Research in to Brain Tumours
Introducing Professor Geoff Pilkington, BSc PhD CBiol FSB FRCPath
Geoff is Professor of Cellular and Molecular Neuro-oncology at the Institute of Biomedical and Biomolecular Sciences at Portsmouth University and Head of the Brain Tumour Research Cellular and Molecular Neuro-oncology Research Group. Geoff was previously Professor of Experimental Neuro-oncology at the Institute of Psychiatry, Kings College London.
He is a Fellow of the Royal College of Pathologists, a Fellow of the Society of Biology, President of the British Neuro-oncology Society and an Executive
Board Member of the European Association for Neuro-oncology. He is also a Member of the British Neuroscience Association, the British Neuropathalogical Society, the British Association for Cancer Research, the European Association for Cancer Research, the Society for Neuro-oncology (USA) and a Fellow of the Royal Society of Medicine.
Geoff has published numerous scientific papers, sits on multiple editorial boards and has lectured on brain tumours throughout the world, including the European Parliament in Brussels. In addition to his work with Brain Tumour Research he has established the South of England Brain Tumour Alliance (SEBTA) and was a founder member of the International Glioma Invasion Forum. He advises or sits on the board of several related charitable organisations. Geoff regularly attends the quarterly meetings of the All Party Parliamentary Group on Brain Tumours at Westminster. He has also advised for a range of TV dramas and has often assisted the national press on television and radio.
Professor Geoff, please introduce your talented team!
My Principal Research Fellow is Dr Helen Fillmore PhD, who has over 20 years of experience in brain cancer research. Her knowledge of the field is excellent, she has received several honours and she is the type of scientist who not only seeks to push back the frontiers of our knowledge, but also strives for and delights in having those advances applied for the betterment of society.
Dr Peter Nunn is our Honorary (Visiting) Senior Lecturer who has enormous experience in toxicology and pharmacology, as well as biochemistry, as applied to diseases of the central nervous system. Dr Qian An is a Senior Research Fellow, who has done 3-4 post doctoral research projects on cancer and published around 30 papers. Her current research focuses on the genetic mechanisms underlying brain tumour development, with a view to identifying new therapeutic (ie treatment) targets.
Dr Rhiannon Lloyd is a Research Fellow researching the mitochondrial genes of brain tumours. We have two Senior Research Associates just completing their first post doctoral research posts, and another research fellow and two senior research associates just beginning their second post doctoral research posts.
We currently have four ‘home’ (ie EU) PhD students, one overseas PhD student from Iraq and two visiting PhD students from Malaysia who are with us for six months. The PhD students work on specific, individual projects but are also encouraged to share qualities and skills.
We’ll be recruiting more team members including a technician and one or two research nurses to facilitate all the tissue side. In addition to all the above members, we have three internal university collaborators and nine external collaborators based both in the UK and abroad. We also have several Erasmus students from several European universities on 4-6 month internships.
You established SEBTA. What is that?
Information sharing is something that I am passionate about. I formed the South of England Brain Tumour Alliance, which comprises seven regional bases with a strong interest and involvement in diagnosis, treatment and research in the field of neuro-oncology. The centres can share tissue for research. It means that for every biopsy that comes from a patient, we potentially have seven groups working on it as opposed to one and we maximise the amount of resulting data.
So the idea is to share tissue but also to share expertise and to do co-operative and collaborative research between the groups. Some of the centres can gain through the fantastic equipment and the expertise we have here in Portsmouth, while we can gain from the clinical expertise of the hospitals through their neurosurgery and individual strengths like we see at Kings College in London, who are very strong on diagnosis. We use the combined skills of seven centres, rather than just one of them.
Portsmouth is also the first, important location in a long term plan for Brain Tumour Research, isn’t it?
To have a sustainable laboratory environment with staff at the right level, plus factoring in some building, equipment and running costs etc we are targeting £1million a year. At the entrance to our department is our Wall of Hope which filled with plaques, each representing £2,740 of sponsorship which we have received. Multiplied by 365 that comes to £1million.
