Targeting of CYP17A1 Lyase by VT-464 Inhibits Adrenal and Intratumoral Androgen Biosynthesis and Tumor Growth of Castration Resistant Prostate Cancer.

Sankar N Maity,Jing-Fang Lu,Elsa M Li-Ning-Tapia,John C Araujo,S Ramachandran,Christopher J Logothetis,Guanglin Wu,Eleni Efstathiou,Revekka Gyftaki,Mark A Titus

doi:10.1038/srep35354

Abstract

Cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) is a validated treatment target for the treatment of metastatic castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA) inhibits both 17α-hydroxylase (hydroxylase) and 17,20-lyase (lyase) reactions catalyzed by CYP17A1 and thus depletes androgen biosynthesis. However, coadministration of prednisone is required to suppress the mineralocorticoid excess and cortisol depletion that result from hydroxylase inhibition. VT-464, a nonsteroidal small molecule, selectively inhibits CYP17A1 lyase and therefore does not require prednisone supplementation. Administration of VT-464 in a metastatic CRPC patient presenting with high tumoral expression of both androgen receptor (AR) and CYP17A1, showed significant reduction in the level of both dehydroepiandrosterone (DHEA) and serum PSA. Treatment of a CRPC patient-derived xenograft, MDA-PCa-133 expressing H874Y AR mutant with VT-464, reduced the increase in tumor volume in castrate male mice more than twice as much as the vehicle (P < 0.05). Mass spectrometry analysis of post-treatment xenograft tumor tissues showed that VT-464 significantly decreased intratumoral androgens but not cortisol. VT-464 also reduced AR signaling more effectively than abiraterone in cultured PCa cells expressing T877A AR mutant. Collectively, this study suggests that VT-464 therapy can effectively treat CRPC and be used in precision medicine based on androgen receptor mutation status.

Highlights

DHEA can be converted into potent androgen DHT in prostate[3]
Inhibition of 17α-hydroxylase by AA depletes the adrenal biosynthesis of glucocorticoids, which induces an increase in adrenocorticotropic hormone from the anterior pituitary gland producing side effects that are only partially suppressed by co-administration of the cortisol replacement prednisone[7]
The patient was treated with LHRH antagonist, Leuprolide, and androgen receptor (AR) antagonist Bicalutamide to January 2012 followed by 3 months of somatostatin analog, Lanreotide, due to rising Prostate specific antigen (PSA)

Summary

Introduction

Published study demonstrated that CRPC tumors contain key steroidogenic enzymes including CYP17A1 that can drive intratumoral de novo steroid biosynthesis[4]. Medical castration treatment inhibits production of testicular testosterone but does not impact production of adrenal DHEA or intratumoral androgen, which can be responsible for driving CRPC. Inhibition of 17α-hydroxylase by AA depletes the adrenal biosynthesis of glucocorticoids, which induces an increase in adrenocorticotropic hormone from the anterior pituitary gland producing side effects that are only partially suppressed by co-administration of the cortisol replacement prednisone[7]. CYP17A1 inhibition provides significant benefits to CRPC patients due to suppression of androgen signaling, which stimulates prostate tumor growth. A selective inhibitor of CYP17A1 lyase has the potential to improve the side effect profile of the AA-prednisone therapy. The effects of VT-464 were compared to those of abiraterone or its orally available acetate form

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