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Title: Prognostic biomarkers for head and neck squamous carcinoma
Author: El-Attar, Radien
Awarding Body: King's College London (University of London)
Current Institution: King's College London (University of London)
Date of Award: 2013
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Head and neck cancer is the 6th most common cancer and is generally treated with surgery and post surgical radiotherapy (RT) alone or in combination with chemotherapy (CT). Over 50% of the patients fail to respond to such treatment while suffering the undesirable side effects of radio-chemotherapy. This highlights the need for new strategies to be able to select patients who could benefit from a specific treatment type to spare cost and suffering to the patients. Furthermore, there is need for targeted and effective therapeutics for this disease. TRAIL and Smac mimetics are novel promising anticancer agents. However, their effect on head and neck cancers so far has not been tested. The main objective of this research was to investigate biomarkers which could predict response of head and neck squamous cell carcinoma (HNSCC) to novel and conventional therapies. This has been conducted using two different approaches: The first was to test the sensitivity of HNSCC cell lines to two novel anticancer therapeutic agents, TRAIL and Smac mimetics, and further to identify the biomarkers which could predict response of HNSCC cell lines to these drugs. Furthermore, the underlying mechanisms by which these two agents induce apoptosis in HNSCC cell lines were examined. Nine HNSCC cell lines were tested for their sensitivity to either recombinant TRAIL (h-IZTRAIL) and/or Smac mimetic (Smac59). The pathways involved in their apoptotic response were studied using western blotting, enzyme linked immunosorbent assays and FACS analysis. Overexpression and knockdown experiments were used to examine the importance of certain apoptotic regulators in response to TRAIL and Smac59 treatment. All 9 HNSCC cell lines were found to be successfully killed with either TRAIL or Smac59. TNF-a, caspaseS, bc!2 and EGFR expression levels correlated with TRAIL/Smac59 sensitivity. There was no correlation between the expression of inhibito. The second part of the study was a retrospective study to assess response of HNSCC to treatment (surgery and/or radiotherapy) by selecting patients who have been treated with surgery and/or radiotherapy and for whom 5 years follow up data was available. For this part of the project, paraffin embedded formalin fixed biopsies from HNSCC patients were used to construct tissue microarray blocks. The expression of a number of genes involved in the DNA damage repair pathway and tumour hypoxia including PTEN, Ku80, RadSl, XRCC1, ERCC1 and HEP-la was tested using immunohistochemistry staining IHC. The tested genes were found to be expressed at varying levels in HNSCC patients. Associations between the level of the expression and gender, site of origin, tumour differentiation, TNM stage, lymph node metastases, overall and disease free survival and treatment outcome were investigated using statistical analysis programme SPSS. Using univariate analysis, ERCC1 expression was significantly associated with poor outcome to treatment. HIF-la high expression was significantly associated with short disease free survival and poor treatment outcome. Using multivariate analysis, PTEN expression was significantly associated with poor treatment outcome. In summary, it could be concluded that HNSCC cell lines could be killed effectively using TRAIL and Smac59 and their sensitivity could be predicted by level of caspase-8, TNF-a, Bcl-2 and EGFR proteins. TRAIL and Smac59 induce caspase-dependent apoptosis in HNSCC cell lines which consequently results in depletion of XIAP. Smac59 induces TNF-a autocrine secretion in Smac59 sensitive cell lines and adding rhTNF-a sensitised Smac59 resistant cells to Smac59. miRNA expression could be a marker for sensitivity of HNSCC cell lines to TRAIL and Smac59, however more investigation is required to validate this finding. In conclusion, these findings suggest a potential molecular signature that may be able to predict response of head and neck cancers to TRAIL and Smac59 for the treatment of HNSCC. Expression of genes involved in DNA damage repair and tumour response to hypoxia could be potential biomarkers for patient’s prognosis and response to treatment.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available