Written evidence from Professor Geoff Pilkington (BTR0005)
First of all I would like to send you my sincere thanks on behalf of professional, patient and charity led brain tumour sectors in overseeing our case for increased awareness of the lack of funding for dedicated brain tumour research within the United Kingdom. I was very impressed with your sensitivity and control in chairing of the sessions which I have attended over the past few weeks.
The one thing that did come through from the MPs present, however, was the emphasis on clinical matters rather than on the important research strategies which will underpin improvements in clinical outcome for patients suffering from this devastating group of tumours. While I am sure you will carefully read the transcript of the dialogue of the session from Tuesday, I thought it might be worthwhile in putting my contribution in writing, since the time did not allow a full exploration of the factors which have led to Maria Lester and the Realf family forwarding the initial petition.
To start of with I think it is necessary to define what we mean by brain tumour research. Research can take a number of different formats which would include on the one hand qualitative research based on questionnaires and accrual of information gleaned from previous research studies and clinical trials. This form of research may be of considerable value on issues such as epidemiology, quality of life etc. The other major research format is of a quantitative nature, whereby original data is generated from practical investigative studies. This latter form is generally far more expensive in terms of the equipment, running costs and personnel requirements and can be divided into the following sections:
a) Basic science – whereby, for example specific genes or proteins are identified and characterised.
b) Applied science – here, the role of such genes and proteins in biological behavioural mechanisms are investigated. This may applied specifically to defined diseases.
c) Translational research – here, the use of certain novel therapeutic approaches may be investigated through for example animal models or, and particularly in the case of repurposed drugs, through three dimensional in vitro (cell and tissue culture) models in order to inform about possible progression towards clinical trials.
d) Clinical trials – these may inform about toxicity, comparison of new agents/approaches with current gold standard therapies and efficacy in the clinical arena.
Why is there a problem with brain tumour research funding?
I started my brain tumour research career in 1971 when obtaining funding for brain tumour research was reasonably straightforward. In those days both the Medical Research Council (MRC) and the Cancer Research Campaign (CRC) were the major source. As you will know the CRC merged with the Imperial Cancer Research Fund (ICRF) and Cancer Research UK (CRUK) was duly formed. In the early 1990s, however, grant funding was sparse and at that stage I was centrally involved with the formation and nurturing of a number of brain tumour charities. These charities have undergone change and development and are now the major source of income for laboratory based researchers such as me. Some of the brain tumour charities have chosen to support research into different forms of brain tumour, while others have concentrated more on patient support and education.
What makes brain tumour research different from that into other cancers?
Complexity of these tumours, together with the paucity of funding available, is certainly responsible for ‘scaring off’ would-be researchers. While the brain itself is a complex organ, controlling the multitude of functions within the organism (man), and thus presenting signs and symptoms associated with the diagnosis of brain tumour are diverse, the vast range of cells present within the brain results in many very different types of brain tumour (over 120 currently according to the WHO classification system). Tumours may arise from the substance of the brain itself, from the covering layers around the brain, from the cranial nerves and from other cancers outside of the nervous system which spread or metastasise into the brain via the blood vessels (breast cancer, lung cancer and melanoma are the most prevalent in this context). While the outcome is determined to a large extent by the type and grade of malignancy of the tumour, any tumour within the brain is potentially life threatening. Indeed, low-grade/benign primary brain tumours in adults almost invariably progress to become high-grade/malignant tumours. Malignancy in fact is somewhat different in primary brain tumours compared with cancers elsewhere in the body. In the latter case malignancy is determined by the propensity of the tumour to metastasise to other sites within the body. Malignant primary brain tumours, however, rarely metastasise, but show a marked propensity for local infiltrative invasion of the surrounding brain tissue.
The fact that brain tumours can be detected in utero and can affect children and adults of all ages renders them as having the most marked socio-economic impact of all cancers. In this context average life years lost to brain tumours stands at around 21 years while life years lost to breast cancer are approximately 13 years.
The perceived rarity of primary brain tumours is actually questionable and indeed a few short years ago the registration of cases became more realistic and I am sure we will see the number of cases rising quite markedly over the next couple of decades.
The site within the brain, encased within the bony cranium, renders tissue availability for important research programmes scarce and this is not helped by a somewhat cumbersome ethics permissions system.
Research staff dwindling
The above factors have resulted in limited funding streams which have, in turn, led to the reduction in numbers of dedicated tenured scientific researchers within neuro-oncology. This has led to missing rungs in the career ladder, so it is now essential to replace these rungs to build career progression pathways for junior researchers. The lack of research funding support has led to many PhD students who have graduated in neuro-oncology having to find employment working on other diseases and, as a result, well qualified postdoctoral researchers in this discipline have dwindled. While recruiting senior scientists with experience in other cancer fields may in part be a short term answer to the problem, brain tumours are so different from generic cancers that the learning curve for these researchers is steep indeed. The real answer therefore is to recruit some senior researchers from overseas and to steadily build up our own home-grown research stars of the future. The neuro-oncology research structure also, perhaps, differs between the United Kingdom and North America/mainland Europe in as much as clinicians rarely get sufficient time to spend in the laboratory so well trained non-clinical scientists undertake much of the research workload.
