Mp15-08 a Pre-Clinical Organoid Model to Select Suitable Bladder Cancer Patients for Targeting Ezh2 Treatment

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology I (MP15)1 May 2024MP15-08 A PRE-CLINICAL ORGANOID MODEL TO SELECT SUITABLE BLADDER CANCER PATIENTS FOR TARGETING EZH2 TREATMENT Hongda Zhao, Jason Liao, Kang Liu, Xuan Chen, Hongwei Wu, Peter Ka-Fung Chiu Chiu, Chi-Fai Ng, and Jeremy Yuen-Chun Teoh Hongda ZhaoHongda Zhao , Jason LiaoJason Liao , Kang LiuKang Liu , Xuan ChenXuan Chen , Hongwei WuHongwei Wu , Peter Ka-Fung Chiu ChiuPeter Ka-Fung Chiu Chiu , Chi-Fai NgChi-Fai Ng , and Jeremy Yuen-Chun TeohJeremy Yuen-Chun Teoh View All Author Informationhttps://doi.org/10.1097/01.JU.0001009500.87761.bf.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Recently, patient-derived organoids (PDOs) have gained increasing attention as a valuable tool for tumour modeling. However, there is a lack of studies that have specifically explored the pre-clinical application of PDOs, particularly in the context of bladder cancer. METHODS: We selected four long-term patient-derived organoid lines from our biobank for analysis. The sensitivity of these organoids to the EZH2 inhibitor was assessed using the CellTiter-Glo 3D assay. Additionally, single-cell RNA sequencing (scRNA-seq) was performed to comprehensively characterize the transcriptional changes induced by EZH2 inhibition in the organoids. To investigate the role of EZH2 in KDM6A-null organoids, flow cytometry, immunoblotting, and organoid killing assays were conducted. RESULTS: BCORG23 PDO exhibited a frameshifting deletion in the KDM6A gene, which is known to influence the sensitivity of tumour cells to EZH2 inhibition. In contrast, KDM6A-wild-type PDOs displayed a reduced sensitivity to EZH2 inhibition. Through scRNA-seq analysis, we observed a significant upregulation of HLA-B expression in the BCORG23 PDO upon treatment with the EZH2 inhibitor, a finding that was validated by flow cytometry and immunoblotting. Moreover, our PROGENy pathway analysis revealed an elevated activity of the PI3K pathway and a concomitant downregulation of the Hypoxia pathway in BCORG23 following EZH2 inhibitor treatment. In addition, organoid killing assays demonstrated an enhanced T-cell mediated killing of tumour cells when EZH2 was pharmacologically inhibited. CONCLUSIONS: In summary, our study underscores the therapeutic implications of inhibiting EZH2, particularly for bladder cancer patients with KDM6A-null mutations. By demonstrating the non-cell-autonomous function of EZH2, our in-vitro model holds promise for enhancing anti-PD-1 treatment, particularly in the context of KDM6A-null bladder cancer. These findings have important implications for developing more effective and personalized treatment strategies for bladder cancer patients. Source of Funding: None © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e232 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Hongda Zhao More articles by this author Jason Liao More articles by this author Kang Liu More articles by this author Xuan Chen More articles by this author Hongwei Wu More articles by this author Peter Ka-Fung Chiu Chiu More articles by this author Chi-Fai Ng More articles by this author Jeremy Yuen-Chun Teoh More articles by this author Expand All Advertisement PDF downloadLoading ...