982 COMBINED TARGETING OF PI3K/AKT AND AR PATHWAY WITH AZD5363 AND ENZALUTAMIDE INDUCES ANTICANCER ACTIVITY IN PRECLINICAL MODELS OF PROSTATE CANCER (2013)

You have accessJournal of UrologyProstate Cancer: Basic Research (V)1 Apr 2013982 COMBINED TARGETING OF PI3K/AKT AND AR PATHWAY WITH AZD5363 AND ENZALUTAMIDE INDUCES ANTICANCER ACTIVITY IN PRECLINICAL MODELS OF PROSTATE CANCER Paul Toren, Soojin Kim, Martin Gleave, and Amina Zoubeidi Paul TorenPaul Toren Vancouver, Canada More articles by this author , Soojin KimSoojin Kim 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.2013.02.564AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Recent advances in castrate resistant prostate cancer (CRPC) treatment using androgen receptor (AR) targeted therapies such as enzalutamide (MDV3100) have produced striking survival advantages in clinical studies. However, the next major clinical challenge that we will face is how to prevent and treat the emergence of MDV3100 resistant tumors that rapidly occur in some CRPC patients. We and others found that MDV3100 induces phospho-activation of AKT (pAKT) and that inhibition of AKT results in feedback signaling leading to activation of AR suggesting that inhibiting AKT alone is not a good strategy to combat MDV3100 resistance. Here we investigate the effect of dual targeting Akt using AZD5363 and the AR pathway using MDV3100. METHODS Human prostate cancer cell lines LNCaP, C4-2, 22RV1 and MDV3100 resistant cell line (MR49C) were treated with AZ5363, MDV3100 or AZ5363 plus MDV3100. Cell proliferation was assessed by crystal violet, cell cycle population was assessed by FACS analysis, and cell apoptosis was assessed by PARP cleavage and caspase-3 activity. AR transcriptional activity was assessed by probasin luciferase and AR signaling pathway was assessed by western blot and qRT-PCR. For in vivo anti-cancer activity, male athymic nude mice were injected s.c. with LNCaP cells and castrated after start of tumor growth. Animals were randomly selected for vehicle, AZD5363, MDV3100 and AZD5363+MDV3100 once CRPC was identified. Tumor volume and serum PSA are being monitored weekly. RESULTS We found that combination therapy was more potent than mono-therapy. AZD5363 and MDV3100 synergize and induce cell apoptosis showing PARP cleavage and caspase 3 activity as well as increase of subG1/G0 population in all cell lines including the MDV3100-resistant MR49C. Moreover, we found that MDV3100 abrogates AZD5363 induced up-regulation of AR transcriptional activity and up-regulation of AR dependent genes both at mRNA and protein levels. The effect of the combination in an in vivo model of prostate cancer progression is currently under evaluation. CONCLUSIONS Combined blockade of the AKT and AR pathway with AZD5363 and MDV3100 demonstrates significant induction of apoptosis and proliferation and provides a preclinical proof of principle for using these two drugs in the clinic in CRPC. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e403 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Paul Toren Vancouver, Canada More articles by this author Soojin Kim 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 ...