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Title: Human papillomavirus-mediated response of head and neck cancer cells to therapeutic agents
Author: Ayaz, Bushra
ISNI:       0000 0004 6058 1329
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2016
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The dramatic increase in oropharyngeal squamous cell carcinomas (OPSCC) over the past few decades is attributable to oncogenic types of human papillomaviruses (HPV). The presence of HPV in OPSCC has important clinical significance since patients with HPV-positive OPSCC tumours have improved response to conventional therapeutic agents such as radiation and cisplatin compared to those with HPV-negative tumours. The overall aim of this study was to investigate potential mechanisms of improved therapeutic response of HPV-positive OPSCC. Following confirmation of HPV status in a panel of five HPV-positive and two HPV-negative head and neck cancer cell lines, an in vitro model of relative sensitivity to conventional therapeutic agents was established. All HPV-positive cells were more sensitive to radiation and cisplatin compared to HPV-negative cells. Stabilisation of functional p53 tumour suppressor protein was observed following treatment of HPV-positive cells to radiation and cisplatin. Attenuation of p53 in HPV-positive cells increased resistance to these agents indicating sensitivity of these cells to conventional therapeutic agents in vitro is p53- dependent. Furthermore, abrogation of the HPV oncogene E6 also caused stabilisation of p53 and slightly sensitised cells to radiation and cisplatin. The functional role of E6 was further explored by expressing this protein in p53 mutant HPV-negative cells. Interestingly, expression of E6 increased sensitivity of HPV-negative cellsto radiation and slightly to cisplatin. This study went on evaluate the response of the aforementioned panel of cells to targeted and novel therapeutic agents. By contrast to conventional therapeutic agents, HPV-positive cells were more resistant to cetuximab (an inhibitor of the Epidermal Growth Factor Receptor, EGFR) and Tumour Necrosis Factor-related Apoptosis-Inducing Ligand (TRAIL). Expression of EGFR protein in HPV-negative cell lines was consistently high whereas there was variable protein expression in HPV-positive cells; response to cetuximab corresponded to the EGFR protein levels in the latter. An inverse correlation between HPV status EGFR protein expression was also present in formalinfixed paraffin embedded OPSCC tissue samples, but EGFR protein levels did not provide additional prognostic value beyond HPV status in the study cohort. The current study provides an in vitro model of relative sensitivity in HPVpositive OPSCC and possible supportive mechanisms to explain this observation. This study also raises the possibility that HPV-positive OPSCC may be relatively resistant to EGFR-targeted and TRAIL therapies.
Supervisor: Thavaraj, Selvam James ; Tavassoli, Mahvash Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available