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Inhibition of Autophagy Protease ATG4B as a Therapeutic Option for Pancreatic Ductal Adenocarcinoma

Aley, Natasha Amy; (2023) Inhibition of Autophagy Protease ATG4B as a Therapeutic Option for Pancreatic Ductal Adenocarcinoma. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Pancreatic ductal adenocarcinoma is a horrific disease, with only ~7% of patients surviving more than 5 years. Growing evidence shows that autophagy inhibition could reduce tumour progression and synergise with chemotherapeutics. Autophagy is a recycling system within cells, which is hijacked by cancer to sustain aberrant proliferation. ATG4B is a cystine protease involved in the autophagy process. Knockout or inhibition of ATG4B causes a reduction in autophagy. The aim of this thesis is to validate ATG4B as a drug target for pancreatic ductal adenocarcinoma and to identify novel small molecules and PROTACs that inhibit ATG4B activity. In Chapter 3 pancreatic ductal adenocarcinoma cell lines and ATG4B knockout cell lines are characterised. In Chapter 4 these cell lines are used in the development of a pancreatic ductal adenocarcinoma 3D model, which shows that ATG4B knockout can cause spheroids to disintegrate. This is further investigated in Chapter 5, which shows that ATG4B knockout in PANC-1 causes changes in motility, clonality, protein and mRNA expression. Interestingly, b-catenin expression is highly significantly reduced in ATG4B knockout PANC-1 cells, which cannot be rescued with the addition of ATG4B back into ATG4B knockout (Chapter 6). Finally, in Chapter 7 compounds and PROTACs were screened for ATG4B inhibition and degradation, respectively. Overall, this thesis of work shows that ATG4B knockout can impact spheroid formation, motility, clonality, protein and mRNA expression, accompanied by a reduction in b-catenin expression. These findings could hold great therapeutic advancements for patients with pancreatic ductal adenocarcinoma.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Inhibition of Autophagy Protease ATG4B as a Therapeutic Option for Pancreatic Ductal Adenocarcinoma
Language: English
Additional information: Copyright © The Author 2023. 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 Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10172387
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