Clinical Fellow Profile – Jag Dhanda

Jag Dhanda is a BAOMS/Saving Faces – FSRF Head and Neck Research Fellow at the University of Liverpool. Here he answers some questions about his work.

How did you come to do a PhD in oral cancer?

I am currently midway through a PhD, having taken time out of my higher surgical training in Oral and Maxillofacial Surgery. This training pathway requires both a medical and a dental degree, with up to eight years of further surgical training. My ambition is to pursue a career in academic head and neck surgical oncology and this is one of the reasons why I have interest in oral cancer research.

Without doubt the paucity of clinical and translational research in head and neck oncology has been a major obstruction to improving outcomes for patients in the past. Despite all the advances in surgical approaches, imaging techniques and chemoradiotherapy, only small overall improvements have been seen in patient survival. This is also evident with only 2.4% of head and neck cancer patients recruited to randomised trials. Comparative research from other malignancies such as haematological and breast have made significant progress by combining the disciplines of translational molecular studies, clinical trials and clinical practice with obvious clinical benefit measured in outcomes.  It is this observation that has been a key motivator for me to undertake research in translational cellular and molecular oncology in head and neck cancer.

What is your project about?

Oral cancer remains a debilitating disease and can profoundly affect speech and swallowing. The most adverse factor for survival in oral cancer is extracapsular spread (ECS), where the disease spreads from the mouth to lymph nodes in the neck and subsequently spills out from them. ECS is the most biologically aggressive metastatic phenotype in oral cancer. Our research group has previously demonstrated a genetic expression pattern in oral tumours that could be used as a molecular signature to predict the likelihood of individuals having ECS. One of the main aims of my research was to validate this expression profile in biopsy tissue collected from 110 patients with oral cancer, and to provide clinical data to determine how good this molecular signature is at predicting ECS.  The clinical data from patient follow-up after surgery confirmed the devastating consequences of ECS and were consistent with a larger previous study in which only 23% of patients with ECS survived 5 years. Current methods for detecting ECS prior to surgery using MRI scans were shown to be only accurate in detecting the disease in 6.8% of patients.

The second aim of the project was to establish head and neck cancer cell lines from patients with and without ECS. These will be used in future work looking at factors influencing cell migration and invasion. Six cell lines from patients with ECS, one with lymph node metastasis without ECS and two cell lines from patients without metastasis have been created in the laboratory by growing cells from tumour tissue. We will examine their behaviour to see if there any difference between the cells and to try to explain these differences, at the molecular level, and how this may lead to ECS. By identifying the molecular processes that cause ECS we hope to identify potential targets for future therapies.

What did you find so far? What are the implications of your work?

I have developed three dimensional culture models using these cell lines with different cell types. By comparing the features of these models with the original tumours I was able to demonstrate consistency in the appearance of invading cells in both the original tumour and the models. I have also show that a more aggressive invasive appearance can be induced in a cell type associated with cancer, called keratinocytes, by mixing them with another type called fibroblasts, from patients with non-metastastic disease.

The next phase of my research is to explore the affects of existing drugs used in the treatment of metastatic head and neck cancer on the models that I have developed. In the future I will investigate the affects of promising new therapies, which could someday have a role to play in the treatment of ECS in head and neck cancer.

Together with the insights form the gene expression signature and the culture models I have developed I hope to contribute to the development of biomarkers for ECS. Upon discovery of such biomarkers there are obvious clinical applications, such as selection criteria for randomised trials.A sensitive form of pre-treatment molecular classification would be invaluable in guiding the application of new therapeutic approaches such as chemotherapy, monoclonal antibodiesor neoadjuvant TPF (taxane, platinum, 5-FU) for which a phase III trial has been recently funded by CRUK in Liverpool.

Who are the people who help you with your research?

My research experience and ambitions have been supported by the kind support given by the Saving Faces Charity and the British Association of Oral and Maxillofacial Surgeons. They have funded the second year of my PhD am I am very grateful for the opportunity that Professor Iain Hutchison has given me. The first year was funded by the Royal College of Surgeons with a Surgical Research Fellowship and further support was also obtained from the Clatterbridge Cancer Research Charity.

I have also had guidance and inspiration from my supervisor Mr Richard Shaw and would also like to thank my other supervisors Professor Ross Sibson and Dr Janet Risk. The Oral and Maxillofacial Consultants at Aintree Hospital in Liverpool, Professor James Brown, Professor Simon Rogers and Ms Fazilet Bekiroglu have also kindly supported this research.