Anticancer Activity of a Novel Selective CYP17A1 Inhibitor in Preclinical Models of Castrate-Resistant Prostate Cancer

Abstract

VT-464 is a novel, nonsteroidal, small-molecule CYP17A1 inhibitor with 17,20-lyase selectivity. This study evaluates the anticancer activity of VT-464 compared with abiraterone (ABI) in castrate-resistant prostate cancer cell lines and xenograft models that are enzalutamide (ENZ)-responsive (C4-2) or ENZ-resistant (MR49C, MR49F). In vitro, androgen receptor (AR) transactivation was assessed by probasin luciferase reporter, whereas AR and AR-regulated genes and steroidogenic pathway enzymes were assessed by Western blot and/or qRT-PCR. The MR49F xenograft model was used to compare effects of oral VT-464 treatment to vehicle and abiraterone acetate (AA). Steroid concentrations were measured using LC-MS chromatography. VT-464 demonstrated a greater decrease in AR transactivation compared with ABI in C4-2 and both ENZresistant cell lines. At the gene and protein level, VT-464 suppressed the AR axis to a greater extent compared with ABI. Gene transcripts StAR, CYP17A1, HSD17B3, and SRD5A1 increased following treatment with ABI and to a greater extent with VT-464. In vivo, intratumoral androgen levels were significantly lower after VT-464 or AA treatment compared with vehicle, with the greatest decrease seen with VT-464. Similarly, tumor growth inhibition and PSA decrease trends were greater with VT-464 than with AA. Finally, an AR-antagonist effect of VT-464 independent of CYP17A1 inhibition was observed using luciferase reporter assays, and a direct interaction was confirmed using an AR ligand binding domain biolayer interferometry. These preclinical results suggest greater suppression of the AR axis with VT-464 than ABI that is likely due to both superior selective suppression of androgen synthesis and AR antagonism.

Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer

“…The authors speculate that this resulted from patient crossover in Europe and North America to abiraterone and enzalutamide, which had been recently approved and were widely available in these areas. Our data and data from others raise the possibility that the inability of orteronel to inhibit the AR may limit its clinical efficacy and has played a factor in its failure to affect the overall survival of patients with CRPC (36).…”

“…In particular, galeterone has been reported to decrease AR activity in part through a mechanism that involves degradation of the receptor (16,(30)(31)(32)(33). Abiraterone and its metabolite, D4A, have also been suggested to directly inhibit AR activity and impact AR protein levels, but results have varied across studies, and the clinical relevance of D4A has yet to be established (16,(31)(32)(33)(34)(35)(36). Seviteronel, a CYP17 lyase-selective inhibitor, was also recently reported to have direct effects on AR function, although the molecular basis for this activity was not determined (37).…”

Oral simvastatin administration delays castration-resistant progression and reduces intratumoral steroidogenesis of LNCaP prostate cancer xenografts

“…23 Briefly, tumors (50-150 mg) were homogenized in two volumes of water using a bead mill (Precellys Tissue Homogenizer, Rockville, MD, USA). Internal standards (deuterated testosterone/DHT; C/D/ N isotopes) were added and homogenates were extracted twice with 60/40 hexane/ethyl acetate.…”

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

“…Darolutamide is characterised by a different chemical scaffold from its cognate antagonists, and is able to antagonise AR mutants F876L, W741L and T877A [121] . Figure 4), a non-steroidal CYP17A1 inhibitor with 17,20-lyase selectivity (see above), has been found to show AR-antagonist activity independent of CYP17A1 enzyme inhibition, with evidence of direct binding to the AR LBD [40] . Similarly, also galeterone (3, Figure 4) is a competitive AR antagonist mediated by binding of the drug to the steroid-binding pocket of AR and concomitantly inhibiting T biosynthesis through inhibition of CYP17A1 lyase activity [36] .…”

“…Seviteronel (VT-464), anorally administered nonsteroidal CYP17A1 lyase inhibitor, is at the present under clinical development [40] . Similar to galeterone, seviteronel works downstream of abiraterone to inhibit CYP17A1 lyase and does not cause the same degree of mineralocorticoid production.…”