シイハラ　マサヒロ   Shiihara Masahiro   椎原　正尋    所属   医学部 医学科（東京女子医科大学病院）    職種   助教
論文種別	原著
言語種別	英語
査読の有無	査読なし
表題	Development of a system combining comprehensive genotyping and organoid cultures for identifying and testing genotype-oriented personalised medicine for pancreatobiliary cancers.
掲載誌名	正式名：European journal of cancer 略　 称：Eur J Cancer ISSNコード：18790852/09598049
掲載区分	国外
巻・号・頁	148,pp.239--250
著者・共著者	Shiihara Masahiro, Ishikawa Tomohiko, Saiki Yuriko, Omori Yuko, Hirose Katsuya, Fukushige Shinichi, Ikari Naoki, Higuchi Ryota, Yamamoto Masakazu, Morikawa Takanori, Nakagawa Kei, Hayashi Hiroki, Mizuma Masamichi, Ohtsuka Hideo, Motoi Fuyuhiko, Unno Michiaki, Okamura Yasunobu, Kinoshita Kengo, Furukawa Toru
担当区分	筆頭著者
発行年月	2021/05
概要	BACKGROUND: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.METHODS: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.RESULTS: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.CONCLUSIONS: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.
DOI	10.1016/j.ejca.2021.01.047
PMID	33752134