318 SYNERGISTIC TARGETING OF PI3K/AKT-PATHWAY AND ANDROGEN-RECEPTOR AXIS SIGNIFICANTLY DELAYS CASTRATION-RESISTANT PROSTATE CANCER PROGRESSION IN VIVO (2013)

You have accessJournal of UrologyProstate Cancer: Basic Research (II)1 Apr 2013318 SYNERGISTIC TARGETING OF PI3K/AKT-PATHWAY AND ANDROGEN-RECEPTOR AXIS SIGNIFICANTLY DELAYS CASTRATION-RESISTANT PROSTATE CANCER PROGRESSION IN VIVO Christian Thomas, Francois Lamoureux, Claire Crafter, Barry Davies, Eliana Beraldi, Ladan Fazli, Soojin Kim, Daksh Thaper, Martin Gleave, and Amina Zoubeidi Christian ThomasChristian Thomas Vancouver, Canada More articles by this author , Francois LamoureuxFrancois Lamoureux Vancouver, Canada More articles by this author , Claire CrafterClaire Crafter Macclesfield, United Kingdom More articles by this author , Barry DaviesBarry Davies Macclesfield, United Kingdom More articles by this author , Eliana BeraldiEliana Beraldi Vancouver, Canada More articles by this author , Ladan FazliLadan Fazli Vancouver, Canada More articles by this author , Soojin KimSoojin Kim Vancouver, Canada More articles by this author , Daksh ThaperDaksh Thaper Vancouver, Canada More articles by this author , Martin GleaveMartin Gleave Vancouver, Canada More articles by this author , and Amina ZoubeidiAmina Zoubeidi Vancouver, Canada More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1703AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The PI3K/AKT pathway plays a major role in the development of castration-resistant prostate cancer (CRPC). However, its inhibition leads to reactivation of the androgen-receptor (AR)-axis. We hypothesize that simultaneous inhibition of both pathways might result in a long-lasting remission of CRPC. METHODS LNCaP and C4-2 cells were treated with the novel AKT-pathway inhibitor AZD5363 −/+ the anti-androgen bicalutamide and submitted to westernblot, qRT-PCR and luciferase assay. Cell viability was assessed by crystal violet and cell cycle by FACS analysis. In vivo, two different animal models to mimic hormone-sensitive and CRPC progression were used. In both models, male athymic nude mice were injected s.c. LNCaP cells and castrated after start of tumor growth. Animals were randomly selected for vehicle or AZD5363 in the hormone-sensitive model. In the CRPC model, mice were randomly selected for vehicle, AZD5363, bicalutamide or the combination of both. Tumor volume and serum PSA were evaluated consistently for documentation of tumor response. RESULTS AZD5363 significantly inhibits cell growth and induces Caspase-3 dependent cell apoptosis compared to control. These biologic events are accompanied by inhibition of downstream PI3K/AKT signaling and reactivation of the AR-axis. In vitro, AZD5363 synergizes with bicalutamide, thereby circumventing upregulation of the AR-axis. In vivo, pharmacological targeting with AZD5363 significantly delays progression to CRPC and beyond. Most important, the combination treatment of AZD5363 plus bicalutamide significantly enhances antitumoral activity and progression-free survival in the CRPC xenograft model compared to each single treatment. CONCLUSIONS This study provides a preclinical proof-of-principle that targeting PI3K/AKT pathway with AZD5363 plus simultaneously inhibiting the AR-axis with bicalutamide results in a long-lasting remission of CRPC in vivo. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e129 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Christian Thomas Vancouver, Canada More articles by this author Francois Lamoureux Vancouver, Canada More articles by this author Claire Crafter Macclesfield, United Kingdom More articles by this author Barry Davies Macclesfield, United Kingdom More articles by this author Eliana Beraldi Vancouver, Canada More articles by this author Ladan Fazli Vancouver, Canada More articles by this author Soojin Kim Vancouver, Canada More articles by this author Daksh Thaper Vancouver, Canada More articles by this author Martin Gleave Vancouver, Canada More articles by this author Amina Zoubeidi Vancouver, Canada More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...