We are funding this through the Brain Tumour Research charity itself and the component charities, also working with corporate sponsorship and community fundraising in the region to bring in enough money to make that £1million per year sustainable for the foreseeable future
Brain Tumour Research hope to have two new centres opening in 2013 in the UK. Ultimately we are aiming to have at least seven centres in the UK, perhaps even twelve, regional centres of excellence each conducting dedicated laboratory-based brain tumour research to the tune of £1million per year.
These will be geographically disparate and working on slightly different areas of interest but complimenting the work of the others. The centres will collaborate with each other, with clinical centres across the region and also develop national and international collaborations too. We here in Portsmouth are the flagship centre. I think it is rather appropriate that Portsmouth is the flagship. And we are now looking for victory!
What are your priorities for funding right now?
Top of the hit list are key pieces of equipment that we desperately need to feed into a number of the issues we are working on. These wouldn’t just benefit the team in Portsmouth, the key molecular equipment would benefit people across the SEBTA coalition. That would really help us in terms of getting high quality data to get us out there on the cutting edge so we can apply for the Medical Research Council grants that would help support us.
To get our lab up to full speed, where we can be competitive for grant applications for key projects, there is probably about £450,000 of equipment that we need.
Portsmouth has already raised the flag on the global stage, hasn’t it?
I like to fly the flag because the UK had the first national, professional brain tumour society in action. It is now called the British Neuro-oncology Society and I am currently president of that. It speaks for the whole of the UK’s effort on brain tumours, whether nursing or any of the medical disciplines, research etc. We have lots of power in terms of talking to the government and various organisations, professional bodies and societies to get the message through about brain tumours and expertise in that area.
I’m now on the executive board of the European Association of Neuro-oncology and downstream of that, we now also have the Japanese Society, the USA/North American society, New Zealand and now many others. 2013 sees the inaugural meeting of the World Federation of Neuro-oncology Societies, which I have been involved with. Now everyone can communicate more readily and with budget coming in from all these societies we can start to underpin what is happening in the Third World, to try to bring all nations up to a similar, high standard. We also want to send young people who are working in the field to spend time in the other locations, so we can all learn from each other. The smaller the world becomes, the more knowledge will transfer from one centre to another.
All countries will be able to plumb in to see what is going on with the rest of the world. The fact that we are in sunny Portsmouth doesn’t make one iota of difference because we wide collaborations reaching all over the world.
A mere 0.7% of national cancer research funding goes to brain tumour research. Why is it so massively under-funded?
The 0.7% covers all forms of brain tumour research. Actual scientific, laboratory-based research is only one part of it. Furthermore, when you scratch the surface of what is being spent in that 0.7% it is not always actual brain tumour research, but in areas such as neuro-endocrinology or something else. Any increases in spending in the area are coming from the charity sector, not in government spending and that is something we are trying to address through Parliament.
There is a perception that brain tumours are a low incidence disease but the government statistics are wrong. It is said that 16,000 people are diagnosed with a brain tumour each year but the statistics exclude, for example, benign brain tumours in adults, which invariably become malignant with the passage of time, meningiomas, which are tumours which are derived from the covering layers of the brain and secondary tumours, ie those tumours which emanate in the breast and the lung and which have a high propensity to spread to the brain. Additionally, there are a lot of misconcepts as to what constitutes brain tumours and what doesn’t. If you take into account all these ‘missing’ statistics that figure of 16,000 will double, if not triple.
A brain tumour registry has recently been established, so hopefully that will eventually highlight the true level of incidence and eventually we will get more representation. Lobbying parliament is incredibly important, in trying to push the agenda forward and to inform people who appear, quite obviously, to be misinformed. It is an important facet of what we are doing at Brain Tumour Research.
People are surviving for longer compared to previous decades, so there are greater numbers being diagnosed with brain tumours. They affect every type of age group, right the way through to people in their 80s and 90s, with specific types affecting different age groups. You can even have brain tumours diagnosed in the unborn foetus.
