PD32-01 PRE-CLINICAL RATIONALE FOR COMBINATION PI3K AND BRD4 INHIBITION IN ADVANCED PROSTATE CANCER

Abstract

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) III1 Apr 2016PD32-01 PRE-CLINICAL RATIONALE FOR COMBINATION PI3K AND BRD4 INHIBITION IN ADVANCED PROSTATE CANCER Paul Toren, Jared Allman, Soojin Kim, and Amina Zoubeidi Paul TorenPaul Toren More articles by this author , Jared AllmanJared Allman More articles by this author , Soojin KimSoojin Kim More articles by this author , and Amina ZoubeidiAmina Zoubeidi More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.677AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The PI3K/Akt pathway is frequently activated in aggressive and resistant prostate cancer. This study details our pre-clinical evaluation of AZD8186, a novel β- and δ- selective PI3K small molecule inhibitor in prostate cancer models. We and others have recently noted the role of the oncogene myc as a mechanism of resistance to monotherapy treatment with PI3K/Akt inhibitors. Therefore, we further evaluated co-targeting strategies against both the PI3K/Akt pathway and the epigenetic reader protein BRD4. METHODS Human prostate cancer cell lines LNCaP and 22RV1 were tested for sensitivity to AZD8186 in vitro. Caspase-3 activity and flow cytometry were used to assess apoptosis. Western blotting and RT-qPCR were used to measure AR and myc pathway genes and protein expression. Castrate resistant LNCaP xenografts were treated with 10mg/kg and 25mg/kg doses of AZD8186 given orally 4 days on, 3 off. RESULTS LNCaP cells demonstrated sensitivity to AZD8186 with decreases in cell proliferation and increases in apoptosis. In vivo, castrate resistant LNCaP xenografts demonstrated a dose-dependent decrease in tumor growth velocity with AZD8186. On-target decreases in pAkt was observed in xenograft tumour samples by western blot analysis. Further, increases in myc protein and mRNA levels were seen in xenograft samples treated with AZD8186 compared to control. Downstream increases in EGFR and IGF-IR mRNA transcripts induced by AZD8186 were also seen in vitro and in vivo. Increases in myc, EGFR and IGF-IR was also seen in prostate cancer cell lines and xenograft tumours treated with an Akt inhibitor. Addition of the BDR4 inhibitor JQ1 decreased the elevation of myc transcript levels induced by AZD8186 and also partially abrogated the increases in EGFR, IGFR transcript levels. Greater suppression of PSA expression was seen with the combination of AZD8186 and JQ1 compared to AZD8186 and enzalutamide. Similar results were seen in the 22RV1 cell line. CONCLUSIONS Inhibition of PI3K with AZD8186 inhibits growth of PTEN-negative LNCaP cells. However, feedback activation of myc and AR pathways occurs and may result in treatment resistance. We demonstrate BRD4 inhibition using JQ1 as a rationale combination strategy with PI3K inhibition. This strategy co-targets both myc and AR feedback pathways and warrants further investigation in prostate cancers with an activated PI3K/Akt pathway. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e761 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Paul Toren More articles by this author Jared Allman More articles by this author Soojin Kim More articles by this author Amina Zoubeidi More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...