MP24-04 CO-TARGETING CLUSTERIN AND THE ANDROGEN RECEPTOR WITH OGX-011 AND AN AR ANTISENSE SYNERGISTICALLY ENHANCES ACTIVITY OF ENZALUTAMIDE-RESISTANT PROSTATE CANCER (2014)

You have accessJournal of UrologyProstate Cancer: Basic Research I1 Apr 2014MP24-04 CO-TARGETING CLUSTERIN AND THE ANDROGEN RECEPTOR WITH OGX-011 AND AN AR ANTISENSE SYNERGISTICALLY ENHANCES ACTIVITY OF ENZALUTAMIDE-RESISTANT PROSTATE CANCER Yoshiaki Yamamoto, Hiroaki Matsumoto, Hidetoshi Kuruma, Eliana Beraldi, Tianyuan Zhou, Youngsoo Kim, Brett P. Monia, A. Robert MacLeod, Ladan Fazli, Amina Zoubeidi, and Martin Gleave Yoshiaki YamamotoYoshiaki Yamamoto More articles by this author , Hiroaki MatsumotoHiroaki Matsumoto More articles by this author , Hidetoshi KurumaHidetoshi Kuruma More articles by this author , Eliana BeraldiEliana Beraldi More articles by this author , Tianyuan ZhouTianyuan Zhou More articles by this author , Youngsoo KimYoungsoo Kim More articles by this author , Brett P. MoniaBrett P. Monia More articles by this author , A. Robert MacLeodA. Robert MacLeod More articles by this author , Ladan FazliLadan Fazli More articles by this author , Amina ZoubeidiAmina Zoubeidi More articles by this author , and Martin GleaveMartin Gleave More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.285AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Suppression of androgen receptor (AR) signaling with potent inhibitors like Enzalutamide/MDV3100 (ENZ) remains a therapeutic goal for castration resistant prostate cancer (CRPC); however, ENZ-resistant (ENZ-R) CRPC frequently occurs. Clusterin (CLU) is induced by AR pathway inhibition and its overexpression confers treatment resistance and the CLU inhibitor, OGX-011, potentiates anticancer therapies in many preclinical models. In this study, we tested whether OGX-011 sensitized AR knockdown activity of AR-ASO and delayed ENZ-R progression in LNCaP model. METHODS Effects of single vs. combination AR-ASO and OGX-011 or CLU siRNA regimens on parental and ENZ-R LNCaP cell growth rates, protein, and gene expression were analyzed. Effects of combination AR-ASO and OGX-011 on ENZ-R LNCaP progression rates were assessed in castrated male athymic mice. RESULTS ENZ-R LNCaP-derived sub-lines expressed high levels of CLU and AR compared to CRPC LNCaP cell lines. LNCaP cells overexpressing CLU acquire resistance to AR-ASO induced apoptosis as shown by decreased cell growth inhibition rates and apoptosis induction. AR-ASO induced time- and dose-dependent increases in CLU levels in parental and ENZ-R LNCaP cells. Co-targeted suppression of CLU and AR synergistically inhibited ENZ-R cell growth rates compared to monotherapy. Increased apoptosis (PARP and caspase-3 cleavage, sub G0/G1 fraction) together with reduced AKT phosphorylation was most enhanced with combined therapy. In vivo, combined OGX-011 + AR-ASO significantly delayed ENZ-R LNCaP tumor progression compared to scramble ASO + AR-ASO. CONCLUSIONS Suppression of CLU combined with AR knockdown inhibited ENZ-R LNCaP cell growth, providing pre-clinical proof-of-principle as a promising AR co-targeting approach in ENZ-R CRPC. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e260-e261 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Yoshiaki Yamamoto More articles by this author Hiroaki Matsumoto More articles by this author Hidetoshi Kuruma More articles by this author Eliana Beraldi More articles by this author Tianyuan Zhou More articles by this author Youngsoo Kim More articles by this author Brett P. Monia More articles by this author A. Robert MacLeod More articles by this author Ladan Fazli More articles by this author Amina Zoubeidi More articles by this author Martin Gleave More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...