Mp52-01 Combination of Indomethacin and Enzalutamide to Treat Castration-resistant Prostate Cancer
Year: 2018
Type: article
Abstract: You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) III1 Apr 2018MP52-01 COMBINATION OF INDOMETHACIN AND ENZALUTAMIDE TO TREAT CASTRATION-RESISTANT PROSTATE CANCER Chengfei Liu, Wei Lou, Chong-xian Pan, Primo Lara, Christopher Evans, Mamta Parikh, Ralph deVere White, Marc Dall'Era, and Allen Gao Chengfei LiuChengfei Liu More articles by this author , Wei LouWei Lou More articles by this author , Chong-xian PanChong-xian Pan More articles by this author , Primo LaraPrimo Lara More articles by this author , Christopher EvansChristopher Evans More articles by this author , Mamta ParikhMamta Parikh More articles by this author , Ralph deVere WhiteRalph deVere White More articles by this author , Marc Dall'EraMarc Dall'Era More articles by this author , and Allen GaoAllen Gao More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.1652AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Enzalutamide (Enza) and abiraterone (Abi) have been approved for the treatment of mCRPC. However, almost all patients eventually develop resistance. We discovered that a critical steroidogenic enzyme AKR1C3 was significantly elevated in Enza-resistant prostate cancer cells; and that indomethacin (Indocin) inhibited AKR1C3 activation and sensitized resistant CRPC cells to Enza and Abi. The goal of this project is to test the combination of Indo with Enza for the treatment of CRPC and to study the underlying mechanisms of action. METHODS Xenograft tumors were processed and intratumoral steroids were analyzed by Liquid Chromatography-Mass Spectrometry (LC/MS). ChIP assay was performed to examine recruitment of AR to the PSA promoter. In an investigator-initiated Phase Ib/II trial, eligible patients (pts) with progressive CRPC and serum testosterone ≤50 ng/dl were enrolled. No prior Enza was allowed. In the Phase Ib cohort, pts received Enza 160 mg po qd and Indocin 50 mg po tid. The Phase II expansion will enroll 26 patients with disease progression after Abi. Co-primary endpoints include toxicity and response as determined by the Prostate Cancer Working Group 2 criteria. RESULTS Overexpression of AKR1C3 increased AR-V7 expression, while inhibition of AKR1C3 downregulated AR-V7. AKR1C3 inhibition significantly decreased PSA luciferase activity and reduced the recruitment of AR to the AREs (Androgen Responsive Elements). Targeting AKR1C3 by Indocin decreased tumor testosterone level and enhanced Enza treatment in vitro and in vivo. In the ongoing phase Ib/II trial, four pts (Age: 63-80) have been enrolled and treated in the Phase Ib cohort, without any dose-limiting toxicities. Two patients had ≥50% PSA decrease and remain on study. The other two patients did not meet the criteria of response with further treatment discontinued. To understand the potential mechanisms of this combination, patient peripheral blood and tumor specimens were collected. AKR1C3, AR and AR-V7 are measured and correlated to tumor response. CONCLUSIONS AKR1C3 is involved in intratumoral androgen synthesis, reprograms AR signaling and serves as a potential target for the treatment of CRPC. The combination of Indocin and Enza is well tolerated. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e694 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Chengfei Liu More articles by this author Wei Lou More articles by this author Chong-xian Pan More articles by this author Primo Lara More articles by this author Christopher Evans More articles by this author Mamta Parikh More articles by this author Ralph deVere White More articles by this author Marc Dall'Era More articles by this author Allen Gao More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...
Source: The Journal of Urology
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2795880260