AUA 2011 - Clusterin antisense inhibitor OGX-011 synergizes activity of second generation anti-androgen, MDV3100, in castrate resistant prostate cancer model - Session Highlights

WASHINGTON, DC USA ( - This presentation importantly shows that dual inhibition of clusterin using OGX-011 in combination with the anti-androgen MDV3100 is superior to either drug alone.

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.


The opinions expressed in this article are those of the Contributing Editor and do not necessarily reflect the viewpoints of the American Urological Association.



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