Identifying non-toxic chemoradiation combinations for abdominopelvic tumours using an intestinal epithelial organoid assay

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Worldwide annually half a million patients receive radiotherapy to their abdomen or pelvis, for gastrointestinal and genitourinary cancers, often in combination with chemotherapy, which can make the local bowel side effects of radiotherapy worse. These can have a major impact on the patient’s quality-of-life. There is therefore an urgent clinical need to find less toxic radiosensitisers. One method of studying potential agents is to perform the intestinal crypt assay in mice, but if an in vitro assay could be developed which mimics the crypt assay, this would allow us to study many more compounds. Both murine and human intestinal epithelial organoids can now be generated in vitro for testing.

We wish to test the hypothesis that mouse and human in vitro epithelial organoids can replace the benchmark in vivo intestinal crypt assay in assessing intestinal toxicity of established and proposed new chemoradiation combinations.

The student shall develop methods using mouse and human intestinal epithelial organoids which give a similar read-out of crypt damage/regeneration to the in vivo crypt assay and investigate the differential effects of RT and CRT on gene expression (mRNA) along the GI tract, as this may influence responses to the same treatment in different tumour sites. Secondary supervision will be provided by Anderson Ryan.

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