MP52-08 TARGETING IGFBP-2 AND IGFBP-5 IN CASTRATION AND ENZALUTAMIDE RESISTANT PROSTATE CANCER (2014)

You have accessJournal of UrologyProstate Cancer: Basic Research V1 Apr 2014MP52-08 TARGETING IGFBP-2 AND IGFBP-5 IN CASTRATION AND ENZALUTAMIDE RESISTANT PROSTATE CANCER Joseph Ischia, Mototsugu Muramaki, Yi Xia, Eliana Beraldi, Hideaki Miyake, Amina Zoubeidi, Michael Cox, and Martin Gleave Joseph IschiaJoseph Ischia More articles by this author , Mototsugu MuramakiMototsugu Muramaki More articles by this author , Yi XiaYi Xia More articles by this author , Eliana BeraldiEliana Beraldi More articles by this author , Hideaki MiyakeHideaki Miyake More articles by this author , Amina ZoubeidiAmina Zoubeidi More articles by this author , Michael CoxMichael Cox More articles by this author , and Martin GleaveMartin Gleave More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1618AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives Castration and the next generation androgen receptor (AR) antagonist enzalutamide have been shown to improve survival in men with advanced prostate cancer. However, resistance will inevitably develop via a multitude of possible mechanisms which include insulin-like growth factor (IGF) signaling. Targeting insulin-like growth factor-binding protein (IGFBP) -2 and IGFBP-5 using a novel bispecific antisense oligodeoxynucleotide (ASO), designated OGX-225, presents as one strategy to treat castration and enzalutamide-resistant prostate cancer. Methods Effects of OGX-225 on IGFBP-2 and IGFBP-5 expression levels, cell growth, and apoptosis were evaluated in human castrate sensitive (LNCaP), castrate resistant (PC-3, 22RV1 and V16D), and enzalutamide-resistant (MR42D and MR49F) prostate cancer cell lines in vitro. The effect of OGX-225 on LNCaP and PC-3 xenograft growth was also evaluated. Results Whole transcriptome analysis demonstrated that mRNA for IGFBP-2 is overexpressed (4 fold) in castrate resistant prostate cancer cell lines; and that the expression of IGFBP-5 increases over 300 fold in enzalutamide-resistant MR42D prostate cancer cells compared to LNCaP parental cells. OGX-225 induced potent dose-dependent, sequence-specific knockdown of IGFBP-2 in LNCaP, 22Rv1, MR42D, and MR49F, and IGFBP-5 expression in PC3 cells. This treatment decreased cell viability by over 50% in all cell lines through induction of a strong apoptotic response. Compared to control ASO, OGX-225 significantly suppressed castrate-resistant progression of LNCaP xenografts as measured by delayed tumor growth and serum prostate-specific antigen levels. OGX-225 also inhibited growth of androgen-independent PC-3 xenografts. Pharmacodynamic activity of OGX-225 in vivo was demonstrated through significant down-regulation of IGFBP-2 and IGFBP-5 mRNA levels in the LNCaP and PC3 xenografts, respectively. Conclusions This study reports the first preclinical proof-of-principle data that a novel bispecific inhibitor of IGFBP-2 and IGFBP-5, OGX-225, delays prostate cancer progression and displays specific anti-cancer activity in enzalutamide-resistant prostate cancer cell lines. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e582-e583 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Joseph Ischia More articles by this author Mototsugu Muramaki More articles by this author Yi Xia More articles by this author Eliana Beraldi More articles by this author Hideaki Miyake More articles by this author Amina Zoubeidi More articles by this author Michael Cox More articles by this author Martin Gleave More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...