About 25% of cancers in children are brain tumours but the survival times are worse than they are in leukaemia patients and that is linked very directly into the amount of input that there has been in terms of research. Over the last 30 years there has been an enormous amount of money put into leukaemia research and as a result, the survival times have just got better and better.
Brain tumours are known as ‘the orphan disease’. Why is that?
People are not researching brain tumours as much as other types because it is a very complex area; there are in excess of 120 different types of brain tumour. And now, because we are able to do molecular profiling, we can see that there are subtypes of those too. And that’s a really important development because that gives us the handle on developing more specific, targeted treatments which are less toxic to the patient. We are almost custom-building therapy for individual patients.
Researchers also have to be an expert in oncology (cancer), and also an expert in the nervous system because the brain is a very complex organ with a multitude of different cell types (unlike, for example, the liver which only has one cell type) so it is not straightforward.
The umpteen different types of brain cell all form a tissue and they work together, resulting in multiple types of tumour evolving. The biology of brain tumours is totally different from another other body cancer.
Given this and the funding issue, people are not encouraged to work in this discipline. Brain tumours have become the poor relation because of the lack of support there and that is why it is known as ‘the orphan disease’.
Can you give us some examples of the sort of work you are doing?
Our research covers many aspects. Some of the agents we can effectively treat cancers with can’t get into the brain so we are trying to work out how they can be delivered effectively to tumours there. We are also looking at how secondary tumours get into the brain from primary cancer sites in the breast or lung, for example. Some tumours get into the brain and others don’t so we are looking at the genetic control mechanisms involved in how those might gain access to the brain, or not. We use three-dimensional, in-vitro model using all human cells, to answer those questions.
There has been great success in the prognosis with medullablastoma which is a paediatric tumour of the cerebellum, at the back of the brain. About 70-80% of the children with that type of tumour can now be cured. However, the level of toxicity of the treatment is high, so quite a lot of those survivors have some compromised quality of life, for example with intellectual or sexual development. So what we are trying to do is develop almost a personalised medicine which gives the patient the most affective treatment with the lowest toxicity.
One of the ways we are looking at this is to study the location on a chromosome which houses genes regulating the ability of cells to respond to various drugs which are affecting the DNA. We can work out whether a patient is more or less likely to respond to different drug approaches.
We are also doing some gene therapy type studies, trying to get a bit of DNA into a cell which encodes for a particular enzyme which will modify a particular molecule already sitting on the brain tumour cell. And when we modify it, that particular molecule will go into the cell and it will cause cell suicide. So we can get them to self-destruct by using a gene therapy modality as opposed to using a drug.Another line of research involves the poliovirus receptor which sits on the surface of a cell and was originally found to pick up the polio virus and pull it into the cell (hence the name). In certain cells if you block something called CD44 it impairs the ability of the poliovirus receptor to pick up the polio virus. CD44 and CD155 are both present on brain tumour cells and ‘grab’ other cells in the brain. Qian’s research looked at blocking them, silencing a particular gene which stops this receptor being formed and therefore ceasing movement and stop the cells from spreading to the surrounding brain. This is an example of a potential anti-invasive targets which could be achieved with therapeutic, rather than a drug-mediated therapy.
We are still also looking at a range of archival drugs, new drugs and novel agents things like Boswellia, which is derived from frankincense, new targets and so on and so forth.
One really exciting area is this; most of the ways of killing brain tumour cells are going through the nucleus, the central control centre which contains the DNA. DNA is also contained within things called mitochondria which are embedded around it. They produce all the energy for a cell. There is a difference between the thickness in the outside of a cancer cell mitochondrian and a normal cell and there are certain agents that won’t go through normal cell mitochondria but will get into the cancer cell one. We are working with the University’s molecular structure group who are looking down into the real minutiae of what goes on in specific molecules within the cells. They will identify tiny little therapeutic targets that will be specific to engineer drugs or other agents. This is fantastic stuff.
