-Privilege in GBM—An Immuno-Evasion Strategy

“…Instead of beginning with cholesterol, steroid-sulfates are utilized, imported by fetal/placental transporters SLC22A11, SLC22A19, and SLCO4A1: the 'side-entry' synthetic route. These GBM then utilize AKR1C1 and AKR1C3 for 'backdoor' steroidogenesis [131,134,135,[137][138][139][140]. Tumors lacking this non-canonical importation (asteroidogenic) were identified by low levels of all five gene transcripts.…”