Lu Xiongbing, Hu Chao, Duan Lingxing, Chen Ke, Hao Hua, He Yuanqiao
Department of Urology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China.
Department of Pathology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, 200090, China.
Clin Transl Oncol. 2025 May;27(5):2207-2219. doi: 10.1007/s12094-024-03666-3. Epub 2024 Oct 22.
Bladder cancer is one of the most common malignancies of the urinary system and there's a significant unmet need for new effective therapeutics for bladder cancer. The limited number of available models to study malignant bladder tumors is one of the obstructions in developing bladder cancer therapeutics. Patient-derived xenograft (PDX) and organoid (PDO) models are more representatives of human cancer than cell lines and cell line-derived xenograft (CDX) and are likely to be more promising and efficient in predicting drug response and finding new therapeutics.
Three pairs of patient-derived xenograft (PDX) models of bladder cancer and their corresponding PDX-derived organoids (PDXOs) were successfully established. These models were utilized to assess the efficacy of abemaciclib. The sensitivity of the drug was determined through the Cell Counting Kit-8 (CCK8) assay in PDXO cultures, corroborated by the EdU incorporation assay. Additionally, the in vivo tumor growth was monitored in the matched PDX models.
In vitro PDXO cultures and in vivo PDX tumor models consistently demonstrated that abemaciclib had varying degrees of inhibitory effects across different bladder cancer (BC) patients. Notably, our study further revealed that treatment with abemaciclib significantly modified the expression patterns of CyclinD1/CDK4. This was achieved by not only diminishing their expression levels but also by shifting their expression from a membrane-associated localization to the nucleus.
Our research provided compelling evidence attesting to the reliability and potential of PDX and PDXO models in the realm of precision medicine. These models are instrumental in identifying patients who are likely to respond favorably to a specific drug treatment.
膀胱癌是泌尿系统最常见的恶性肿瘤之一，对新型有效的膀胱癌治疗方法存在重大未满足需求。用于研究恶性膀胱肿瘤的可用模型数量有限是开发膀胱癌治疗方法的障碍之一。患者来源的异种移植（PDX）和类器官（PDO）模型比细胞系以及细胞系来源的异种移植（CDX）更能代表人类癌症，并且在预测药物反应和寻找新的治疗方法方面可能更有前景和效率。
成功建立了三对膀胱癌患者来源的异种移植（PDX）模型及其相应的PDX衍生类器官（PDXO）。利用这些模型评估阿贝西利的疗效。通过在PDXO培养物中进行细胞计数试剂盒-8（CCK8）测定来确定药物的敏感性，并通过EdU掺入测定进行证实。此外，在匹配的PDX模型中监测体内肿瘤生长。
体外PDXO培养和体内PDX肿瘤模型一致表明，阿贝西利对不同的膀胱癌（BC）患者具有不同程度的抑制作用。值得注意的是，我们的研究进一步表明，阿贝西利治疗显著改变了细胞周期蛋白D1/细胞周期蛋白依赖性激酶4（CyclinD1/CDK4）的表达模式。这不仅通过降低它们的表达水平来实现，还通过将它们的表达从膜相关定位转移到细胞核来实现。
我们的研究提供了令人信服的证据，证明了PDX和PDXO模型在精准医学领域的可靠性和潜力。这些模型有助于识别可能对特定药物治疗有良好反应的患者。