I am very keen to invest heavily in this area of research. We have been targeting the nucleus in brain tumour cells for forty years but the survival curve for malignant brain tumours has only seen a small increase. We are continually using new generations of drugs, each of which only just improves things a little bit. I think a whole new approach is required here and for my money, this is an area worth a considerable investment in our time as a research group.
What about paediatric brain tumour research?
The most frequent tumour generally in children is a low-grade astrocytoma, which occurs in the back of the brain, but which doesn’t invade very much so those, particularly grade one, tumours can be excised.
We are concentrating most of our effort on medullablastoma, which is the most frequent of malignant tumours in childhood. Brain tumours in adults are predominantly in the front, in the supratentorial area. Childhood tumours tend to be in the infratentorial area, which is the cerebellum, the brain stem and the spinal cord.Parents of children with brain tumours always ask “what did I do to cause this brain tumour in my son or daughter?” The answer is “nothing”. We really don’t have a handle on what is going on. There may be a relatively small number of cases where there is an inherent genetic trait which is carried on in the line from patient to patient but those only account for a tiny proportion. Li-Fraumeni syndrome, which is caused by a mutation in the gene called P53 which regulates the ability of the cells to divide, is responsible for some brain tumours but again, only a tiny proportion.
There are lots of things that have the potential to cause tumours. People have talked about viruses, chemicals, hairsprays, all sorts of bizarre things but there currently isn’t very much evidence for anything. Of course we Portsmouth team do want to understand the causes, that is inherent in our studies because the more we understand, the better we can target particular genes or proteins. But if we were to get involved in that we would need to be a neuro-epidemiology centre which concentrated solely on that. There are people within SEBTA that are specifically looking at epidemiology and what causes cancers.
What is your personal motivation in researching brain tumours?
Eight years into my research career in 1979, my mother was diagnosed with a brain tumour. I was able to play a role in getting her an appointment with a neurologist and then seeing her through the neurosurgery and then her radiotherapy, which she was having in the hospital where I was working in central London. She survived for sixteen months. So there is a personal side to my work as well. My resolve to work on brain tumours was always there and I would have carried on working regardless but in a way, it just focussed my attention a little bit more.
I’ve had other people working in my lab who’ve had relatives who have died of brain tumours and we have also worked with people who have eventually been diagnosed themselves so we do know a little of what it is like being on the other side of the counter. Only recently I spent some time with a Reader who was supervising a PhD project of my former undergraduates; two weeks after hearing my lecture on brain tumours he was diagnosed with a malignant brain tumour himself. That’s just how close to home it can be.
Many of the patients we meet keep in touch, I get emails and calls every week, so there is plenty of interaction over and above all the actual research. We have lots of people visiting our labs; patients, representatives from the Brain Tumour Research charities or those interested in supporting it, sometimes medics too. We don’t sit in our ivory tower, we encourage an open door policy. It all brings us back to reality.
What material do you use for your research?
All the work we do is in vitro, that is, we use live human tissue derived from human biopsies. We do a lot of 3-dimensional stuff as well as just growing the cells on little plates. We do not use laboratory animals.
The main tumour types we are focussing on are medullablastoma and glioblastoma, which is in the brain stem. Glioblastoma cells are quite rare because of the danger of operating on patients with brain stem tumours. They are actually quite difficult to get hold of and there is a paucity of viable cells that we can work on.
Only 1% of brain tumour tissue that comes out of biopsy reaches a research lab for brain tumours due to the increasingly complex ethics procedure. But for our work, which involves maintaining the cells in a dynamic, living fashion, we need that tissue to come in very rapidly into the labs.
Are your team aware of the personal stories behind some of the charities who are funding the work?
The personal side of things filters through a lot. Throughout the lab we have rooms and pieces of equipment with insignia not only from the charities but from individual people as well, all of which reflect the history and the genesis of the group.
Helen and I are very good at instilling that personal connection in our team because that’s what drives us. It helps us so much to interact and to have visitors from charities such as the Ollie Young Foundation to the lab. If you have an experiment going overnight or if you have to be here until midnight you might think, “what am I doing here?”
Then you see pictures of the folks of our charities and you think, “this is why I am here.”