Abstract 4836: A colorectal cancer organoid library provides a promising screening tool for assessment of chemosensitivity

Abstract

Abstract Colorectal cancer (CRC) is a leading cause of cancer mortality and the third most common cancer worldwide. Annually, there are more than 900,000 cases occur worldwide, nearly 500,000 of which are fatal. CRC have accumulated defects in oncogenes and tumor suppressor genes. Many CRCs likely arise through clonal outgrowth and evolution of an epithelial cell or cells in an adenomatous precursor lesion via so-called adenoma-carcinoma sequence. Intensive studies have uncovered that the spectra of these genetic modifications are highly variable across the tumors. While genetic changes in tumors of individual patients can be assessed in several stratified methods, these data still need to be properly interpreted for necessitating model systems for analysis of chemosensitivity of CRC patients, which could enable us to organically coordinate among genotype-to-phenotype correlations, clinicopathological features and clinical outcomes. One of the most plausible models for implementing this magnificent scheme is most likely to be “organoid”, which is a novel 3D intestinal stem cell culture system and has successfully reconstitute normal and cancerous colonic crypts in in vitro through using the specific niche factors in a dish, such as EGF, Wnt3a, Rspondin-1 and Noggin, together with a TGF-b inhibitor and a p38 inhibitor. Two groups, Van der Wetering et.al and Fujii et.al, have previously reported the establishment of organoid biobank of colorectal cancer patients, and both of them proved the usefulness of this platform for underpinning the significance of genotype-phenotype analysis in every single patient and providing insights into tailor-made therapy in CRC. In this present study, we generated a pairs of cancerous and normal adjacent organoids from a number of CRC patients and aimed to figure out sustainability and reproducibility of CRC organoids especially in terms of phenotypic and genotypic features even after several times of passage. We compared growth activity and histopathological features of the CRC organoids among several time points after the passage by evaluating ki-67 labeling index and morphology of the organoids. In order to confirm the stability of genetic status of representative cancer-related genes, we focused on TP53, KRAS, BRAF, and MSI status. We then tried to elucidate the difference of chemosensitivity between MSI-high and MSI-low/MSS CRC cases with similar genetic background in most of the representative cancer-related genes. Although further in-depth studies on CRC organoids are needed, our approach would be instrumental in accurately predicting the drug sensitivity of CRC patients, which could possibly lead to the establishment of personalized medicine in CRC. Citation Format: Naoya Sakamoto, Akira Ishikawa, Ririno Honma, Takao Hinoi, Naohide Oue, Kazuhiro Sentani, Shoichiro Mukai, Tomohiro Adachi, Hiroyuki Egi, Hideki Ohdan, Wataru Yasui. A colorectal cancer organoid library provides a promising screening tool for assessment of chemosensitivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4836. doi:10.1158/1538-7445.AM2017-4836