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 ENZ-resistant 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.
Highlights
Recent clinical trials have clearly established that castrate-resistant prostate cancer (CRPC) continues to remain sensitive to agents that inhibit the androgen receptor (AR) pathway [1, 2]
In the ENZ-resistant MR49C and MR49F cell lines, only VT-464 demonstrated decreases compared with control, whereas ABI was similar to controls or increased transactivation
This study demonstrated more potent inhibition of androgen synthesis by VT-464 in CRPC models compared with ABI in the ENZ-resistant cells, MR49C and MR49F
Summary
Recent clinical trials have clearly established that castrate-resistant prostate cancer (CRPC) continues to remain sensitive to agents that inhibit the androgen receptor (AR) pathway [1, 2]. Abiraterone acetate (AA) in combination with prednisone has demonstrated improved overall survival (OS) in both pre- and postchemotherapy patients with CRPC in phase III trials [2, 4]. AA and irreversibly inhibits both CYP17 hydroxylase and lyase [5]. Inhibition of 17a-hydroxylase by AA prevents the synthesis of glucocorticoids and produces side effects due to mineralocorticoid excess, which are partially suppressed by coadministration of the cortisol replacement, prednisone [6]. The development of selective CYP17A1 lyase inhibitors has potential to obviate the
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