Department of Investigative Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Gastrointestinal Surgery, Tokyo Women's Medical University, Tokyo, Japan.
Department of Investigative Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Eur J Cancer. 2021 May;148:239-250. doi: 10.1016/j.ejca.2021.01.047. Epub 2021 Mar 19.
Pancreatobiliary cancer is a highly aggressive tumour with a dismal prognosis. Personalised medicine represents a promising and effective therapeutic approach for this intractable disease. In this study, we aimed to establish a system for identifying and testing genotype-oriented targeted drugs for pancreatobiliary cancers by combining exome sequencing and organoid culture of primary tumours.
Tumour cells isolated from resected tumours were subjected to organoid cultures based on published protocols with modifications. Exome sequencing was performed on the primary tumours. Histopathological and molecular features of the primary tumours were validated in the corresponding organoids. Genotype-oriented candidate targeted drugs were identified from exome sequencing, and their efficacies were tested in the organoids.
Organoid cultures succeeded in 30 of 54 (55.6%) cases. Six primary cancers of the biliary tract and gall bladder were subjected to exome sequencing, which revealed a variety of somatic mutations of genes involved in signalling pathways, epigenetic modifiers, genome maintenance and metabolic enzymes. Most of the organoids of these 6 cases showed identical histopathological features and genomic aberrations as those of the primary tumours. Some of the aberrations were candidates for targeted therapies. Integrin-linked kinase (ILK) was one such candidate target, and an ILK inhibitor was confirmed to suppress proliferation of patient-derived organoids.
By combining exome sequencing and organoid culture, our model enabled to identify genotype-oriented targets for personalised medicine and to test efficacies of candidate targeted drugs in the organoids. The current proof-of-concept approach could increase therapeutic opportunities for patients with pancreatobiliary cancers.
胰胆管癌是一种侵袭性很强且预后极差的肿瘤。个性化医疗代表了一种针对这种难治性疾病的有前途且有效的治疗方法。在这项研究中，我们旨在通过外显子组测序和原代肿瘤类器官培养相结合，建立一种用于鉴定和测试胰胆管癌基于基因型的靶向药物的系统。
从切除的肿瘤中分离出肿瘤细胞，根据已发表的方案并加以修改进行类器官培养。对原发肿瘤进行外显子组测序。在相应的类器官中验证原发肿瘤的组织病理学和分子特征。从外显子组测序中确定基于基因型的候选靶向药物，并在类器官中测试其疗效。
在 54 例（55.6%）病例中成功进行了类器官培养。对 6 例胆道和胆囊的原发性癌症进行了外显子组测序，揭示了涉及信号通路、表观遗传修饰剂、基因组维持和代谢酶的基因的各种体细胞突变。这 6 例中的大多数类器官均表现出与原发肿瘤相同的组织病理学特征和基因组异常。其中一些异常是靶向治疗的候选者。整合素连接激酶（ILK）就是这样的候选靶点，一种 ILK 抑制剂被证实可抑制患者来源的类器官的增殖。
通过结合外显子组测序和类器官培养，我们的模型能够鉴定针对个性化医疗的基于基因型的靶标，并在类器官中测试候选靶向药物的疗效。这种当前的概念验证方法可以为胰胆管癌患者增加治疗机会。
