972 A NOVEL ANTIANDROGEN PF-05234848 SUPPRESSES CASTRATION-RESISTANT AND MDV-3100-RESISTANT PROSTATE CANCER GROWTH IN VITRO AND IN VIVO (2012)

You have accessJournal of UrologyProstate Cancer: Basic Research V1 Apr 2012972 A NOVEL ANTIANDROGEN PF-05234848 SUPPRESSES CASTRATION-RESISTANT AND MDV-3100-RESISTANT PROSTATE CANCER GROWTH IN VITRO AND IN VIVO Hidetoshi Kuruma, Hiroaki Matsumoto, Masaki Shiota, Andrea Fanjul, David Briere, Gerrit Los, Francois Lamoureux, Christian Thomas, Martin Gleave, and Amina Zoubeidi Hidetoshi KurumaHidetoshi Kuruma Vancouver, Canada More articles by this author , Hiroaki MatsumotoHiroaki Matsumoto Vancouver, Canada More articles by this author , Masaki ShiotaMasaki Shiota Vancouver, Canada More articles by this author , Andrea FanjulAndrea Fanjul San Diego, CA More articles by this author , David BriereDavid Briere San Diego, CA More articles by this author , Gerrit LosGerrit Los San Diego, CA More articles by this author , Francois LamoureuxFrancois Lamoureux Vancouver, Canada More articles by this author , Christian ThomasChristian Thomas 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.2012.02.1071AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The androgen receptor (AR) plays a critical role progression of castration-resistant prostate cancer (CRPC) following first line androgen deprivation therapy. Several 2nd generation anti-androgens (AA) have demonstrated anti-cancer activity in CRPC models. In this study, we evaluated the effects of a novel AA, PF-05234848, on cell growth and AR transcriptional activity in prostate cancer compared to the second generation antiandrigen MDV-3100. METHODS Cell growth assays and apoptotic rates, along with AR nuclear translocation and transcriptional activity, were used to assess on-target in vitro effects of the AA in AR-positive prostate cancer LNCaP and C4-2 cells, and AR-negative PC-3 and DU145 cells. Additionally, an MDV-3100-resistant LNCaP subline MRT49F cells was generated from an MDV-3100 resistant LNCaP xenograft to assess effects of PF-05234848 in an AA-resistant model. The effects of MDV-3100 and PF-05234848 on castrate-resistant LNCaP and MRT49F tumor growth were evaluated in castrated male athymic mice. RESULTS In vitro, PF-052334848 more potently suppressed LNCaP and C4-2 cell growth, as well as AR protein expression and transcriptional activity, compared to MDV-3100. PF-052334848, but not MDV-3100, induced apoptosis in LNCaP cells. In in vivo studies, MDV-3100 and PF-05234848 equally suppressed LNCaP CRPC tumor growth after 5-weeks treatment: tumor volume increased 488%, 19 %, and 7 % in vehicle, MDV-3100 and PF-05234848 groups, respectively, while changes in serum PSA were +619%, -32% and -27%. MDV-3100-resistant MR49F cells expressed both AR and PSA but were resistant to MDV-3100 treatment in vitro and in vivo. In contrast, PF-05234848 suppressed AR activity and cell growth in MR49F cells in vitro and suppressed MR49F MDV3100-resistant tumor growth in vivo. After 3 weeks of treatment, MR49F tumor growth increased 324%, 389%, and 138% in vehicle, MDV-3100, PF-05234848 groups, while serum PSA increased 708%, 1,013%, and 485%, respectively. CONCLUSIONS PF-05234848 inhibited AR activity and cell growth in both castrate-resistant as well as MDV-3100-resistant LNCaP cells in vitro and in vivo, supporting PF-05234848 as a promising next generation AA in CRPC. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187 Issue 4S April 2012 Page: e396 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.Metrics Author Information Hidetoshi Kuruma Vancouver, Canada More articles by this author Hiroaki Matsumoto Vancouver, Canada More articles by this author Masaki Shiota Vancouver, Canada More articles by this author Andrea Fanjul San Diego, CA More articles by this author David Briere San Diego, CA More articles by this author Gerrit Los San Diego, CA More articles by this author Francois Lamoureux Vancouver, Canada More articles by this author Christian Thomas 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 ...