Clusterin is upregulated with castration and in CRPC. OGX-011 is an antisense oligonucleotide that synergistically enhances both castration and chemotherapies in prostate cancer (CaP) models. This research tested whether OGX-011 sensitized MDV3100 and delayed castrate-resistant progression in LNCaP model. Effects of monotherapy vs. combination therapy using MDV3100 and OGX-011 regimens on AR-positive LNCaP cell growth rates, protein, and gene expression were analyzed using crystal violet assay, flow cytometry, western blotting and RT-PCR, respectively. AR transcriptional activity was measured by PSA-luciferase reporter assay, while AR degradation was assessed by cycloheximide chase assay. The effects combination treatment on castrate-resistant LNCaP tumor growth was assessed in castrated male athymic mice.
The combination of OGX-011 + MDV3100 had a synergistic effect and more potently suppressed LNCaP cell growth rates in a dose and time dependent manner compared to OGX-011 or MDV monotherapy. PARP cleavage, sub G0/G1 apoptotic fraction and repressed AKT phosphorylation was most enhanced with combined therapy. A particularly novel finding was that OGX-011 accelerated AR degradation and repressed AR transcriptional activity in combination with MDV3100. In mice, combined OGX-011 + MDV3100 significantly delayed castration-resistant LNCaP tumor progression compared to scramble antisense oligonucleotide + MDV3100 at 12weeks. OGX-011 and MDV3100 are in Phase III trials, but not as combined therapy.
Presented by Martin Gleave, et al. at the American Urological Association (AUA) Annual Meeting - May 14 - 19, 2011 - Walter E. Washington Convention Center, Washington, DC USA
Reported for UroToday by Christopher P. Evans, MD, FACS, Professor and Chairman, Department of Urology, University of California, Davis, School of Medicine.