Final Report Summary - COLONCAN (Targeting downstream effectors of Wnt signaling in colorectal cancer) Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer death. The APC (Adenomatous Polyposis Coli) gene in mutated in approximately 80% of CRC and is the initiating driver mutation. The aims of this project were to:1) Understand how another common mutation, of the KRAS gene, cooperates with loss of APC2) Develop models of CRC that recapitulate metastatic colon cancer.We utilised state of the art technologies (translation, metabolism and protein profiling) to elucidate the mechanisms by which Kras mutation alters signalling within APC deficient cells. Our work suggests that there is increased protein production, nutrient stress and dependency upon metabolism. There is also resistance to many targeted therapies used in colon cancer. We hope that targeting nutrient stress and/or metabolism may specifically kill CRC cells carrying both APC and KRAS mutations (approximately 40%). Importantly we have identified exciting combinations that appear to have efficacy in this genetic background. Secondly, we have generated a suite of new mouse models of invasive CRC, using genetic engineering and ex vivo organoid cultures. Importantly, by using the recently developed "crypt culture/organoid" technology, these models are transplantable. Most of our new models have mutations or overexpression of the TGFβ pathway. These new models recapitulate gene expression signatures of human colorectal cancer and can be used to test therapeutic agents and for modelling stratified clinical trials. We have encouraging data that inhibiting TGFβ or CXCR2 signalling may be of benefit even when metastatic disease is present. These models should also provide an excellent platform for testing immunotherapy combinations.
