Abstract 3870: Validation of a canine intestinal organoid model as a preclinical screen to assess GI toxicity in novel oncology drug development

Abstract

Abstract Gastrointestinal (GI) toxicity is a common and often severe dose-limiting side effect of chemotherapy. Symptoms include diarrhea, dehydration and ulceration leading to increased susceptibility to infection, due in part to the damage or loss of crypt and/or villi structures in the small intestine. As improvements in oncology therapeutics are pursued to acquire more efficacious agents, assessment of their potential GI toxicity is therefore crucial. The mouse small intestinal in vitro organoid model was first described by Sato et al. in 2009 and has been used to help understand the intestinal stem cell hierarchy and their regulatory genes. In parallel the pharmaceutical industry has been gaining interest, with the aim of validating organoids as a screening step prior to in vivo studies. We have previously developed and validated the organoid model as a screening tool to predict GI toxicity or mucosal regeneration in three species: mouse, rat and human. These techniques have recently been employed with canine tissue, successfully establishing canine organoids and assessing their suitability in our screening models in comparison to other species. The intestinal organoid culture conditions were designed to mimic the stem cell niche allowing cell differentiation and proliferation to occur. All expected intestinal lineages were present in the canine organoids and the epithelial hierarchy closely resembled that observed in vivo. The response of canine organoids to cytotoxic insult via treatment with common colorectal chemotherapy drugs correlated with their known responses in vivo. The organoid branches, which represent the crypts and contain the proliferative cells, were first lost upon treatment before complete organoid death, presumably due to the loss of stem cells within the branches. The level of toxicity associated with these chemotherapy agents was determined by calculation of IC50 values, which were then compared to published in vivo data, upon which correlation in drug sensitivity within the GI was observed. In summary, we conclude that the canine organoids, alongside other already validated organoid species, are a predictive preclinical model that can be used to identify any potential on-target, off-tissue GI toxicities induced by novel oncology therapeutics. Toxicity and mechanism of action can all be addressed in vitro to potentially reduce in vivo experimentation. Citation Format: Sarah M. Hoyle, Nicola Tonge, Charlotte Seaman, Mark Drinkwater, Adam Bonas, Vicky Murray-Tait, Aude-Marine Bonavita, Cath Booth. Validation of a canine intestinal organoid model as a preclinical screen to assess GI toxicity in novel oncology drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3870.