Nerve fibres in a healthy adult human brain, MRI, Wellcome Images. Credit: Zeynep M. Saygin, McGovern Institute, MIT, Wellcome Images via Flickr/CC BY-NC-ND 2.0
Despite some phenomenal progress, there are some forms of cancer where things have been much less encouraging, and where patients desperately need more options.
Recognising this, in 2014 we set out on a mission to accelerate progress in four particular types of cancer which all have three things in common:
- compared with other cancer types, there’s a smaller community of researchers working on them
- as a result, they have lower levels of research funding
- survival is generally poor, and has barely changed for decades
We identified these four cancers of particular ‘unmet need’ as pancreatic, lung and oesophageal cancers, and brain tumours. And in a series of posts, we’ll be exploring the challenges researchers working on each of these cancer types face.
But it’s in brain tumour research where scientists have come up against perhaps the most difficult set of challenges, so it’s in this field that we’ll begin.
The story so far…
Cancer Research UK has funded brain tumour research for decades. In the 1990s, our scientists developed a new brain tumour drug – temozolomide. Approved for use on the NHS in 2001, it’s made a big difference to the care of people affected by several forms of brain tumour.
And since 2003, more than £60 million of the money we’ve raised has been spent directly on research into cancers affecting the brain and nervous system, allowing us to make crucial laboratory discoveries about the faulty molecules involved in these tumours, and run trials of new drugs.
It’s also allowed us to recruit many new younger researchers through our Fellowship schemes to help focus and build the brain tumour research community.
And as part of our renewed focus, we’ve recently made several high-profile investments to try to boost progress even further, recruiting one of the world’s leading brain tumour researchers, Professor Richard Gilbertson, from the US to run our Cambridge Centre, and funding a £4.4million project, led by Dr Steven Pollard at our Edinburgh Cancer Research Centre, to collect tissue samples from patients around the UK, and build a world-class resource to accelerate research and drug discovery.
We’ve also just announced funding that will allow UK children with ependymoma – the third most common childhood brain tumour – to enrol on a large international clinical trial.
But brain tumours still claim more than 5,200 lives a year. They’re the most common cause of cancer deaths in the under-40s. And for many forms, treatment hasn’t changed for decades. So it’s clear that we need to do much more.
There are four key areas that need to be prioritised:
- how brain tumours are diagnosed and classified
- their fundamental biology
- how they develop and evolve
- and – most of all – working out how to turn this knowledge into new treatments
Let’s look at each of these in turn.
Improving an over-simplistic rulebook
According to Dr Pollard, the sheer number of different types of cell making up nervous tissue – compared to, say, the skin or liver – makes the brain “the most complex structure in our body, perhaps even in the universe.”
And this means that ‘brain tumours’ are actually a collection of more than 130 very different diseases, all arising from the tissue of the brain or nervous system.
To make sense of this diversity, and get the right treatments to the right patients, doctors use an international classification system which, at the moment, is based on the appearance and type of cells in a tissue sample, and on where the tumour is physically located in the brain.
But the more researchers reveal about molecular nature of different types of brain tumour, the more it’s becoming apparent that this system needs an upgrade – something Professor Gilbertson thinks is needed urgently.
“Ironically, one of the biggest challenges is the medical system itself. Despite working out a huge amount of biology, particularly of children’s brain tumours – understanding that allows us to classify these tumours accurately into distinct diseases – this knowledge hasn’t yet made its way into routine use. And it needs to.”
Partly, Gilbertson says, this is because the technology to do this has only recently become widely available. But he also suspects there have been challenges for many pathologists in adopting these developments in research.
As an example of how this could change things, earlier this year Gilbertson’s team identified the reason why a subtype of a common childhood brain tumour called medulloblastoma is far more sensitive to chemotherapy than the others. This form of the disease can be readily identified using a molecular test to look at molecular markers on the tumour DNA called ‘epigenetic’ marks.
“But the treatment these children get is still essentially determined by looking down the microscope at their tumours, rather than at the molecular hallmarks of their tumour – so we treat all medulloblastoma patients similarly.”
This lack of sophistication is also partly why many brain tumour drug trials haven’t been as successful as hoped – they’ve inadvertently recruited from too diverse a population, and any ‘success signals’ – patients responding to the treatment – have likely been drowned out by the ‘noise’ of patients for whom the treatment didn’t work.
That’s why many experts believe it’s time the brain tumour classification rulebook was rewritten.
“It’s an extremely urgent issue, which could have a real impact on how we treat these children – molecular classification is a much more potent, and accurate, way of diagnosing brain tumours. There is no reason why this cannot be brought in to complement the way we do things at the moment,” says Gilbertson.
Understanding the basic biology of the brain
The second fundamental challenge is the incredible complexity of the brain itself.
Because, while the various types and subtypes of brain tumours differ from each other, they all have one thing in common: their location in the brain. And this means they all have certain shared features that other forms of cancer lack. So research advances and clinical practices in other cancer types often can’t be applied to brain tumours.
For starters, says Pollard, it affects how brain tumours are detected, and monitored during treatment. “The brain is located within the skull – the organ responsible for all our thoughts, emotions, and behaviours. So for obvious reasons, it isn’t easy to monitor early stages of the disease or take biopsies.
“This is very different to, say, blood or skin cancers, where early diagnosis and monitoring is, if still challenging, then at least possible”.
Another such (literal) barrier is the so-called ‘blood-brain barrier’, that regulates which chemicals enter the brain – and which keeps many widely used chemo drugs out.
“Your body contains a few ‘privileged’ organs, that need special protection,” says Gilbertson, “and the brain is one of them. The blood-brain barrier is, in one sense, a physical barrier – the cells lining the brain’s blood vessels are much more tightly knitted together, regulating what gets in and out.
