MP66-07 TARGETING ANDROGEN RECEPTOR N-TERMINAL DOMAIN FOR PROSTATE CANCER IMAGING AND THERAPY

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research V1 Apr 2015MP66-07 TARGETING ANDROGEN RECEPTOR N-TERMINAL DOMAIN FOR PROSTATE CANCER IMAGING AND THERAPY Yusuke Imamura, Amy H. Tien, Nasrin R. Mawji, Jian Kun Zhong, Jinhe Pan, Kuo-Shyan Lin, Raymond J. Andersen, and Marianne D. Sadar Yusuke ImamuraYusuke Imamura More articles by this author , Amy H. TienAmy H. Tien More articles by this author , Nasrin R. MawjiNasrin R. Mawji More articles by this author , Jian Kun ZhongJian Kun Zhong More articles by this author , Jinhe PanJinhe Pan More articles by this author , Kuo-Shyan LinKuo-Shyan Lin More articles by this author , Raymond J. AndersenRaymond J. Andersen 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.2015.02.2360AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Resistance to therapies that target the androgen receptor (AR) ligand-binding domain (LBD) may be due to expression of constitutively active AR splice variants that lack the LBD. EPI small molecules bind to AR N-terminal domain (NTD) and inhibit transcriptional activity of AR. We developed an analogue of radiolabeled iodine 123- (123I) EPI for imaging of prostate cancer using single-photon emission computed tomography (SPECT). Currently the approach to image AR uses positron emission tomography with 16β-[18F]-fluoro-5α dihydrotestosterone (F18-FDHT) that binds to AR LBD. F18-FDHT cannot detect AR splice variants lacking LBD. Our approach would ultimately employ sequential imaging with F18-FDHT to detect solely full-length (fl)-AR and 123I-EPI to detect NTD of both fl-AR and truncated AR splice variants. A discordant distribution or discordant level of uptake between 18F-FDHT and 123I-EPI may indicate expression of splice variants lacking LBD. METHODS Effects of non-radiolabeled iodine (I)-EPI was evaluated in castrate-resistant prostate cancer (CRPC) model LNCaP95 cells and xenograft-bearing mice. EPI was successfully radiolabeled with the isotope 123I. Binding experiments of 123I-EPI to endogenous AR in cells were evaluated in vitro. 123I-EPI uptake and plasma clearance by quantifying 123I-EPI in harvested organs at various time points as whole-body distribution were evaluated, and small animal SPECT imaging study were conducted with LNCaP95 xenograft-bearing mice. RESULTS I-EPI was specific for blocking AR transcriptional activity. It decreased AR-dependent growth and had no toxicity at therapeutic doses in vivo. Consistent with EPI targeting the AR, I-EPI showed efficacy at 10mg/kg body weight and decreased the tumor size of LNCaP95 xenografts in castrated mice. 123I-EPI showed specific covalent binding to endogenous AR in LNCaP95 cells. Co-treatment with therapeutic doses of EPI significantly blocked the accumulation of 123I-EPI in the LNCaP95 xenograft. Furthermore, 123I-EPI enabled visualization of the LNCaP95 xenograft within 4hrs after injection. The compound appeared to be excreted via the liver rather than the kidney. Low level of uptake was found in the bladder after 1 hour; bone and muscle uptake was also low. CONCLUSIONS An AR NTD-targeted molecular imaging probe such as 123I-EPI would be useful to select patients for subsequent antiandrogen therapies, monitor treatment response, and provide insight into the role of all AR species in resistance mechanisms. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e818 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yusuke Imamura More articles by this author Amy H. Tien More articles by this author Nasrin R. Mawji More articles by this author Jian Kun Zhong More articles by this author Jinhe Pan More articles by this author Kuo-Shyan Lin More articles by this author Raymond J. Andersen More articles by this author Marianne D. Sadar More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...