Activity of VT-464, a selective CYP17 lyase inhibitor, in the LNCaP prostate cancer xenograft model.

Abstract

64 Background: With the recent FDA approval of abiraterone acetate, CYP17 (17α hydroxylase/C17, 20-lyase) has become a proven target for the treatment of castration- resistant prostate cancer. Inhibition of CYP17-lyase causes a decrease in circulating androgens, severely hampering activation of the androgen receptor signaling pathway that prostate cancer relies on for proliferation. However, inhibition of CYP17-hydroxylase, a second enzymatic activity of CYP17, leads to an increase in upstream steroids that can cause mineralocorticoid excess syndrome as well as a decrease in cortisol production. VT-464 is a novel, selective CYP17 lyase inhibitor with decreased activity against CYP17 hydroxylase. The study objectives were to observe the effects of VT-464 in a prostate cancer xenograft model and to compare its activity to abiraterone acetate and surgical castration. Methods: SCID mice were implanted subcutaneously with LNCaP cells. When tumors reached 100mm3, mice were randomized to receive vehicle (0.5% CMC in saline, 5ml/kg), or VT-464 at 15, 50, or 100mg/kg p.o. bid. A second cohort of LNCaP tumor-bearing mice received vehicle, surgical castration, or VT-464 or abiraterone acetate at 100mg/kg p.o. bid for 28 days. Results: In the LNCaP xenograft model, percent growth inhibition (± S.E.) of 9.6 (±15.6), 38.5(±12.4), and 73.9 (±13.2) was observed on day 21 of treatment for the VT-464 doses of 15, 50, and 100 mg/kg, respectively. VT-464 -treated (100mg/kg) mice had a significantly reduced tumor volume ratio (V/V0) on day 28 compared to control and abiraterone acetate (p<0.05, p<0.01, respectively). Reduction in tumor volume ratios were similar between VT-464-treated (100 mg/kg) and castrate animals. Conclusions: VT-464 exhibited dose-dependent growth inhibition with significantly reduced tumor growth at the highest dose compared to abiraterone acetate. The reduction in tumor growth in VT-464-treated animals was similar to that of castrate animals. These preclinical results show promising activity of VT-464 in the treatment of prostate cancer.