Wu, Yiting;
(2024)
Novel small molecule drug candidate (ULI-015) to reduce bowel cancer development: From discovery in familial adenomatous polyposis patient-derived intestinal organoid models to translation in intestinal neoplasia animal models.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
My PhD research project aimed to discover and develop new compounds isolated from traditional Chinese medicines to treat serious gastrointestinal diseases. I searched the published scientific literature and acquired 38 sources of dried plant material. One extract, PLE015, redirected in vitro cell production of precancerous APC+/- cystic intestinal organoids into healthy-appearing organoids (18 familial adenomatous polyposis (FAP) patients, Apc Min/+ mice, and APC1311/+ pigs). The APC tumour suppressor gene is the first step in a series of mutations leading to intestinal polyps and colorectal cancer (CRC). I collaborated closely with two expert chemists to isolate and extensively characterise the biological and physiochemical properties of the active component(s) in the PLE015 extract. It involved optimising extraction and purification strategies using high performance counter current chromatography (HPCCC) followed by preparative reverse phase HPLC to isolate the active small molecule, ULI-015, to homogeneity. Extensive physiochemical characterisation of ULI-015 revealed a stable, soluble compound with predicted gut permeability. Oral administration of the PLE015 extract and ULI-015 small molecule to Apc/+ Min mice reduced polyp formation in young mice and established polyps in older mice compared to the vehicle control. No in vivo toxicity has been observed. Half of the PLE015 and ULI-015 mice survived three weeks longer than vehicle control mice. The anatomy and physiology of the APC1311/+ pig model is more relevant to humans. Endoscopic examination after one month indicated a reduction in the number and size of polyps in APC1311/+ pigs treated daily with the PLE015 extract compared to untreated controls. Organoids derived from polyps of treated pigs showed normal cell production compared to precancerous cysts in untreated pigs. PLE015 profoundly reduced polyp progression at 3.5 months. After six months, the polyps from treated pig regressed and the health of mucosa restored.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Novel small molecule drug candidate (ULI-015) to reduce bowel cancer development: From discovery in familial adenomatous polyposis patient-derived intestinal organoid models to translation in intestinal neoplasia animal models |
| Language: | English |
| Additional information: | Copyright © The Author 2024. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10193687 |
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