Head and neck squamous cell carcinoma (HNSCC) is the sixth commonest cancer in the UK. Despite recent therapeutic developments, survival rates remain poor, particularly in advanced cancer and Human Papilloma Virus (HPV) negative disease. Novel treatments approaches are therefore urgently required. The type-1 insulin-like growth factor receptor (IGF-1R) regulates cellular growth and survival and is over-expressed in a range of cancer types. Other groups reported that inhibition of IGF-1R reduces HNSCC cell survival and sensitises to ionising radiation, but a clinical trial of IGF-1R inhibition as monotherapy was inactive in unselected palliative patients with HNSCC. These data suggest that predictive biomarkers for response to IGF-1R inhibition are required. The aims of this project were threefold. The first objective was to define factors associated with morbidity and mortality in patients with oropharyngeal cancer (OPSCC) treated with primary surgery alone or with adjuvant chemoradiotherapy. The five-year overall and disease specific survival rates were 68% and 78% respectively. In line with previous data, HPV negative status, current smoking status, high tumour T stage and the presence of perineural spread of tumour or lymphovascular invasion were associated with adverse survival outcomes. In surviving patients, quality of life outcomes were evaluated using the University of Washington Quality of Life score and functional outcomes were assessed with the MD Anderson Dysphagia Inventory. Increasing age, higher tumour T stage, lip-splitting mandibulotomy and free flap reconstruction were associated with reduced quality of life outcome scores following multivariate analysis. The second aim was to assess the significance of IGF-1R expression in HNSCC and test for correlates with clinico-pathological variables. Immunostaining of cores from 346 primary HNSCCs showed that IGF-1R expression was higher in tumour tissue than matched benign epithelium. High IGF-1R was significantly associated with reduced overall and disease specific survival, HPV negative status and high tumour T stage, although was not an independent predictor of survival in multivariate analysis. The final aim was to test the utility of IGF-1R inhibition in HNSCC cell lines as monotherapy and in combination with established treatments, aiming to identify predictive biomarkers for resistance to IGF-1R inhibition. In a panel of 6 HNSCC cell lines, the IGF-1R inhibitor BMS-754807 reduced IGF-1R, AKT and ERK phosphorylation in a dose dependent manner. IGF-1R inhibition with BMS-754807 reduced cell survival and sensitised cells to ionising radiation in clonogenic assay, although the magnitude of this effect varied between cell lines. Combination of BMS-754807 with the EGFR inhibitor Gefitinib caused supra-additive reduction in cell survival. Correlation analysis showed a trend towards an association between high levels of phosphorylated AKT and resistance to BMS-754807 monotherapy. To test the hypothesis that RAS signalling conferred resistance to IGF-1R inhibition, cells were infected with retroviral constructs encoding wild-type or mutant activated HRAS. Cells expressing mutant HRAS were more resistant to BMS-754807 than empty vector or wild-type HRAS infected controls, suggesting that HRAS mutation status may represent a biomarker of resistance to IGF-1R inhibition in HSNCC. Taken together, the results from this project highlight the significance of IGF-1R biology in HNSCC, and form the basis for further in-vivo and clinical research.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:689948 |
| Date | January 2016 |
| Creators | Dale, Oliver |
| Publisher | University of Nottingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://eprints.nottingham.ac.uk/33533/ |
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