MP24-02 DEVELOPMENT OF AN IMAGING APPROACH TO DETECT SPLICE VARIANTS OF ANDROGEN RECEPTOR IN PROSTATE CANCER (2014)

You have accessJournal of UrologyProstate Cancer: Basic Research I1 Apr 2014MP24-02 DEVELOPMENT OF AN IMAGING APPROACH TO DETECT SPLICE VARIANTS OF ANDROGEN RECEPTOR IN PROSTATE CANCER Yusuke Imamura, Amy Tien, Jinhe Pan, Jian Kunzhong, Kuo-Shyan Lin, Raymond Andersen, and Marianne Sadar Yusuke ImamuraYusuke Imamura More articles by this author , Amy TienAmy Tien More articles by this author , Jinhe PanJinhe Pan More articles by this author , Jian KunzhongJian Kunzhong More articles by this author , Kuo-Shyan LinKuo-Shyan Lin More articles by this author , Raymond AndersenRaymond Andersen More articles by this author , and Marianne SadarMarianne Sadar More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.283AboutPDF 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-001/EPI-002 small molecules bind to AR amino-terminal domain (NTD). We propose to develop an analogue of radiolabeled iodine 123- (123I) EPI-002 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 employ sequential imaging with F18-FDHT to detect solely full-length (fl)-AR and 123I-EPI-002 to detect NTD of both fl-AR and variant AR. A discordant distribution or discordant level of uptake between 18F-FDHT and 123I-EPI-002 may indicate expression of splice variants lacking LBD. METHODS Activity and specificity of non-radiolabeled iodine (I)-EPI-002 for inhibiting AR were confirmed in cells using reporter gene constructs for the AR and related steroid hormone receptors, glucocorticoid receptor (GR) and progesterone receptor (PR). Competitive ligand binding assays to detect the displacement of fluorescently labeled ligand from recombinant LBDs of AR, PR, GR and estrogen receptor (ER) by R1881, MDV3100, EPI-002 or I-EPI-002 were performed. EPI-002 was successfully radiolabeled with the isotope 123I. On-going experiments include: binding experiments of 123I-EPI-002 to recombinant proteins AR activation function-1 and fl-AR, as well as to endogenous fl-AR and variant AR in cells; evaluation of 123I-EPI-002 in whole-body distribution including dosimetry in xenografts by small animal SPECT imaging; and evaluation of 123I-EPI-002 uptake and plasma clearance by quantifying 123I in harvested organs at various time points. Biological, physical and effective half-life of 123I-EPI-002 will be determined. RESULTS In cell-based assays, I-EPI-002 was specific for AR and blocked the induction of AR-driven reporter activity in response to androgen, but did not inhibit either PR or GR transcriptional activities in response to ligand. I-EPI-002 does not bind to LBDs of AR, PR, GR and ER. Ongoing in vivo experiments will reveal the potential of 123I-EPI-002 for clinical application. CONCLUSIONS An AR NTD-targeted molecular imaging probe such as 123I-EPI-002 may 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. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e260 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Yusuke Imamura More articles by this author Amy Tien More articles by this author Jinhe Pan More articles by this author Jian Kunzhong More articles by this author Kuo-Shyan Lin More articles by this author Raymond Andersen More articles by this author Marianne Sadar More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...