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Developing stem-cell containing organoids as a pre-clinical model for colorectal cancer therapeutics

Badder, Luned 2017. Developing stem-cell containing organoids as a pre-clinical model for colorectal cancer therapeutics. PhD Thesis, Cardiff University.
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Colorectal cancer (CRC) is the second most common cause of cancer related deaths in the UK. Whilst identification of molecular events that contribute to the initiation and progression of CRC have facilitated the development of predictive biomarker-driven therapeutics, their success in the clinic has been restricted by the lack of anticipated responses. Furthermore, not all genetic signatures of a tumour have been linked to related drug targets, highlighting the need for novel development of compounds and better therapeutic rationales for the treatment of patient subsets. The limited success of targeted therapies, both within the clinic and drug discovery pipeline, has been attributed to a lack of effective preclinical models that are capable of capturing the complexity of deregulated signalling networks. The development of functional readouts that better represent tumour complexity, is therefore imperative to confirm the effects of hypothesis-driven therapeutics. This thesis therefore aimed to investigate whether 3D CRC organoids , which show a degree of greater complexity compared to preceding in vitro models, could be applied as suitable readouts for stratified medicine programmes and novel compounds within the drug discovery setting. To achieve this, a panel of 3D patient-derived CRC organoids cultures were generated. Suitable methodologies were established to facilitate organoids towards quantifiable, robust assay formats. This platform enabled the study of organoids within an in vitro clinical trial setting, based upon treatments administered within the ongoing FOCUS 4 stratified medicine trial, exploring organoids’ capacity to predict responses to targeted therapeutics. Organoids were differentially sensitive to therapies, irrespective of their genotypic background. It will be interesting to see whether prediction-response correlations observed in this study are typical of those seen in patients and whether functional readouts will be required to support stratified medicine approaches. Quantitative image-based analysis was also found to identify signatures of organoid responses against novel Wnt signalling inhibitors, suggesting that organoids may constitute a platform that can be used to study the effects of targeting a prospective cancer stem cell (CSC) population. Taken together, the findings in this thesis highlight the utility of patient derived organoid models as a functional model to evaluate novel therapeutic strategies, potentially generating clinically relevant hypotheses.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Subjects: Q Science > QH Natural history > QH301 Biology
Funders: Cancer Research Wales
Date of First Compliant Deposit: 1 March 2018
Last Modified: 20 May 2021 13:52

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