The Importance and Recognition of our work
Smart Drugs to improve outcomes after Radiotherapy
Head and neck cancer affects approximately 750,000 people worldwide every year. In the last decade, we have significantly improved outcomes for patients with this disease through technical advances and by treating patients with chemotherapy drugs during radiotherapy. Recently, we have made huge strides in understanding the biology of head and neck cancer and this has revealed that we are dealing with a spectrum of diseases that can be categorised into different groups based on lifestyle, clinical and radiological (Xray) variables and by measuring the specific genes expressed by the tumour. These different types of head and neck cancer have very different outcomes to treatment, but we currently treat all patients with standard protocols according to a "one size fits all" philosophy. This approach is inappropriate and results in undertreatment of "high-risk" disease and overtreatment of "low-risk" disease".
Therefore, a major component of research funded by Oracle Cancer Trust aims to develop a more individualised approach to treating head and neck cancer based on the use of so-called targeted drugs. These approaches will be applicable in both "high-risk" and "lowrisk" head and neck cancer, since both of these tumour types have specific defects in their ability to respond to the effects radiation damage during treatment.
"High-risk" disease is characterised by previous or current tobacco/alcohol use, bulky tumours in the voice box or lower part of the throat, spread to the lymph nodes and absence of infection with human papilloma virus (HPV). Such tumours require intensified treatment in which we will test the addition of new targeted drugs to standard chemotherapy/radiotherapy. In contrast, "low-risk" disease is characterised by tumours in the upper part of the throat in patients with minimal prior tobacco use and evidence of infection by HPV. For these tumours, we are testing new approaches that involve a reduction in treatment intensity and in which we will consider replacing the currently used toxic drugs with novel targeted agents.
In both cases ("high-risk" and "low-risk" disease), we are testing combinations of radiation, chemotherapy and targeted drugs in laboratory studies which will allow us to select the most appropriate combinations to take forward in to early clinical trials. We anticipate that we will be able to translate laboratory data in to new treatments for patients within a 5 year period with the twin goals of improving cure rates and reducing sided effects.
The role of Oracle Cancer Trust is to support the development of pioneering scientific and clinical investigations in the field of head and neck cancer. In the past this has involved supporting a diverse range of activities varying from experimental preclinical studies, audits of surgical practice, quality of life analysis and clinical studies of novel anti-cancer therapies.
Our Vision for the future is to maintain this 'pioneering' approach to specific projects which will form the blueprint for the development of national studies in order to significantly improve the quality of life for our patients.
In future, our core research activities will consolidate around a number of major themes and will be organised such that a senior researcher supervises a post-doctoral junior team leader and a research student. Each programme will encompass a three-year development programme which if successful in achieving its objectives will expand to a national roll out programme in collaboration with our partners at Institute of Cancer Research and the Royal Marsden Hospital. In addition, the successful application by members of the RMH Head and Neck Unit for a Cancer Research UK Programme Grant that activated in April 2012 has provided significant impetus to a number of key research themes (see below for specific details).
Preservation of the Senses
Whilst our over-arching aim is to ensure the very best survival rates for all our patients, once we have ensured their safety, primary fundamental goal of our research is to ensure that our treatments and clinical practices maintain normal functions (eg the senses) that are so often affected by radiotherapy and chemotherapy.
1. Improving Radiotherapy Delivery by enhanced Functional Imaging
This is one of our most important current research initiatives and examines how important functional imaging (specific scans which assess the size and tissue appearance of tumours) is in improving our accuracy in predicting treatment response and thereby improving our delivery of personalised treatments. In sum, the outcomes of this project will:
• Define the extent of the tumour more accurately
• Reduce the volumes of tissues receiving high dose irradiation, thereby reducing levels of delivery to adjacent critical organs
• Enable us to more accurately identify areas of high tumour resistance as targets for increased radiation
This theme was one of the main components of the Cancer Research UK Programme Grant application. The funding that was secured is exploying a clinical research fellow and 2 post-doctoral fellows who are supporting imaging-related projects.
2. New Radiosensitisers to Improve Radiotherapy Responses
The standard-of-care treatment for patients with Localised Advanced Head and Neck Cancer (LAHNC) is a combination of drug therapy with chemoradiotherapy. However, recent research data suggests that this is a significant oversimplification. Some of our patients with a poor prognosis may receive insufficient treatment, while those with good prognosis disease may be over treated with unnecessary risks of toxicity.
Therefore, the goal of this project is to develop effective, specifically targeted therapeutic strategies that offer personalised treatment to individual LAHNC patients based on more predicable factors.
We propose to develop personalised treatment plans for patients in the different, identified sub-groups and will focus on developing combinations of radiotherapy or chemoradiotherapy that will exploit the differences between malignant and normal tissues.
This project is supported by one of the post-doctoral positions secured as part of the Cancer Research UK Programme Grant application.
3. Modelling Radiation Effects in Tumour and Normal Tissues
IMRT (intensity-modulated radiation therapy)
Radiotherapy and chemotherapy are by their very nature, highly intensive and toxic to both normal and cancerous cells, but the benefits of IMRT are that it is very carefully targeted to the cancer volume and a primary benefit of this is that in most cases the salivary glands are not damaged or completely destroyed during treatment.
