Candiolo Cancer Institute - FPO IRCCS, Candiolo, Torino, Italy.
Department of Oncology, University of Torino, Candiolo, Torino, Italy.
Nat Commun. 2024 Aug 29;15(1):7495. doi: 10.1038/s41467-024-51909-2.
The breadth and depth at which cancer models are interrogated contribute to the successful clinical translation of drug discovery efforts. In colorectal cancer (CRC), model availability is limited by a dearth of large-scale collections of patient-derived xenografts (PDXs) and paired tumoroids from metastatic disease, where experimental therapies are typically tested. Here we introduce XENTURION, an open-science resource offering a platform of 128 PDX models from patients with metastatic CRC, along with matched PDX-derived tumoroids. Multidimensional omics analyses indicate that tumoroids retain extensive molecular fidelity with parental PDXs. A tumoroid-based trial with the anti-EGFR antibody cetuximab reveals variable sensitivities that are consistent with clinical response biomarkers, mirror tumor growth changes in matched PDXs, and recapitulate EGFR genetic deletion outcomes. Inhibition of adaptive signals upregulated by EGFR blockade increases the magnitude of cetuximab response. These findings illustrate the potential of large living biobanks, providing avenues for molecularly informed preclinical research in oncology.
癌症模型的广度和深度有助于药物发现工作的成功临床转化。在结直肠癌 (CRC) 中，由于缺乏来自转移性疾病的大规模患者来源异种移植 (PDX) 和配对类器官的大型数据集，模型的可用性受到限制，而这些正是通常测试实验性疗法的地方。在这里，我们介绍了 XENTURION，这是一个开放科学资源，提供了一个包含 128 个转移性 CRC 患者 PDX 模型的平台，以及匹配的 PDX 衍生类器官。多维组学分析表明，类器官保留了与亲本 PDX 广泛的分子保真度。一项基于类器官的针对抗 EGFR 抗体西妥昔单抗的试验显示出可变的敏感性，与临床反应生物标志物一致，反映了匹配 PDX 中的肿瘤生长变化，并重现了 EGFR 基因缺失的结果。抑制 EGFR 阻断上调的适应性信号增加了西妥昔单抗反应的幅度。这些发现说明了大型活体生物库的潜力，为肿瘤学中基于分子的临床前研究提供了途径。
