title: 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 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.
authors.affiliation: Vancouver Prostate Centre, Department of Urological Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Toren
authors.affiliation: Vancouver Prostate Centre, Department of Urological Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: Soojin
authors.initials: S
authors.lastname: Kim
authors.affiliation: Vancouver Prostate Centre, Department of Urological Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Pham
authors.affiliation: Vancouver Prostate Centre, Department of Urological Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: Azzra
authors.initials: A
authors.lastname: Mangalji
authors.affiliation: Vancouver Prostate Centre, Department of Urological Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: Hans
authors.initials: H
authors.lastname: Adomat
authors.affiliation: Vancouver Prostate Centre, Department of Urological Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: Emma S Tomlinson
authors.initials: ES
authors.lastname: Guns
authors.affiliation: Vancouver Prostate Centre, Department of Urological Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: Amina
authors.initials: A
authors.lastname: Zoubeidi
authors.affiliation: Viamet Pharmaceuticals, Durham, North Carolina.
authors.forename: William
authors.initials: W
authors.lastname: Moore
authors.affiliation: Vancouver Prostate Centre, Department of Urological Sciences, University of British Columbia, Vancouver, Canada. m.gleave@ubc.ca.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
mesh_terms: D000736:Androstenes / Q000008:administration & dosage; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D009281:Naphthalenes / Q000008:administration & dosage* / Q000494:pharmacology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000008:administration & dosage* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000736:Androstenes; D000970:Antineoplastic Agents; D009281:Naphthalenes; D011944:Receptors, Androgen; D014230:Triazoles; C000601472:VT-464; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; C089740:abiraterone