Mp20-16 novel function of ptupb in akr1c3/ar/ar-v7 axis inhibition and enzalutamide sensitization in advanced prostate cancer

You have accessJournal of UrologyCME1 Apr 2023MP20-16 NOVEL FUNCTION OF PTUPB IN AKR1C3/AR/AR-V7 AXIS INHIBITION AND ENZALUTAMIDE SENSITIZATION IN ADVANCED PROSTATE CANCER Joy Yang, Pengfei Xu, Bo Chen, Shu Ning, Hans Adomat, Sung-Hee Hwang, Allen Gao, Martin Gleave, Bruce Hammock, Christopher Evans, and Chengfei Liu Joy YangJoy Yang More articles by this author , Pengfei XuPengfei Xu More articles by this author , Bo ChenBo Chen More articles by this author , Shu NingShu Ning More articles by this author , Hans AdomatHans Adomat More articles by this author , Sung-Hee HwangSung-Hee Hwang More articles by this author , Allen GaoAllen Gao More articles by this author , Martin GleaveMartin Gleave More articles by this author , Bruce HammockBruce Hammock More articles by this author , Christopher EvansChristopher Evans More articles by this author , and Chengfei LiuChengfei Liu More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003245.16AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The steroidogenic enzyme Aldo-keto Reductase 1C3 (AKR1C3) is a major factor that contributes to the progression of castration-resistant prostate cancer (CRPC) and treatment failure. However, none of the available AKR1C3 inhibitors has shown promising results in clinical settings. Thus, there is an unmet need to develop superior AKR1C3 inhibitors for clinical testing. METHODS: PTUPB was synthesized by linking two pharmacophores, celecoxib and TPPU. In vitro and in vivo pharmacological activities of PTUPB in combination with enzalutamide were evaluated in several enzalutamide-resistant cell lines, conditional reprogrammed cell cultures, and patient-derived organoid models. The mechanism of action of PTUPB was examined via RNA sequence analysis, immunoblot analysis, co-immunoprecipitation, steroid measurement, and enzyme activity assays. Animal studies using PTUPB in combination with enzalutamide were performed in the castration-relapse VCaP tumor model. RESULTS: AKR1C3 levels are reciprocally regulated by the full-length androgen receptor (AR-FL) by binding to the distal enhancer region of AKR1C3. A novel function of PTUPB in AKR1C3 inhibition was discovered: at the same dose (0.5 µM) PTUPB suppressed the AKR1C3 activity more than indomethacin (60% vs. 40%) and celeboxib (60% vs. 0, p<0.05). And at the same dose (20 µM), PTUPB was more effective than indomethacin (98% vs. 22% of inhibition, p<0.05) and celecoxib (98% vs. 60% inhibition, p<0.05) in inhibiting CRPC cell growth. PTUPB synergizes with enzalutamide treatment for tumor suppression and gene signature regulation. Combination treatment with PTUPB and enzalutamide provides benefits by blocking AR and its variant (AR-V7) signaling, which inhibits the growth of VCaP castration-relapse tumors with 2.8-fold more inhibition (p<0.05) in tumor weights between the single (PTUPB) and combination treatments (Enza+PTUPB). There was also more inhibition in the growth of the patient-derived xenograft organoids by PTUPB alone or in combination with Enza. CONCLUSIONS: Targeting the ARK1C3/AR/AR-V7 axis with PTUPB and enzalutamide may overcome drug resistance to AR signaling inhibitors in advanced prostate cancer. Source of Funding: This work was supported in part by grants NIH/NCI R37CA249108 (C. Liu) and R01CA251253 (C. Liu) © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e281 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Joy Yang More articles by this author Pengfei Xu More articles by this author Bo Chen More articles by this author Shu Ning More articles by this author Hans Adomat More articles by this author Sung-Hee Hwang More articles by this author Allen Gao More articles by this author Martin Gleave More articles by this author Bruce Hammock More articles by this author Christopher Evans More articles by this author Chengfei Liu More articles by this author Expand All Advertisement PDF downloadLoading ...