What do we study in the laboratory?
While we can learn a little from the research findings on other cancers the biology of primary brain tumours differs markedly through the presence of a blood brain barrier, heterogeneity of cellular components and their response to therapeutic agents, their diffuse invasive behaviour and the lack of cellular clonality. By studying other forms of cancer which spread to the brain, however, we may be able to prevent this problem and thus reduce the dismal prognosis for such patients suffering from brain metastatic disease.
In our Brain Tumour Centre at Portsmouth we have developed five specific research subgroups.
1) Blood brain barrier – here we have developed dynamic 3D cell culture models to study metastasis of cancers from elsewhere in the body into the brain, as well as investigating novel delivery systems for getting effective drugs across the barrier.
2) Tumour micro-environment – here we study the complex interaction between a wide range of brain host cells and invading tumour cells. A knowledge of this interactive behaviour, as well as on the oxygen levels and immune function within the tumour are central to establishing improved treatments for this group of tumours.
3) Mitochondria –these are the small bodies which produce the energy required for all the activities of cells including cell division, cell movement, production of proteins etc. Historically, brain tumour treatments have focussed on killing tumour cells by damaging DNA within the nucleus of the cell; an approach which has changed outcome for malignant brain tumour patients little over the past 5 decades. By identifying the mitochondria as additional targets we have greater expectations of producing tumour cell specific agents with increased potency as well as reduced toxicity.
4) Paediatrics – brain tumours constitute the largest group of solid cancers of childhood years. Their types, manifestation and biology differ somewhat from that of adult brain tumours and the delicate, developing, natureof the brain in this age group renders their treatment particularly challenging.
5) Therapeutics – we are working on a number of new agents (supplied by Biotech and pharmaceutical companies), repurposed drugs, gene therapy and immunotherapy protocols.
Funding streams?
The fact of the matter is that brain tumour researchers get very little money from the MRC and CRUK. Indeed, many researchers have chosen to simply give up applying to these organisations. The reasons for this are complex and politically sensitive. The ‘quality’ is often questioned (although I have refereed innumerable applications from both these bodies on sound brain tumour research projects which have not been funded). This outcome may be due to lack of appropriate brain tumour representation on MRC/CRUK committees. Lead roles are also frequently taken by clinicians rather than laboratory based scientists and the competition for sparse funds has sadly led to a lack of collegiality and even ‘back stabbing’.
It is also apparent that many grant giving bodies are only interested in funding ‘no-risk’ research programmes, thus applicants frequently have to produce a considerable amount of pilot data before they can even apply for funding. This in itself may limit the flare, flexibility and enthusiasm of dedicated career based neuro-oncology researchers and funding streams might better be placed around at least some ‘blue skies’ type research. The need for centres with a critical mass of experienced researchers is evident. Moreover, waiting for periods of 20 or more years for translation from the laboratory to clinic is wholly unacceptable.
Other factors, which limit the effectiveness of research endeavour might result from the over bureaucratising of national bodies and the perception that centralisation of research to Russell group centres such as Oxbridge and UCL ignores the huge volume of excellent work in our field which emanates from smaller, less prestigious centres/universities, such as Nottingham Trent University, Plymouth University, Portsmouth University, University of Central Lancashire and University of Wolverhampton, to name a few. In most cases the lead players in these centres moved out of environments which were more prestigious, but unsympathetic to the growth of brain tumour research within the UK.
So, what do we want this Committee/Government to do about the situation?
While I fully appreciate that other site specific cancers will justifiably fight their own corners too, I believe brain tumours to represent the most challenging and most devastating form of cancer known to mankind. My recommendations would be as follows:
a) Establish a working group of MPs with senior brain tumour research scientists to establish a strategic statement/plan. We should recognise the admixture of qualitative, laboratory based and clinical trials areas and establish subsections for each area.
b) Attempt to establish a brain tumour specific research fund to help with the establishment of centres within the UK building growth and sustainability of the workforce and discipline.
c) Help centres through an infrastructural/equipment fund by working directly with universities (not merely DoH/NHS sector).
d) Work closely with the charity sector representing brain tumours in pressing for increased speed of translation from laboratory findings to clinical application.
I apologise for the length and wordiness of this text, but I thank you and any of your colleagues who will read it for your time and interest in this important area of medicine. In addition, should you or other members of the panel wish to visit our Portsmouth Brain Tumour Research Centre, we would be delighted to welcome you and show you around our advanced research facilities, as well as meet some of our enthusiastic and committed young PhD students and postdoctoral researchers.
November 2015