预测每位患者肿瘤的治疗反应对于改善肌层浸润性膀胱癌的长期预后至关重要。本研究旨在建立代表患者肿瘤的离体膀胱癌患者来源的类器官 (PDO) 模型，并确定标准护理和策划的实验疗法的潜在疗效。前瞻性地从同意的膀胱癌患者中收集肿瘤材料，以生成短期 PDO 模型，在离体三维培养中针对一组临床相关药物进行筛选。利用多组学分析来验证 PDO 模型，建立每个肿瘤的分子特征，并识别药物反应的潜在生物标志物。使用 Spearman 等级相关系数评估配对原代组织和 PDO 样本之间的基因表达 (GEX) 模式。使用 Pearson 相关系数和 Kruskal-Wallis 检验以及 Dunn 事后配对比较测试来确定治疗反应的分子相关性。从 97 名患者中收集了总共 106 个肿瘤，其中 65 个样本为完整的多组学分子表征和 PDO 筛查提供了足够的材料。 6 至 32 种药物/组合。短期 PDO 忠实地代表了肿瘤分子特征，维持了多样化的细胞类型，并避免了长期 PDO 培养所伴随的基于 GEX 的亚型变化。利用综合方法，确定了离体药物反应与基因组改变、GEX 和蛋白质表达之间的新相关性，包括吉西他滨反应的多组学特征。离体药物反应的阳性预测价值和新型多组学吉西他滨反应特征需要在未来的研究中得到验证。短期 PDO 培养保留了肿瘤组织的分子特征，并避免了困扰长期的基于表达的亚型变化文化。多组学分析和离体药物筛选数据的整合可识别潜在的预测生物标志物，包括吉西他滨反应的新特征。需要更好的模型来预测患者对膀胱癌治疗的反应。我们开发了一个平台，使用短期培养来最好地模拟每位患者的肿瘤并评估对治疗的潜在敏感性。版权所有 © 2024 欧洲泌尿外科协会。由 Elsevier B.V. 出版。保留所有权利。

Predicting response to therapy for each patient's tumor is critical to improving long-term outcomes for muscle-invasive bladder cancer. This study aims to establish ex vivo bladder cancer patient-derived organoid (PDO) models that are representative of patients' tumors and determine the potential efficacy of standard of care and curated experimental therapies.Tumor material was collected prospectively from consented bladder cancer patients to generate short-term PDO models, which were screened against a panel of clinically relevant drugs in ex vivo three-dimensional culture. Multiomic profiling was utilized to validate the PDO models, establish the molecular characteristics of each tumor, and identify potential biomarkers of drug response. Gene expression (GEX) patterns between paired primary tissue and PDO samples were assessed using Spearman's rank correlation coefficients. Molecular correlates of therapy response were identified using Pearson correlation coefficients and Kruskal-Wallis tests with Dunn's post hoc pairwise comparison testing.A total of 106 tumors were collected from 97 patients, with 65 samples yielding sufficient material for complete multiomic molecular characterization and PDO screening with six to 32 drugs/combinations. Short-term PDOs faithfully represent the tumor molecular characteristics, maintain diverse cell types, and avoid shifts in GEX-based subtyping that accompany long-term PDO cultures. Utilizing an integrative approach, novel correlations between ex vivo drug responses and genomic alterations, GEX, and protein expression were identified, including a multiomic signature of gemcitabine response. The positive predictive value of ex vivo drug responses and the novel multiomic gemcitabine response signature need to be validated in future studies.Short-term PDO cultures retain the molecular characteristics of tumor tissue and avoid shifts in expression-based subtyping that have plagued long-term cultures. Integration of multiomic profiling and ex vivo drug screening data identifies potential predictive biomarkers, including a novel signature of gemcitabine response.Better models are needed to predict patient response to therapy in bladder cancer. We developed a platform that uses short-term culture to best mimic each patient's tumor and assess potential sensitivity to therapeutics.Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.