Peritoneal metastasis of colorectal cancer (pmCRC): Identification of predictive molecular signatures by a novel preclinical platform of matching pmCRC PDX/PD3D models

14 PDX models of pmCRC were established, including 9 matched PD3D/PDX models, and treatment response to 17 SoC and targeted therapies was monitored, which resulted in drug-dependent inter- and intra-patient specific growth inhibition. Analysis of the molecular data of the models and patient tissue resulted in the identification of predictive biomarkers for treatment with 5-FU, irinotecan, trametinib, erlotinib, cetuximab and avastin, oxaliplatin, selumetinib, docetaxel and everolimus. Conclusions: The establishment of a preclinical drug testing platform based on in vitro and in vivo matched pmCRC models, molecularly characterized by multi-omics technology, facilitated the identification of predictive biomarkers for treatment response, as well as cancer relevant signatures for effective therapies, ready for validation in clinical cohorts. Transcriptomic analysis of pmCRC patient metastases (n=13), corresponding PDX tumors (n=14) and matching PD3D cell culture models (n=8).

本研究构建了14例患者来源转移性结直肠癌（patient-derived metastatic colorectal cancer, pmCRC）患者来源异种移植（Patient-Derived Xenograft, PDX）模型，其中包含9株匹配的患者来源三维（Patient-Derived 3D, PD3D）/PDX模型；本研究对17种标准治疗（Standard of Care, SoC）及靶向治疗的治疗响应进行监测，结果观察到药物依赖性的患者间及患者内特异性生长抑制现象。通过对模型及患者组织的分子数据开展分析，本研究成功鉴定出针对5-氟尿嘧啶（5-Fluorouracil, 5-FU）、伊立替康（irinotecan）、曲美替尼（trametinib）、厄洛替尼（erlotinib）、西妥昔单抗（cetuximab）、贝伐珠单抗（avastin）、奥沙利铂（oxaliplatin）、司美替尼（selumetinib）、多西他赛（docetaxel）以及依维莫司（everolimus）治疗的预测性生物标志物。结论：本研究构建了基于体外-体内匹配pmCRC模型的临床前药物检测平台，该平台通过多组学技术完成分子表征，可助力识别治疗响应相关预测生物标志物以及有效治疗方案的癌症相关特征，相关成果可在临床队列中开展验证。本研究对13例pmCRC患者转移灶、14株对应PDX肿瘤及8株匹配的PD3D细胞培养模型进行了转录组学分析。