Leading the fight against children's brain tumours: Prof Richard Gilbertson on CRUK's new centre
The new Cancer Research UK Centre of Excellence in Cambridge and London aims to improve treatment and survival rates
Since he watched a little girl die from a brain tumour while he was a medical student, Richard Gilbertson has always known what his career focus should be.
Determined to improve the chances for those with such a devastating diagnosis, he has dedicated three decades to children’s brain tumours.
Now he is leading the biggest push yet to bring about a major change in survival rates as director of the new Cancer Research UK Children’s Brain Tumour Centre of Excellence at the University of Cambridge and the ICR (Institute for Cancer Research) in London.
“This grew out of a recognition by Cancer Research UK, and in fact a global recognition, that brain tumours are generally under-funded and little progress has been made in most brain tumours over the last 20 years,” he says.
“There are a number of reasons for that. One is that they are intrinsically bad diseases – they are difficult tumours in the first place. The second is that they’re in the brain. Whereas you can lose half your bowel or remove a breast, you can’t remove half your brain. The brain is a fragile site, which means you can’t do a lot with it.
“The third thing is they are relatively rare. That impedes the ability to do clinical trials readily.”
CRUK is investing £25million over five years to fund two Centres of Excellence – the second will open later this year and focus on adult brain tumours. This is in addition to the £13million it already invests annually into tackling the disease.
The government, meanwhile, is investing £20million into brain tumour studies through the National Institute for Health Research (NIHR) over five years – with the aim of doubling that sum once new high-quality research proposals become available. This month, it is putting out the call for projects.
Prof Gilbertson, whose father died of glioblastoma, says the CRUK centre will offer a fresh approach to developing treatments as the traditional method of exposing potential new drugs to models then taking them to the clinic has not yielded the results needed.
He explains: “One of the main reasons is our pre-clinical evaluation of drugs has not been accurate enough. Our predictions of what might work when we take them to patients has largely failed.
“When you add in the rarity of the disease and therefore the difficulty of doing clinical trials, you can end up running a five-year trial on a drug that was probably doomed to fail from the start.
“Our Centre of Excellence in Cambridge and the Institute for Cancer Research in London will completely change that paradigm, engaging broad expertise through a global interaction.
“We have very strong pre-clinical expertise in Cambridge in the biology of brain tumours along with very strong laboratory models of those diseases. The idea is to expose those diseases to the same treatment that a child would get – surgery, radiotherapy and chemotherapy – along with a new agent, and that way make a much more accurate prediction in the lab about whether something is likely to work in the clinic.”
The ICR will then help turn those compounds into drugs.
“We’ve screened about 1.4million compounds already across the whole nature space – stuff from the Amazon, from the bottom of the ocean – and have found a series of very attractive compounds which seem to be very effective at killing children’s brain tumour cells and leaving normal cells alone,” says Prof Gilbertson.
“We’ll test the actual drugs back through the pipeline so that what we deliver to the clinic is not just a new agent but how to use it, when to use them and what dose to use them at.”
This screening took place over five years while Prof Gilbertson was director of St Jude Children’s Research Hospital in Memphis, Tennessee, the world’s biggest children’s academic cancer centre.
And international collaboration is a key aim of the new centre.
Six weekly webinars will be hosted on the pre-clinical studies being carried out at the centre, which will also become the organising centre for the international brain tumour community and will help train the scientists and doctors of the future.
It is hoped that in the four-year period initially funded by CRUK, a drug will enter the clinic based on the centre’s new approach.
“That will be a major achievement because even getting through the regulatory process, through clinical trials, can take two years,” says Prof Gilbertson. “Having established that pipeline, we would hope to add a novel clinical trial perhaps every two years. It would involve repurposed drugs or developing our own.”
For Prof Gilbertson, such progress could help fulfil the aim he set himself when embarking on a career focused on children’s brain tumours.
“I’ve been studying them since 1987-88,” he recalls. “I always knew I wanted to do paediatrics. I love working with children. But three key events all happened around my second year at medical school.
“I was witness to a child dying of a brain tumour. It was an incredibly powerful experience, in a negative way. It was a very difficult thing to watch because I got to know the family. It was also inspirational, because I thought this was completely unacceptable. Then, medicine had literally nothing to offer this child. That was very frustrating.
“I was fortunate enough to work with a very inspirational mentor called Andy Pearson who was then a professor of paediatric oncology in Newcastle. He took me under his wing and I did my first research project with him.
“Then there was something I’ve never forgotten. I was in the pub with a friend of mine called Nigel who said: ‘It doesn’t matter what you do by the time you retire, you have to be responsible for a 15 per cent reduction in deaths in a disease’.”
This principle helped guide Prof Gilbertson towards research rather than treating patients in the hospital – but also encouraged him to work on therapies that are “pushing on the door of the clinic”.
In particular, he has focused on medulloblastoma – the type he saw the little girl die of while a student.
