T. Zhan and M. Zimmermann-Kogadeeva propose to combine their complementary expertise in microbiome research and translational oncology to identify and characterise novel links between gut microbiome drug metabolism and response to cancer therapy in CRC.
They propose to assess the gut microbiome contribution to the metabolism of fluoropyrimidines and multi-kinase inhibitors by integrating results from in vitro bacterial drug metabolism assays and metabolomic profiling of blood and faecal samples from CRC patients. They will use bacterial genetics and gnotobiotic mouse models to determine bacterial species and genes responsible for metabolism of candidate drugs and assess their function in vivo. With this approach, they will mechanistically investigate a previously observed association between bacterial pyrimidine metabolism and the host response to 5-fluorouracil. Furthermore, they will determine the biological effects of candidate bacterial metabolites of fluoropyrimidines and multi-kinase inhibitors on CRC signalling and assess their anti-neoplastic effects in organoid and mouse models. Overall, these studies will establish novel microbiome-based predictors of therapy response and drug toxicity, and uncover links between the gut microbiota drug metabolism and CRC biology that can be therapeutically exploited.