You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) III1 Apr 2016PD32-07 GALETERONE SHOWS ANTI-TUMOR ACTIVITY IN MULTIPLE PRE-CLINICAL MODELS THAT EXPRESS ANDROGEN RECEPTOR SPLICE VARIANTS, SUPPORTING CORRELATIVE PATIENT DATA SEEN IN ARMOR2 Vincent Njar, Amina Zoubeidi, Eva Corey, Elahe Mostaghel, Andrew Kwegyir-Afful, Senthilmurugan Ramalingam, and Douglas Jacoby Vincent NjarVincent Njar More articles by this author , Amina ZoubeidiAmina Zoubeidi More articles by this author , Eva CoreyEva Corey More articles by this author , Elahe MostaghelElahe Mostaghel More articles by this author , Andrew Kwegyir-AffulAndrew Kwegyir-Afful More articles by this author , Senthilmurugan RamalingamSenthilmurugan Ramalingam More articles by this author , and Douglas JacobyDouglas Jacoby More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.683AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Galeterone is a selective, multitargeted, small molecule that disrupts androgen signaling at multiple points in the pathway by enhancing androgen receptor (AR) degradation, inhibiting androgen biosynthesis, and antagonizing androgen binding to the AR. AR splice variant-7 (AR-V7) is a truncated, constitutively active splice variant of the AR that lacks the ligand binding domain (LBD), and has been implicated in castration resistant prostate cancer (CRPC) progression. AR-V7 expression is detected in approximately 12-26% of men with metastatic CRPC (mCRPC) prior to second-generation anti-androgens or chemotherapy, and AR-V7 expression has been clinically associated with resistance to enzalutamide (Xtandi) and abiraterone (Zytiga). In this study, multiple experimental approaches examined whether, and by what mechanism, galeterone inhibits the growth of prostate cancer cells or tumors expressing AR splice variants, such as AR-V7. METHODS To measure effects of galeterone on prostate tumor cell signaling and growth, we monitored reductions in AR protein levels, and have used in vitro measures of AR-dependent gene expression and tumor cell viability. In addition, we assessed in vivo efficacy of galeterone in mouse xenograft models and clinically by evaluating PSA responses in patients whose CTCs express truncated AR. RESULTS Our findings show that galeterone attenuates tumor cell proliferation, AR signaling and xenograft tumor growth using cells and tumors that express AR splice variants. Galeterone treatment also causes dose-dependent reductions in AR protein. Reductions in AR splice variant protein were observed in cells that co-express wild-type AR, and in AR negative prostate cancer cells that transiently express AR splice variant protein. These findings support the PSA responses seen clinically with galeterone treatment in men with mCRPC whose tumors contain truncated AR. CONCLUSIONS Galeterone's unique mechanism of AR protein downregulation occurs in both splice variant and full-length AR, supporting that galeterone-induced AR downregulation is independent of the AR LBD. Because preclinical and clinical data support an opportunity for treatment in this setting, Tokai is evaluating galeterone in an ongoing global pivotal trial designed to determine whether treatment with galeterone results in a statistically significant increase in radiographic progression-free survival as compared to enzalutamide in approximately 148 treatment-naïve, AR-V7+ mCRPC patients. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e763 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Vincent Njar More articles by this author Amina Zoubeidi More articles by this author Eva Corey More articles by this author Elahe Mostaghel More articles by this author Andrew Kwegyir-Afful More articles by this author Senthilmurugan Ramalingam More articles by this author Douglas Jacoby More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...