Establishment of organoids derived from biliary tract carcinomas and its application for drug screening

Background Biliary tract carcinomas (BTCs) are epithelial malignancies arising in the region between the intrahepatic bile ducts and the ampulla of Vater. Patients with inoperable BTCs generally receive chemotherapy regimens including gemcitabine. However, the effect of these drugs is limited, and the 5-year survival rates of patients are very low. Currently, however, there are no defined models that can recapitulate the features of BTCs. The newly developed 3D culture system known as “organoid culture” allows long-term expansion of stem cells into cyst-like structures (organoids) with properties resembling those of the original tissues. To develop in vitro preclinical models of BTCs, we established patient-derived BTC organoids and applied them for drug screening. Methods We established organoids using surgically resected cancer tissues obtained from patients with BTC. Driver gene mutations and gene expression profiles were analyzed in these BTC organoids. To investigate the possibility of drug repositioning, we screened a compound library consisting of 339 drugs employed clinically for their ability to suppress BTC organoids. Results We successfully established organoid lines derived from intrahepatic cholangiocarcinoma, gallbladder cancer and neuroendocrine carcinoma of the ampulla of Vater. These patient-derived BTC organoids were cultured stably for over one year and closely recapitulated the histopathological features of the primary tumors. Gene expression profiling of BTC organoids revealed enrichment of cancer-associated genes such as HOXB7, SOX2 and miR-17-92 cluster, and suppression of MMP1 and CD24. From a group of 339 medicines already in clinical use, we successfully screened 22 compounds that were able to significantly suppress BTC organoids. As expected, these compounds were mainly anticancer agents, including antimicrotubule agents, tyrosine kinase inhibitors, antimetabolite agents, mTOR inhibitors and proteasome inhibitors. Interestingly, four compounds that are not classified as anticancer agents showed significant suppression of the growth of BTC organoids. Conclusions These drugs that are not classified as anticancer agents but suppress BTC organoids could be potentially applied for the prevention and treatment of BTC patients with minimal side effects. Patient-derived organoids may be a powerful preclinical model for clarification of molecular pathogenesis and discovery of biomarkers and therapeutic drugs for refractory cancers. Citation Format: Yoshimasa Saito, Toshihide Muramatsu, Nao Yoshikawa, Ryoei Uchida, Ryo Furukawa, Aya Kitahara, Tomoko Yamaguchi, Masaki Kimura, Hidetsugu Saito. Establishment of organoids derived from biliary tract carcinomas and its application for drug screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1921.