“At that stage, it was treated as a single disease,” explains Prof Gilbertson, who is director of the CRUK Cambridge Centre and head of the Department of Oncology at Cambridge. “We knew some kids would do very well and be cured, some would die. In some it would spread and in some it wouldn’t. They had different forms down the microscope but they all occurred in a structure called the cerebellum at the back of the head so they were lumped together as one disease.”
But Prof Gilbertson and others have shown that is not the case.
“That’s been the most satisfying thing over the last 30-odd years,” he says. “We’ve had a large part to play in this, as have other groups around the world. We’ve been able to show this, using transcriptomics to look at the ‘language’ the tumour is speaking – which is the genes they express.
“If I look at different cells in the body, they’ve all got the same genes. But they switch different ones on and off and that’s what makes cells different. The genes are expressed differently. Similarly, when you look in tumours, they’ll use some of the genes, but not all, and that gives them a different expression pattern. That’s like a language that the tumour is speaking to express what it is.”
This technology helped Prof Gilbertson and fellow researchers to group diseases like medulloblastoma into distinct sub-types based on their patterns of gene expression.
“It also happened to segregate the patients who were doing incredibly well from those who were doing badly,” he says.
“When the brain, the spine and the back of the head are developing, you get these different patterns of gene expression, which are the genes telling the cells in the different parts of the brain to be something different.
“The next breakthrough was that we realised the tumours were echoing these different patterns of gene expression. It’s like they represent different accents, from where these tumours were born in the nervous system.
“Most recently, we’ve now been able to model them very accurately in the lab and start to think about the different treatments we could use to target, very selectively, those forms.”
We don’t yet know how many forms there are, as the technology to carry out such detailed analysis is new, but it is thought there are tens of different types of children’s brain tumours that can be sub-divided from the major classes.
“Eighteen years ago, all children with medulloblastoma were prescribed the same surgery, radiotherapy and chemotherapy. But there is a sub-group that does incredibly well and they may be cured without the same level of intensive radiotherapy,” says Prof Gilbertson.
This means that for some children it is possible to avoid the enormous impact on their brain of radiotherapy, which can impair IQ and lead to a loss of independence.
Another fruitful approach is repurposing existing chemotherapies that haven’t been tried in children – one used to treat adult colorectal cancer is being trialled, for example.
“There’s no way to randomly pick these drugs off the shelf and try them. But what these advanced laboratory techniques allow us to do is pick 50 or 100 drugs and try them in pre-clinical systems and see the most promising.
“These are already drugs – you can already prescribe them. You don’t have to turn them into drugs, which takes a long time.
“The last element is developing new drugs, which are definitely needed. We are doing that with these pre-clinical models,” says Prof Gilbertson.
What of new techniques?
“Immunotherapy is a very exciting opportunity because it’s a completely new approach,” notes Prof Gilbertson. “Whereas existing treatments have focused on the ‘mistakes’ that tumours make that allow them to be abnormal, immunotherapy relies on ramping up the body’s own ability to get rid of the cancer.
“One of the challenges with immunotherapy is that in the brain is a privileged site. It is protected from the normal immune system. But it is nonetheless an interesting area.”
Meanwhile, Prof Gilbertson is working with Prof George Malliaras, based at the Nanoscience Centre in Cambridge, on implantable brain interfaces that could work as a delivery system for drugs.
“One of the challenges is getting stuff into the brain because it’s protected behind a wall,” says Prof Gilbertson.
“We’re working to develop special gels that look, feel and taste to the body like normal tissue but you can put a drug into them and implant them directly where the tumour was. That will leach out the drug over a period of time and give a constant delivery.”
With CRUK’s investment, Prof Gilbertson is hopeful that real progress can be made.
“I’m very excited about the future,” he says.
And he’s never forgotten what Nigel said to him in the pub.
The diseases that claim 100 young lives every year
About 400 children are diagnosed with a central nervous system tumour each year in the UK.
This means brain tumours account for about a quarter of childhood cancers.
About 100 children die from them each year – one third of childhood cancer deaths.
Most brain tumours start in glial cells, which surround neurons and provide support and insulation for them. These tumours, collectively known as gliomas, include astrocytomas – the most common, accounting for 40 per cent of cases, or about 155 children – along with ependymomas and oligodendrogliomas.
Tumours arising from embryonal cells are more common in early childhood and account for around 20 per cent of cases. These include medulloblastoma, which is responsible for about 50 of these cases each year, and PNET (primitive neuro-ectodermal tumour), which makes up about 16 cases.
About 10 per cent of childhood CNS tumours are ependymomas.
While the overall five-year survival rate for childhood central nervous system tumours is 75 per cent, the rate varies widely according to the type of tumour, its grade, size and site in the brain or spinal cord.
Low-grade astrocytomas, accounting for 30 per cent of all childhood CNS tumours, have a survival rate of 95 per cent, but high-grade astrocytomas have a five-year survival rate below 20 per cent.
Ependymoma has a five-year survival rate of 71 per cent, while for medulloblastoma it is 64 per cent and for PNETs it is 36 per cent, according to the charity Children With Cancer UK.
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