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Molecular and Imaging Biomarkers of Radioresistance in Head and Neck Squamous Cell Carcinoma

Student thesis: Doctoral ThesisDoctor of Philosophy

The development of individualised treatments in head and neck squamous cell carcinoma (HNSCC) requires understanding of the molecular biology of cancer and the ability to translate this into therapy. Due to the heterogeneity of HNSCCs biomarkers are needed to identify the mechanisms of tumourigenesis and treatment resistance to improve outcome. Radioresistance is a major cause of treatment failure and early identification is key to the development of treatment strategies to overcome resistance and improve disease control.

MicroRNAs are small endogenous non-coding RNAs that regulate gene expression at the post-transcriptional level, and are a potential source of biomarkers. Altered expression has been reported in almost all types of cancer and directly implicated in tumourigenesis. We found miR-196a to be upregulated in a group of patients with HNSCC with recurrent disease after radical treatment. In HNSCC cell lines miR-196a exerted an oncogenic phenotype through targeting the protein annexin A1. In addition miR-196a overexpression resulted in resistance to irradiation, suggesting that it may represent both a prognostic and predictive biomarker in HNSCC.

Hypoxia is a well established biomarker of radioresistance in HNSCC and the association with poor outcome is well known. Many therapeutic strategies to overcome hypoxia have been developed, but accurately detecting tumour hypoxia has limited the translation of hypoxia modification strategies into routine practice. 64Cu-ATSM PET is currently a research tool used to image hypoxia, and in combination with gene expression profiling of diagnostic biopsy samples, could provide early identification as well as the quantification and spatial distribution of hypoxia. We performed a pilot study in 15 patients with locally advanced oropharyngeal squamous cell carcinoma and demonstrated that increasing hypoxic volume defined by 64Cu-ATSM PET was significantly associated with published hypoxia gene signatures in corresponding biopsy samples. We developed a 64Cu-ATSM hypoxic volume specific gene signature, which can be applied prospectively to future samples and correlated with long term follow up to investigate its role as a biomarker. In addition, circulating miR-196a levels in patient plasma samples correlated with increasing tumour volume.

In conclusion, miR-196a may represent a biomarker of aggressive and radioresistant disease, partly through targeting annexin A1. 64Cu-ATSM-defined hypoxic volume correlates with published hypoxia gene signatures, and in conjuction with gene signatures from biopsy samples, may represent a method for early identification of patients with radioresistant disease at a stage when management could be altered to improve outcome.
Original languageEnglish
Awarding Institution
Award date2016


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