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Identification of New Biomarkers and Drug Targets for Head and Neck Cancer using Proteomic Profiling

Summary of Project:

The aim of the project will be to identify new proteins as potential biomarkers and druggable targets in the detection of specific types of oral cancer, forming the basis of further grant proposals for preclinical and clinical validation.

Background

Head and neck squamous cell carcinomas (HNSCC) are the sixth most common cancer worldwide (8,000 cases p.a. in UK) and third most common in developing nations. The incidence of oropharyngeal is the most rapidly increasing of all cancers due to increased smoking and alcohol consumption, but also in Asian populations, as betal nut consumption prevails. Human papilloma virus (HPV) is a contributory factor, with HPV+ve tumours respond more positively to chemotherapeutic and chemoradiation treatments, with improved survival rates, compared to HPV-ve. The reason for this remains unknown, but frequency of smoking plays a significant role in decreasing the survival rate of HPV-ve patients. Consequently, there is considerable interest in providing an adjusted, stratified treatment regimen for HNSCC patients based on HPV prognosis and new druggable targets for poorly responding HPV-ve cases.

Proteomics has been used to study HNSCC, though frequently without discrimination of the different sub-regions of the oral cavity or HPV status. Tonsillar and parotid gland tumours have not been investigated, nor has proteomics been employed to compare matched normal and tumour tissues. The Bradford Head and Neck Tissue Bank (BHNTB), administered by Ethical Tissue (University of Bradford) and Mr. Jim McCall (Bradford Royal Infirmary) currently contains matched normal and tumour biopsies from 105 patients providing a unique resource for identifying protein expression changes. Extensive patient records enable an informed rationale for selection of biopsies to be used in a quantitative proteomics strategy analogous to that previously employed for breast cancer (Figure 1).

Plan of Investgation

The project we propose will comprise a collaboration with Mr. McCall.

  • Determination of HPV status of archived biopsies in the BHNTB using, (i) DNA purified from tissue cryosections to screened for HPV subtypes by multiplex PCR and in situ hybridization, and (ii) confirmation using immunohistochemistry to detect p16 whose expression increases in response to retinoblastoma protein (pRb) pathway inactivation by the high-risk HPV E7 protein. This will provide important information in the selection of biopsies for subsequent proteomics analysis.
  • We will use 8-plex iTRAQ-based quantitative proteomics for comparison of biological samples (Table 1), (i) comparison of matched normal and tumour protein profiles from tongue, salivary, parotid and tonsillar cancers, (ii) comparison of HPV+ve and HPV-ve tumours to determine impact of virus infection on cancer initiation mechanism and (iii) comparison of HPV-ve tumours from patients based on non-viral lifestyle contributory mutagens from smoking or betal nut consumption.
  • We will investigate significantly changed proteins from proteomics data by Western blotting (WB) and immunohistochemistry (IHC) to determine regio-specific expression in a broad cross-section of biopsies from the BHNTB. Furthermore, proteins which change in expression due to HPV status and lifestyle parameters will be investigated by WB and IHC to substantiate proteomics data.
  • Target proteins will also be explored using established expression and function databases to determine if they represent novel targets unique to oral squamous cell types.

Entry requirements:

1st class Honours degree or equivalent.

Supervisors:

Title and name:
Dr Chris Sutton
Position:
Senior Lecturer in Proteomics and Mass Spectrometry
Email address:
Telephone number :
Work+44 (0) 1274 236480
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Title and name:
Dr Klaus Pors
Position:
Senior Lecturer in Chemical Biology & YCR Group Leader
Email address:
Telephone number :
Work+44 (0) 1274 236482
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