“But it’s also full of tiny molecular pumps to pump stuff out that shouldn’t be there.”
This has two consequences. First, it makes getting drugs into the brain a real challenge. But second, the barrier also controls the entry of immune cells in to the brain – making the application of immunotherapies – some of the most promising developments in cancer research – to brain tumour treatment harder too.
A crucial advance would come, Gilbertson says, from understanding exactly how the blood-brain barrier in brain tumours differs from normal brain tissue.
Another area of intense biological interest is the so-called tumour microenvironment – the neighbourhood of otherwise healthy cells supporting a growing tumour. It’s becoming increasingly clear that a tumour’s environment helps dictate how effective treatments are – no matter where in the body it grows. And for many types of tumour, the types of cell inhabiting this neighbourhood are generally similar – meaning strategies to exploit them can be translated across cancer types.
Not so in brain tumours, however. The microenvironment in the brain can be very different – and completely foreign to researchers who work on other cancer types.
“For microenvironment researchers working on other types of cancer, who want to move into brain tumour research, it’s like moving to a completely different country. The shops, the people, they’re all different,” says Gilbertson.
As well as the complexity of the brain itself, another crucial challenge is to understand where brain tumours come from, how they evolve, and how this affects how they respond to treatment. These are areas that are becoming increasingly well-understood in other tumour types, but where brain research lags behind.
“And there’s a big difference between adult and children’s brain tumours,” says Gilbertson. “In children’s cancers, we’re starting to get a much better understanding of how the normal development of the brain goes wrong. In adults, we’re much less clear about how an adult brain changes over time – it’s only recently been accepted that it changes at all.”
Pollard agrees. “It’s clear that many tumours hijack the systems that stem cells use to grow and expand during the formation of your nervous system. But even in adults, a subset of these ‘progenitors’ exist. So lots of effort is going into understanding whether adult cancers arise from these stem cells too, or – whether they can also arise from more mature cells, that ‘de-differentiate’, to reacquire these features of childhood”.
Inside the cells themselves, there’s also a sense that understanding the roots of the underlying genetic chaos in many brain tumours is going to take time to unravel, despite huge advances in understanding other cancers.
“It’s like looking at a load of broken plates at the bottom of a flight of stairs – it’s just a mess. But in brain tumours that ‘smashed chaos’ was caused by a single event – a ‘shove’ that pushed the ordered stack of plates at the top of the stairs. The trick is to try to identify the initial events that set off the chain reaction that leads to the final mess of the disease. If we can work out how the chaos originated, we can make real progress,” says Gilbertson.
Turning laboratory discoveries into new treatments
These first three challenges – classifying brain tumours’ diversity, understanding how to tackle the complexity of the brain, and our poor understanding of how tumours develop and evolve within it – mean there’s a fourth, even more difficult challenge to solve: finding better ways to bring new ideas from the lab into patient trials.
“We need to see much more rigorous pre-clinical testing of drugs, in situations that are actually relevant to patients with brain cancer,” says Gilbertson. “We tend give patients drugs after they’ve had surgery and radiotherapy. So to make real progress, we need to mimic in these situations in the lab – and that means researchers need to work much more closely with clinicians.”
“We need to say, we’re not going to do experiments in the lab unless the clinicians tell us ‘that makes sense’ – and give clinicians as much say in which lab experiments we do as the lab researchers themselves.”
And this sort of rationally designed experiment should make it easier – and more acceptable – to ask patients for biopsy samples to understand why clinical trials do – and don’t – work, something Gilbertson says hasn’t happened nearly enough in the past.
“Sometimes trials don’t work – but you need to understand why they don’t work to make sure you do better next time,” he says.
So how to fix this?
It’s often tempting to think that the way to accelerate progress in cancer research is simply to pump more cash into the system. But just throwing money at a problem rarely solves it. Instead, better results tend to spring from a carefully thought-through strategy, good leadership, and careful use of precious resources.
In the case of brain tumour research, we’re working on all three, and Cancer Research UK has been working with some of the brightest minds in the field – both in the UK and abroad – to work out how to best support researchers to make a difference for patients with brain tumours.
Without doubt, the most important thing is to focus on science, understanding and careful experiments, rather than simply spending every last penny testing drugs that we know in our hearts are not going to be curative
– Dr Steven Pollard
Breakthroughs won’t happen overnight, but over the coming years, we want to support and encourage:
- Experienced cancer researchers from other fields to apply their expertise to brain tumours.
- Younger researchers, at the beginning of their careers, to specialise in brain tumour research.
- Experts in relevant fields outside cancer research – e.g. neuroimmunology (the brain’s immune system) and developmental neurology (how the brain develops) – moving into cancer research.
- Large international collaborative brain tumours studies.
- More sharing of research data and expertise, to build a UK and international network of brain tumour researchers.
- A better environment to run clinical studies, which will ultimately see more patients given the opportunity to take part in clinical research.
- As well as initiatives to reduce the number of brain cancers diagnosed at a late stage, including implementation of the recent cancer strategy for England, and greater support for GPs to use the updated NICE referral guidelines.
But, obviously, more money is needed too. And we will continue to fundraise for brain tumour research, and to prioritise all good-quality research proposals we receive so that we can meet our commitment to increase what we spend in this area by two to three-fold in the next five years. But solving the fearsome challenge of brain tumours is going to take a concerted, collaborative effort, and a new community to power it.
“Significant progress will come as we continue building a brain tumour research community,” says Pollard.
“But without doubt, the most important thing is to focus on science, understanding and careful experiments, rather than simply spending every last penny testing drugs that we know in our hearts are not going to be curative”.
“Because a two-month extension in survival isn’t good enough. We want cures.”