MP22-02 GNRH ANTAGONISTS HAVE DIRECT INHIBITORY EFFECTS ON CASTRATION-RESISTANT PROSTATE CANCER VIA INTRACRINE ANDROGEN AND AR-V7 EXPRESSION (2019)

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) II (MP22)1 Apr 2019MP22-02 GNRH ANTAGONISTS HAVE DIRECT INHIBITORY EFFECTS ON CASTRATION-RESISTANT PROSTATE CANCER VIA INTRACRINE ANDROGEN AND AR-V7 EXPRESSION Vito Cucchiara*, Joy Yang, Chengfei Liu, Hans Adomat, Emma Guns, Martin Gleave, Allen Gao, and Christopher Evans Vito Cucchiara*Vito Cucchiara* More articles by this author , Joy YangJoy Yang More articles by this author , Chengfei LiuChengfei Liu More articles by this author , Hans AdomatHans Adomat More articles by this author , Emma GunsEmma Guns More articles by this author , Martin GleaveMartin Gleave More articles by this author , Allen GaoAllen Gao More articles by this author , and Christopher EvansChristopher Evans More articles by this author View All Author Informationhttps://doi.org/10.1097/01.JU.0000555586.05782.19AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVES: Hormone therapy is currently the mainstay in the management of locally advanced and metastatic prostate cancer (PCa). Degarelix (Firmagon, Deg), a GnRH receptor antagonist demonstrated some advantages over the LHRH agonist Leuprolide (Leup) by avoiding “testosterone flare” and lower FSH levels. We compared the effect of Deg and Leup on prostate cancer (PC) cell progression in vitro and in vivo. METHODS: RT-qPCR was conducted for GnRH type 2 receptor in PC cell lines. PSA-Luc assays were performed coupled with or without AR-V7 transfection in C4-2B cells. PC cell proliferation in the presence of Leup and Deg was evaluated by cell counts. Western blotting analysis and RT-qPCR were performed to examine the levels of AR-FL and AR variants (V7) upon treatments with Leup and Deg alone or in combination with antiandrogens (abiraterone acetate, AA or enzalutamide, Enza). In vivo VCaP xenographs were treated with control, castration, Leup or Deg in a 6-week period of time. Tumor progression was monitored by biweekly calliper measurement. Harvested tumors were stained for Ki67 and subjected to steroid measurement by LC-MS. RESULTS: GnRHR2 was readily detectable in PC cells. AR transcriptional activity reported by PSA-Luc assay was modulated by both Leup and Deg. In LNCaP and C4-2B MDVR cells, 20µM Deg significantly reduced the cell viability (p<0.01). GnRH-antagonist (alone or in combination with AA or Enza) counteracted the transactivation activity of AR by reducing AR-FL and AR variants at the protein level. In C4-2BMDVR cells, Deg reduced AR-V7 protein expression by 26 to 40% alone or combined with AA and Enza compared to control. Leup, however, enhanced variant expression. Deg reduced AR-variant levels from 17 to 41% in monotherapy or combinations compared to control. In mice, Leup slightly suppressed tumor growth compared to controls (p>0.05). However, tumors in Deg-treated group were 1.5-fold smaller than Leup-treated group but 1.7-fold bigger than surgical castration-group. Ki67 IHC staining confirmed the difference in tumor proliferation among groups. Measurements of intratumoral steroids by LC-MS from tumors, serum samples or cell pellets confirmed that Deg decreased the levels of testosterone and steroidogenesis pathway intermediates, comparable to surgical castration; while Leup had no inhibitory effect. CONCLUSIONS: Our results suggest a selective mechanism of action of Deg against AR-variants. The present study provides additional molecular insights regarding the mechanism of Deg compared to GnRH agonist therapy which may have clinical implications. Source of Funding: Ferring Sacramento, CA; Vancouver, Canada; Sacramento, CA© 2019 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 201Issue Supplement 4April 2019Page: e316-e317 Advertisement Copyright & Permissions© 2019 by American Urological Association Education and Research, Inc.MetricsAuthor Information Vito Cucchiara* More articles by this author Joy Yang More articles by this author Chengfei Liu More articles by this author Hans Adomat More articles by this author Emma Guns More articles by this author Martin Gleave More articles by this author Allen Gao More articles by this author Christopher Evans More articles by this author Expand All Advertisement PDF downloadLoading ...