MP46-15 LIPID NANOPARTICLE SIRNA POTENTLY SILENCES CLUSTERIN AND DELAYS PROGRESSION WHEN COMBINED WITH ANDROGEN RECEPTOR CO-TARGETING IN ENZALUTAMIDE RESISTANT PROSTATE CANCER

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research II1 Apr 2015MP46-15 LIPID NANOPARTICLE SIRNA POTENTLY SILENCES CLUSTERIN AND DELAYS PROGRESSION WHEN COMBINED WITH ANDROGEN RECEPTOR CO-TARGETING IN ENZALUTAMIDE RESISTANT PROSTATE CANCER Yoshiaki Yamamoto, Paulo Lin, Fan Zhang, Eliana Beraldi, Yoshihisa Kawai, Jeffrey Leong, Hideyasu Matsuyama, Pieter Cullis, and Martin Gleave Yoshiaki YamamotoYoshiaki Yamamoto More articles by this author , Paulo LinPaulo Lin More articles by this author , Fan ZhangFan Zhang More articles by this author , Eliana BeraldiEliana Beraldi More articles by this author , Yoshihisa KawaiYoshihisa Kawai More articles by this author , Jeffrey LeongJeffrey Leong More articles by this author , Hideyasu MatsuyamaHideyasu Matsuyama More articles by this author , Pieter CullisPieter Cullis More articles by this author , and Martin GleaveMartin Gleave More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1578AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Suppression of androgen receptor (AR) signaling remains a therapeutic goal for castration resistant prostate cancer (CRPC) and despite newer potent AR pathway inhibitors, resistance frequently occurs. While co-targeting the AR with adaptive survival pathways is a rational goal, many biologically relevant genes including clusterin (CLU) are not druggable with small molecule inhibitors. While small interfering RNA (siRNA) offers the promise for very potent and specific gene silencing, in vivo delivery remains a major barrier. The most clinically advanced delivery of siRNA employs lipid nanoparticles (LNP). METHODS To improve siRNA delivery to tumors, we developed a LNP system and show that LNP-LUC siRNA silences its luciferase reporter gene in both subcutaneous and metatastic PC3-Luc xenograft models by the IVIS imaging system. Upon validation, the effect of LNP siRNA targeting CLU was used in combination with AR antisense oligonucleotides (ASO) in an enzalutamide-resistant (ENZ-R) CRPC LNCaP in vitro and in vivo models. RESULTS LNP CLU-siRNA inhibited AR-ASO induced up-regulation of CLU in vitro and in vivo, and significantly suppressed tumor growth and serum PSA levels in ENZ-R LNCaP xenografts compared to AR-ASO monotherapy. Interestingly, we revealed a stress-induced feed-forward loop involving AR-ASO-induced AKT and p90rsk, phosphoactivation of YB-1, and increased expression of CLU. CLU knockdown abrogates AR-ASO-induced phosphorylation of YB-1, AKT, and p90Rsk. CONCLUSIONS These data provide novel proof-of-principle that LNP siRNA can silence target genes in vivo and enable inhibiting traditionally non-druggable genes like CLU and other promising co-targeting approaches in ENZ-R CRPC therapeutics. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e549 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yoshiaki Yamamoto More articles by this author Paulo Lin More articles by this author Fan Zhang More articles by this author Eliana Beraldi More articles by this author Yoshihisa Kawai More articles by this author Jeffrey Leong More articles by this author Hideyasu Matsuyama More articles by this author Pieter Cullis More articles by this author Martin Gleave More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...