MP46-08 THE TYRPHOSTIN, NT157, SUPPRESSES INSULIN RECEPTOR SUBSTRATES AND AUGMENTS THERAPEUTIC RESPONSE OF PROSTATE CANCER (2015)

You have accessJournal of UrologyProstate Cancer: Basic Research II1 Apr 2015MP46-08 THE TYRPHOSTIN, NT157, SUPPRESSES INSULIN RECEPTOR SUBSTRATES AND AUGMENTS THERAPEUTIC RESPONSE OF PROSTATE CANCER Naokazu Ibuki, Mazyar Ghaffari, Hadas Reuveni, Mitaly Pandey, Ladan Fazli, Haruhito Azuma, Martin Gleave, Alexander Levitzki, and Michael Cox Naokazu IbukiNaokazu Ibuki More articles by this author , Mazyar GhaffariMazyar Ghaffari More articles by this author , Hadas ReuveniHadas Reuveni More articles by this author , Mitaly PandeyMitaly Pandey More articles by this author , Ladan FazliLadan Fazli More articles by this author , Haruhito AzumaHaruhito Azuma More articles by this author , Martin GleaveMartin Gleave More articles by this author , Alexander LevitzkiAlexander Levitzki More articles by this author , and Michael CoxMichael Cox More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1571AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Insulin-like growth factor (IGF) signaling is associated with castrate-resistant prostate cancer (CRPC) progression. Insulin receptor substrates 1 and 2 (IRS1/2) mediate mitogenic and anti-apoptotic signaling from IGF-1 receptor (IGF-1R), insulin receptor and other oncoproteins. METHODS We examined expression of IRS1 and IRS2 in the PCa microenvironment of untreated, short term (< 6 mo) neoadjuvant hormone therapy (NHT), long term (6-12 mo) NHT, and CRPC disease by IHC. This study assesses the anti-cancer activity of NT157, a small-molecule tyrphostin targeting IRS proteins, using androgenresponsive (LNCaP) and -independent (PC3) prostate cancer cells in vitro and in vivo. RESULTS IRS1 expression was elevated ∼20% in therapy na□Ee PCa and CRPC when compared to benign epithelium, but was indistinguishable from benign epithelium in NHT-treated specimens. IRS2 expression was up-regulated >2-fold in therapy na□Ee PCa and CRPC specimens, and while indistinguishable from na□Ee specimens in short-term NHT specimens, was increased ∼2-fold compared to benign epithelium in the long-term NHT cohort. NT157 treatment resulted in dose-dependent inhibition of IGF1R activation, suppression of IRS protein expression, inhibition of IGF-1-induced AKT activation, but increased ERK activation in NT157-treated cells in vitro. These effects were correlated with decreased proliferation and increasing apoptosis of LNCaP cells and increasing G2M arrest in PC3 cells. NT157 also suppressed androgen-responsive growth, delayed CRPC progression of LNCaP xenografts. Average tumor growth rate in the NT157 treated cohort was decreased > 35-fold. And NT157 suppressed PC3 tumor growth alone and in combination with docetaxel. Growth rate of tumors in the NT157 and docetaxel cohorts were suppressed ∼4-fold relative to that of the vehicle cohort while the growth rate of the tumors in the combination cohort were suppressed >30-fold relative to the vehicle cohort and ∼7-fold relative to the NT157 and docetaxel alone cohorts. CONCLUSIONS This study reports the first preclinical proof-of-principle data that this novel small-molecule tyrosine kinase inhibitor suppresses IRS1/2 expression, delays CRPC progression, and suppresses growth of CRPC tumors in vitro and in vivo. Demonstration that IRS expression can be increased in response to a variety of stressors that may lead to resistance or reduced effect of the therapies indicate that NT157-mediated IRS1/2 down-regulation is a novel therapeutic approach for management of advanced prostate cancer. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e546 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Naokazu Ibuki More articles by this author Mazyar Ghaffari More articles by this author Hadas Reuveni More articles by this author Mitaly Pandey More articles by this author Ladan Fazli More articles by this author Haruhito Azuma More articles by this author Martin Gleave More articles by this author Alexander Levitzki More articles by this author Michael Cox More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...