Establishing pre-clinical models for advanced colorectal cancer

© 2019 Suad Mohamed AbdirahmanColorectal cancer (CRC) is the third most common cancer worldwide, and one of the most common cancers in Australia. When detected early, there are multiple treatment options for CRC; however, patients often relapse and ultimately succumb to metastatic disease. 5-Fluorouracil (5-FU)-based chemotherapy is a common first-line treatment for CRC. However, chemotherapy response rates remain low, often due to the development of resistance, which is one of the main limitations in the management of the disease. Our understanding of the progression of CRC, and the development of new therapeutics for CRC, has been facilitated in part by animal models. Unfortunately, many murine models of CRC are adenomas, with few patient-derived models, or models of metastatic disease available. As a result, the opportunity to improve our understanding of the pathogenesis of advanced disease, or test the efficacy of novel therapeutics for advanced disease, is limited. The overarching aim of this PhD thesis was to generate new models of CRC to facilitate the study of this devastating disease. A biobank of 16 CRC patient-derived xenografts (PDXs) was successfully established in immunocompromised mice. These PDX lines recapitulated the histopathological, molecular and genetic features of the original patient tumours. These PDXs represent new pre-clinical tool that will allow for testing the efficacy of potential new therapeutics. A selection of four PDX lines underwent serial 5-FU treatment to generate a library of resistant PDXs, and their matched non-resistant chemonaive controls. The 5-FU resistant PDX tumours underwent an upregulation of the IL-11R/STAT3/Bcl-2 pathway in response to 5-FU. This suggests that IL-11 signalling is elevated in response to 5-FU to promote tumour cell survival. Thus, targeting the IL-11/IL-11R signalling may be a promising strategy to overcome chemoresistance. Finally, four different genetically-engineered mouse models (GEMMs) were established to generate a reproducible model of metastatic CRC. It was found that mutations in Apc (or dysregulation of Wnt signalling) restricted to the colonic epithelium lead to the formation of adenomas, as did the addition of mutations in Tp53. The combination of Apc mutations with Tp53 and Kras mutations lead to an earlier tumour onset, but did not result in metastasis, contrary to previous reports in the literature. It was found however, that mutations in Tp53 and Kras in the stem cell compartment, combined with dysregulation of Wnt signalling, lead to potential metastasis to the liver. However, this did not occur in 100% of the animals, and is thus not amenable to therapeutic studies. Future studies will incorporate alterations to TGFb signalling, in an effort to increase the reproducibility of metastasis. These studies highlight the lack of our understanding of the drivers required for tumour cell metastatic potential. Taken together, the research described in this thesis has led to the generation of a number of new animal models of CRC, that may be of use to future studies of the pathogenesis and treatment of this disease