Exploiting a human intestinal organoid platform for development of personalised medicine for colon cancer

Champion, Jordan Hannah Rose (2022) Exploiting a human intestinal organoid platform for development of personalised medicine for colon cancer. Masters thesis, University of East Anglia.

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Abstract

The colonic epithelium forms a vital barrier between harmful luminal contents and the underlying host tissues. It is comprised of millions of invaginations called crypts, at the base of which resides a stem cell population which proliferates and gives rise to all cell types found in the gut. The intestinal epithelium is the most rapidly renewing tissue in the human body, and unsurprisingly it is the site of initiation for a number of diseases including colorectal cancer and Inflammatory Bowel Diseases. Notwithstanding advances in chemotherapeutic strategies, patients with colorectal cancer currently have less than a 50% survival rate after 5 years. Further, the current treatment strategies are highly cytotoxic for all rapidly renewing tissues, and therefore have dose-limiting side effects. This highlights a grave need for the development of novel and better therapies and treatments. Developing a new model system for which these therapies are tested on, is another vital step in the fight for colorectal cancer treatment. The Williams’ Laboratory, have developed a patient-matched organoid and tumouroid personalised medicine pipeline to be used for the investigation of novel chemotherapeutic strategies for CRC. The aim of this thesis was to assess the efficacy of a personalised medicine pipeline, and study the implications that inhibitors have on key pathways that are highlighted by the pipeline.

Using whole exome sequencing the mutational status of key homeostatic genes were determined in four patient matched tumouroid lines (UEA003, UEA005, UEA006 and UEA007). Using cell viability assays the effect of chemotherapy (5-FU) and these key pathway inhibitors were determined on the patient-matched organoid and tumouroids. We observed patient-specific differential sensitivity to standard of care chemotherapy drugs, for example tumouroids derived from patient UEA005 were highly sensitive to low concentrations of SOC chemotherapy, whereas at low concentrations the organoids retained viability. Other tumouroid lines showed less sensitivity to low concentrations of SOC chemotherapy, suggesting that adjuvant or different therapies might benefit these patients more. Taking these factors into consideration holds promise to benefit patient care, in that patients who show little sensitivity to a specific chemotherapy drug could potentially be spared treatment and side effects in the clinic.

The patient-matched organoid and tumouroid system showed promise for the testing of standard of care chemotherapy and inhibitors based upon their mutational status. However further investigation to determine if findings in this thesis matched that of the clinic would be needed. The findings in this thesis could help identify promising next steps for the development of personalised medicine.

Item Type:	Thesis (Masters)
Faculty \ School:	Faculty of Science > School of Biological Sciences
Depositing User:	Chris White
Date Deposited:	14 Dec 2023 11:57
Last Modified:	14 Dec 2023 11:57
URI:	https://ueaeprints.uea.ac.uk/id/eprint/93978
DOI:

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