The saliva has several important roles apart form keeping the mouth moist, like taste and anti-infective agent. The chemicals in the saliva break down the food so that the food receptors in the glands can detect the taste.
This has benefits, not only in the maintenance of taste which can be extremely debilitating, but if the salivary glands are adversely affected, then this can also affect our ability to swallow.
Radiation and chemotherapy adversely affect swallowing, which includes pain and difficulty in swallowing and aspiration of food into the lungs, which can lead to serious lung infections. There are actually 30 muscles needed to create a swallow reflex and all of these muscles have to work together in a co-ordinated fashion and so this is a much more complex action than many people realise.
The good news is that 60% of our patients are surviving after 5 years. But we also have to consider the 40% who have a less positive prognosis.
One of our team leaders (Dr Shreerang Bhide) is leading a research project whose primary aim is to individualise the therapy for each patient recognising that cancer cells work in different ways. The goal will be to predict the responses of cancer cells to chemotherapy and radiotherapy. We can then also try to predict the individual's responses to chemotherapy and radiotherapy.
Key to this work is the understanding that the intention of chemotherapy and radiotherapy is to effectively kill cancerous cells and tumours. However, we also need to understand that individual cells also have the capacity to repair themselves. Luckily, healthy cells repair more efficiently than cancerous cells, however, even the latter do have the capacity to heal themselves.
What we are doing now is to 'mark' some selected cells to highlight their ability to repair themselves - 'Markers for DNA Repair'. We can therefore correlate the ability of cells to repair their DNA to treatment and then the outcome and response to treatment.
Our work here is unique because although research has been undertaken into DNA repair for normal cells, it has not been investigated for cancerous cells.
4. Gene / Viral Therapy of Head and Neck Cancer
In the Targeted Therapy Team which is run by Dr Kevin Harrington in The Institute of Cancer Research, we have expertise in studying the biological effects of combining radiotherapy and viruses in vitro (in plastic dishes) and in vivo (in living organisms). We are therefore developing a systematic approach to virotherapy and radiotherapy in combination.
We are working with a wide network of collaborating scientists and clinician scientists with expertise in virotherapy and gene therapy and have successfully developed collaborations with biopharmaceutical companies as well as influencing the development of experimental agents within this combined approach to treatment. Importantly, we have been able to lead progress from phase I through to phase III clinical trials in this area.
Until recently, this work was supported by funding for a post-doctoral research fellow from Oracle Cancer Trust. As a result of exciting research findings, we have been successful in applying for a research grant that has allowed us to freeze support from Oracle. This is a prime example of the mechanism whereby Oracle can support early stage research as a prelude to its finding independent external funding support.
Oracle Cancer Trust - Research Report December 2010
The Oracle Cancer Trust continues to support research across a wide range of disciplines - including improved radiotherapy techniques, image-guidance for radiotherapy planning and response assessment, evaluation of new targeted treatments and measurement of treatment outcomes. In addition to leading laboratory projects, researchers are involved in practice-changing clinical studies in the Head and Neck Unit at Royal Marsden Hospital. In the last year, research activity at the Sutton site has significantly increased under the direction of Dr Kate Newbold and Dr Shree Bhide.
Currently support is provided to 2 PhD students (Dr R. Dwivedi, Mr J. Roe) who are studying the effect of surgery, radiotherapy and chemotherapy on speech and swallowing outcomes in patients treated for head and neck cancer. Dr Dwivedi submitted his PhD thesis in November 2010 and will be examined early in 2011. Research performed by Dr Ceri Powell under the supervision of Dr Kate Newbold is shedding new light on the use of advanced imaging techniques (DCE-MRI, DW-MRI, PET-CT) on radiotherapy planning in patients with head and neck cancers. Basic laboratory studies are being conducted by Miriam Zimmerman (a research fellow in Dr Sue Eccles's group) who is looking at the significance of tumour stem cells in head and neck cancer - and their influence on treatment resistance. She will submit her thesis in 2011. In addition, Dr Carol Box (Post-Doctoral Fellow) continues to work on EGFR and c-erbB2 receptor signaling and mechanisms of resistance to EGFR-targeted therapies. Dr Joan Kyula (Post-Doctoral Fellow) is studying oncolytic virotherapy in combination with radiation and chemotherapy in support of our portfolio of clinical trials in this area.
In 2010, there have been a number of high profile research publications from the Head and Neck Unit. These include Dr Chris Nutting's PARSPORT study of parotid-sparing IMRT which has been accepted for publication in The Lancet Oncology. Studies of novel viral therapeutics for head and neck cancer have resulted in 2 publications of phase I/II trials in Clinical Cancer Research by Dr Kevin Harrington's team. As a direct result of translational work performed in the Head and Neck Unit, 2 phase III trials of oncolytic virus therapy are now open to recruitment with RMH/ICR as the Chief Investigator site for both protocols.