The 5-year survival rate of head and neck squamous cell carcinoma (HNSCC) has remained at ~50% for over 50 years. HNSCC is categorised by multiple anatomical sites, but oral (oral SCC) and oropharyngeal squamous cell carcinoma (OPSCC) account for approximately 90% of all cases. At the time of writing, only one targeted agent, cetuximab (a monoclonal antibody targeting the epithelial growth factor receptor), has been approved for the treatment of recurrent/metastatic HNSCC. However, despite the high expression of EGFR in oral SCC tumour samples, the clinical benefit of cetuximab has been modest thus far. Using a phenotypic screening approach, I sought to identify putative therapeutic targets. A whole genome siRNA screen carried out using an aggressive patient-derived cell line (‘Liv7k’) in normoxic and hypoxic conditions provided the foundation for this project. In addition, a drug-repurposing screen tested the efficacy of 1,351 compounds, approved for cancer and non-cancer indications. A number of approaches were used to identify potential targets, including a whole genome siRNA screen in normoxic and hypoxic conditions, a drug-repurposing screen, and a data multiplexing approach combining the two screens with pathway analysis and datasets from The Cancer Genome Atlas and the International Cancer Genome Consortium. Genomic characterisation of oral cancer cell lines confirmed the importance of a previously identified frequently amplified region of chromosome three, which contains a number of driver genes in HNSCC. In addition, a differential susceptibility of oral SCC cells in hypoxia formed the basis of a line of inquiry centred on triglyceride and ether lipid metabolism. Finally, compound screening identified a dependence of oral SCCs on cysteinyl leukotriene signalling, which is involved in inflammatory conditions such as asthma.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:744122 |
| Date | January 2018 |
| Creators | Davidson, Matthew Alexander |
| Publisher | University of Glasgow |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://theses.gla.ac.uk/9018/ |
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