مجال التميز | تميز دراسي وبحثي |
البحوث المنشورة |
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البحث (1): | |
عنوان البحث: |
Clinical update on head and neck cancer: molecular biology and ongoing challenges |
رابط إلى البحث: | |
تاريخ النشر: |
15/07/2019 |
موجز عن البحث: |
Head and neck squamous cell carcinomas (HNSCCs) are an aggressive, genetically complex and difficult to treat group of cancers. In lieu of truly effective targeted therapies, surgery and radiotherapy represent the primary treatment options for most patients. But these treatments are associated with significant morbidity and a reduction in quality of life. Resistance to both radiotherapy and the only available targeted therapy, and subsequent relapse are common. Research has therefore focussed on identifying biomarkers to stratify patients into clinically meaningful groups and to develop more effective targeted therapies. However, as we are now discovering, the poor response to therapy and aggressive nature of HNSCCs is not only affected by the complex alterations in intracellular signalling pathways but is also heavily influenced by the behaviour of the extracellular microenvironment. The HNSCC tumour landscape is an environment permissive of these tumours’ aggressive nature, fostered by the actions of the immune system, the response to tumour hypoxia and the influence of the microbiome. Solving these challenges now rests on expanding our knowledge of these areas, in parallel with a greater understanding of the molecular biology of HNSCC subtypes. This update aims to build on our earlier 2014 review by bringing up to date our understanding of the molecular biology of HNSCCs and provide insights into areas of ongoing research and perspectives for the future. |
البحث (2): | |
عنوان البحث: |
EGFR overexpression increases radiotherapy response in HPV-positive head and neck cancer through inhibition of DNA damage repair and HPV E6 downregulation |
رابط إلى البحث: |
https://www.sciencedirect.com/science/article/abs/pii/S0304383520305693?via%3Dihub |
تاريخ النشر: |
31/10/2020 |
موجز عن البحث: |
High-risk Human Papillomavirus (HPV) infections have recently emerged as an independent risk factor in head and neck squamous cell carcinoma (HNSCC). There has been a marked increase in the incidence of HPV-induced HNSCC subtype, which demonstrates different genetics with better treatment outcome. Despite the favourable prognosis of HPV-HNSCC, the treatment modality, consisting of high dose radiotherapy (RT) in combination with chemotherapy (CT), remains similar to HPV-negative tumours, associated with toxic side effects. Epidermal growth factor receptor (EGFR) is overexpressed in over 80% of HNSCC and correlates with RT resistance. EGFR inhibitor Cetuximab is the only FDA approved targeted therapy for both HNSCC subtypes, however the response varies between HNSCC subtypes. In HPV-negative HNSCC, Cetuximab sensitises HNSCC to RT improving survival rates. To reduce adverse cytotoxicity of CT, Cetuximab has been approved for treatment de-escalation of HPV-positive HNSCC. The results of several recent clinical trials have concluded differing outcome to HPV-negative HNSCC. Here we investigated the role of EGFR in HPV-positive HNSCC response to RT. Remarkably, in HPV-positive HNSCC cell lines and in vivo tumour models, EGFR activation was strongly indicative of increased RT response. In response to RT, EGFR activation induced impairment of DNA damage repair and increased RT response. Furthermore, EGFR was found to downregulate HPV oncoproteinE6 expression and induced p53 activity in response to RT. Collectively, our data uncovers a novel role for EGFR in virally induced HNSCC and highlights the importance of using EGFR-targeted therapies in the context of the genetic makeup of cancer. |
المؤتمرات العلمية |
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المؤتمر (1): | |
عنوان المؤتمر: |
NCRI Cancer Conference 2016 |
تاريخ الإنعقاد: |
06/11/2016 |
مكان الإنعقاد: |
Liverpool, UK |
طبيعة المشاركة: |
Poster Presentation |
عنوان المشاركة: |
Assessment of EGFR Modulation in HPV negative Head and Neck Cancer Cells and the effect on response to targeted therapies |
ملخص المشاركة: |
