Patient-derived xenograft (PDX) tumor models are essential for identifying new biomarkers, signaling pathways and novel targets, to better define key factors of therapy response and resistance mechanisms. Therefore, this study aimed at establishing pancreas carcinoma (PC) PDX models with thorough molecular characterization, and the identification of signatures defining responsiveness toward drug treatment. In total, 45 PC-PDXs were generated from 120 patient tumor specimens and the identity of PDX and corresponding patient tumors was validated. The majority of engrafted PDX models represent ductal adenocarcinomas (PDAC). The PDX growth characteristics were assessed, with great variations in doubling times (4 to 32 days). The mutational analyses revealed an individual mutational profile of the PDXs, predominantly showing alterations in the genes encoding KRAS, TP53, FAT1, KMT2D, MUC4, RNF213, ATR, MUC16, GNAS, RANBP2 and CDKN2A. Sensitivity of PDX toward standard of care (SoC) drugs gemcitabine, 5-fluorouracil, oxaliplatin and abraxane, and combinations thereof, revealed PDX models with sensitivity and resistance toward these treatments. We performed correlation analyses of drug sensitivity of these PDX models and their molecular profile to identify signatures for response and resistance. This study strongly supports the importance and value of PDX models for improvement in therapies of PC.
患者来源的异种移植（PDX）肿瘤模型对于识别新的生物标志物、信号通路和新靶点至关重要，有助于更准确地界定治疗反应的关键因素及耐药机制。因此，本研究旨在建立具有全面分子特征表征的胰腺癌（PC）PDX模型，并识别定义药物治疗反应性的特征标志。研究共从120例患者肿瘤样本中成功构建了45个PC-PDX模型，并对PDX与对应患者肿瘤的一致性进行了验证。大多数移植成功的PDX模型为导管腺癌（PDAC）。通过评估PDX生长特性，发现其倍增时间存在显著差异（4至32天）。突变分析揭示了PDX模型具有个体化的突变谱，主要表现为KRAS、TP53、FAT1、KMT2D、MUC4、RNF213、ATR、MUC16、GNAS、RANBP2和CDKN2A等基因的变异。对PDX模型进行标准治疗药物（吉西他滨、5-氟尿嘧啶、奥沙利铂、白蛋白结合型紫杉醇）及其联合方案的敏感性测试，结果显示不同PDX模型对这些治疗方案呈现敏感或耐药特性。我们通过分析这些PDX模型的药物敏感性与分子特征之间的相关性，成功鉴定了治疗反应与耐药的特征标志。本研究有力证实了PDX模型在改进胰腺癌治疗方案方面的重要价值。
肿瘤(癌症)患者之家