MP61-12 AN ANDROGEN RECEPTOR SPLICE VARIANT-TARGETED COMBINATION THERAPY FOR CASTRATION-RESISTANT PROSTATE CANCER USING EPI-002 AND A PI3K/MTOR DUAL INHIBITOR (2015)

You have accessJournal of UrologyProstate Cancer: Basic Research IV1 Apr 2015MP61-12 AN ANDROGEN RECEPTOR SPLICE VARIANT-TARGETED COMBINATION THERAPY FOR CASTRATION-RESISTANT PROSTATE CANCER USING EPI-002 AND A PI3K/MTOR DUAL INHIBITOR Minoru Kato and Marianne D. Sadar Minoru KatoMinoru Kato More articles by this author and Marianne D. SadarMarianne D. Sadar More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2193AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES PI3K/Akt/mTOR pathway is frequently activated through PTEN loss in castration-resistant prostate cancer (CRPC). Previous studies revealed that combination treatments with antiandrogens and PI3K/mTOR inhibitors showed synergetic anti-tumor effects on CRPC. Current antiandrogens such as bicalutamide and enzalutamide target the ligand-binding domain (LBD) of androgen receptor (AR) and have no effect on truncated AR splice variants that lack a LBD. These AR splice variants include AR-V7 and are associated with resistance to current hormone therapies. In the present study, we hypothesized that combination therapy with EPI-002, an AR amino-terminal domain (NTD) targeting drug, and a PI3K/mTOR inhibitor would show a stronger inhibitory effect on CRPC growth by targeting AR splice variant as well as PI3K/mTOR pathway than each monotherapy. METHODS Combination therapy using EPI-002 and BEZ235, a dual inhibitor of PI3K and mTOR, were evaluated in vitro and in vivo using human prostate cancer cells, LNCaP and LNCaP95, an androgen-independent cell line which expresses AR-V7. Effects of single and combination EPI-002 and BEZ235 were assessed on proliferation, AR transcriptional activities, protein and gene expression. A preclinical study was performed to evaluate the effect of combination therapy in castrated NOD/SCID mice bearing LNCaP95 xenografts. RESULTS Co-targeted therapy significantly inhibited cell proliferation as compared to each monotherapy. BEZ235 increased expression of full-length (fl)-AR regulated genes (PSA, FKBP5 and NKX3.1), while it decreased AR-V7 regulated genes (UBE2C and CDC20). Similarly, it stimulated ligand-dependent activation of AR, while inhibited ligand-independent AR-NTD transcriptional activities. EPI-002 inhibited the activity of fl-AR when activated by both ligand-dependent and ligand-independent mechanisms, and prevented the increased transcription of AR-regulated genes caused by BEZ235. Moreover, combination treatment decreased levels of UBE2C and pS6 proteins. In vivo, tumor volume in mice administered EPI-002 and BEZ235 was significantly decreased as compared with that in mice given each monotherapy without any observed toxicity. CONCLUSIONS EPI-002 inhibited AR-V7 transcriptional activity together with BEZ235, and blocked the activation of fl-AR by BEZ235. These data highlight that co-targeting AR splice variants and PI3K/mTOR could be a potential treatment option for CRPC. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e750-e751 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Minoru Kato More articles by this author Marianne D. Sadar More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...