The HPV negative head and neck cancers (HNSCC) have poor outcome due to the aggressive nature of the disease. Epidermal growth factor receptor (EGFR) regulates growth, survival and progression of HNSCCs representing a promising molecular target. Although, 90% of HNSCCs demonstrate overexpression of EGFR, the clinical response to EGFR inhibitors is only 10-15%. Cetuximab, an EGFR-targeted monoclonal antibody, has been approved clinically for advanced HNSCC treatment. There has been no direct correlation between EGFR overexpression and clinical response to cetuximab. This study aimed to assess the effects of EGFR modulation in HPV negative HNSCC cell lines and the response to cetuximab treatment. Method: HPV- HNSCC cell lines SCC-072 and UMSCC-22B, with low endogenous EGFR level were infected with EGFR-retroviral vector. The level of EGFR was assessed by western blot analysis. Functional characterisation of the modulated cell lines was performed by assessment of response to cetuximab, cellular proliferation/migration rate and direct immunofluorescence. Results: The EGFR modulation in both cell lines was successful. EGFR was overexpressed on the cell surface of both cell lines as noted by direct immunofluorescence. EGFR modulation resulted in increased cellular proliferation and migration rates. However, the modulated cell lines were not responsive to cetuximab. Conclusion: The resistance of HPV- cell lines to cetuximab suggest that overexpression of EGFR may not be the only mechanism of response to the drug. The presence of other EGFR family members such as Her2, 3, 4 may influence the response. Additionally, studies are in progress to investigate the activation of other EGFR pathways. Effect of other EGFR inhibitors such as Gefitinib combined with radiotherapy is also being investigated. Notably, HPV+ HNSCCs have low EGFR expression compared to HPV- cancers and the former have favourable prognosis. Therefore, another aim of this study is to investigate whether EGFR is a factor in radiotherapy sensitivity in HPV+ HNSCCs. |
الرابط: | |
المؤتمر (2): | |
عنوان المؤتمر: |
25th Biennial Congress of the European Association for Cancer Research |
تاريخ الإنعقاد: |
30/06/2018 |
مكان الإنعقاد: |
Amsterdam, Netherlands |
طبيعة المشاركة: |
Poster presentation |
عنوان المشاركة: |
Modulation of EGFR to overcome tumour resistance and improve radiotherapy Response in HPV positive and negative head And neck cancer cells |
ملخص المشاركة: |
Squamous cell carcinoma of the head and neck (HNSCC) is a significant cause of morbidity and mortality, with over 6 00 000 new cases diagnosed annually. Development of targeted agents to improve survival and preserve organs is vital. This could be achieved through better understanding of the molecular status of HNSCC and availability of specific biomarkers to enable better detection, prognosis and prediction of treatment response. Epidermal growth factor receptor (EGFR) has a central role in HNSCC, causing excessive growth, survival and progression of cancer cells thus representing a promising molecular target for this disease. Over-expression of EGFR is detected in 80%–90% of HNSCC and correlates with worse disease outcome. More importantly, EGFR expression is lower in HPV positive HNSCC than HPV negative ones with the former demonstrating favourable prognosis. Moreover, hypoxia is a strong factor in solid tumours and is linked to more aggressive phenotype. Despite the development of anti-EGFR agents, limited clinical efficacy has been reported for EGFR inhibitors in HNSCC. In this study we assessed the effects of EGFR over-expression in relation to HPV status and further investigated the role of EGFR response to standard and targeted therapies. Additionally, we aim to understand the link between tumour hypoxia and EGFR signalling as well as the other ErbB family members in HNSCC cell lines. Material and methods: HNSCC cell line SCC072 (HPV negative) and SCC154 (HPV positive) with low endogenous EGFR level were infected with EGFR-retroviral vector. The over-expression of EGFR was confirmed. Functional characterisation of both modulated cell lines was performed by assessment of cellular proliferation, migration, invasion and response to radiation/EGFR inhibitors. Additionally, EGFR activation and other ErbB family members were studied in both modulated cell lines. Results and discussions: Modulation of EGFR in both cell lines showed variance in sub-cellular localisation. EGFR over-expression demonstrated oncogenic phynotype in both modulated cells. HPV- cells were resistance to targeted therapy, which suggest that EGFR over-expression may not be the only mechanism of response to targeted therapy. The presence of other EGFR family members may influence the response. Conclusion: Studies are in progress to investigate EGFR pathways involved in invasion, metastasis and response to therapies. More importantly, is to consider the effect of tumour hypoxia on EGFR response to anti-cancer agents. |
الرابط: |
https://www.esmoopen.com/article/S2059-7029(20)32221-3/fulltext#relatedArticles |
إلهام نافع ابراهيم الصحفي
دكتوراه
الطب والخدمات الصحية
King’s College London