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WHY IS BRAIN CANCER THE BIGGEST KILLER OF YOUNG CHILDREN??

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It’s a good question. The simple answer is threefold:

  • We don’t know what causes brain cancer
  • Current treatments are not good enough
  • We don’t have enough money for research to change this

But in addition, there are specific issues to deal with in paediatric or childhood cases.

Let’s start with the cause: the fact is we don’t know what causes children to develop brain cancer, or adults for that matter. There are various theories, from genetic mutations to epigenetic or environmental factors to viral infections, and research is continually making new discoveries which improve our understanding of the disease. But the more we discover about brain cancer, the more we realise there is still so much more to find out. Take medulloblastoma, for example, which is a common paediatric brain tumour. Because of research and a greater understanding of how brain cancer operates on a molecular level, what was previously thought of as one type of brain cancer is now known to have at least four genetic sub-types, which all require different treatments. As we discover more about the disease, we discover there are even more questions to answer regarding how to treat it.

As well as genetic mutations there are epigenetic factors to consider. A recent Australian study found that fathers working in jobs where they are regularly exposed to benzene in the year before their child is conceived are more than twice as likely to have that child develop a brain tumour. Women working in occupations that expose them chlorinated solvents – found in degreasers, cleaning solutions, paint thinners, pesticides and resins – at any time in their lives also have a much higher risk of their child developing a brain tumour. The researchers stressed that it’s still too early to say whether solvent exposure causes brain tumours. But it is an example of research pointing to epigenetic factors in the development of brain tumours, and specifically the vulnerability of children to brain cancer even before they are born. What we suspect at this stage is that it is likely to be a combination of genetic and environmental factors that lead to increased risk.

The next thing to consider is how effective treatments for children with brain cancer are. The answer: not effective enough. In fact, the internationally recognised expert in childhood brain cancer, Dr Nick Gottardo, describes current treatments as “woefully ineffective”.

Brain cancer is different in children than in adults. There are forms which more commonly affect kids, such as medulloblastoma. But even when typically adult tumours such as high grade gliomas do occur in children, they present very differently on a molecular level.

 

“They look the same under the microscope, but molecularly they are very distinct diseases….Having more information on these tumours can only benefit us in being able to choose more rational therapies in the near future.”

– Dr. Nick Gottardo

Again, we don’t know why children manifest their own versions of this disease. And some paediatric brain tumours, such as DIPG (Diffuse Intrinsic Pontine Glioma) are brain-stem based and therefore usually inoperable; with the limited treatments available, without surgery, the prognosis is very bleak.

Plus, children’s brains are still developing so the standard treatments for brain cancer, which include surgery, radiotherapy and chemotherapy, can result in more substantial and permanent side effects than they would for an adult. This is a massive problem with childhood cases; applying treatment is harder than in the case of adults. Hence a major consideration when developing new treatments for paediatric brain cancer is how to provide quality of life as well as increasing survival.

“We’re all aiming for 100%, that’s our goal – to cure all children. But we also want to cure them, leaving them with a good quality of life in the long term.”

– Dr. Nick Gottardo

Research funded by The Brain Tumour Charity in the UK has been investigating ways to improve quality of life for children diagnosed with a brain tumour. The team at the University of Southampton collected data on children surviving a brain tumour, including looking at the use of an alternative radiotherapy technique called hyperfractionated radiotherapy, which involves dividing the total dose of radiation into a larger number of smaller doses or fractions, to decrease the effect of the radiation on other tissues, such as the brain. The clinical trial was run by the European International Society for Paediatric Oncology and found that hyperfractionated radiotherapy had less of an impact on children’s memory, planning and organisational skills than conventional radiotherapy. The team says this is an example of how adjusting radiation dose can help reduce side effects while still treating the tumour. In a separate study the researchers looked into different tumour types and observed that different tumours have an impact on quality of life. Furthermore, tumour sub-type is important, with children with medulloblastoma tumours containing the ‘sonic hedgehog’ gene experiencing a better quality of life after treatment than those with other medulloblastoma sub-types. This is the first time that tumour biology has been related to quality of life in medulloblastoma sub-types.

“What we want to do is find new therapies that will be more specific against the tumour and with fewer side effects, so that the children are cured and also cured with excellent quality of life in the future”.

– Dr. Nick Gottardo

The next problem is not insignificant, but nor is it insurmountable: funding. Survival rates for brain cancer have hardly changed in 30 years and remain far too low, with only 2 in 10 people surviving for 5 years. The reason for this – and by association, the reason why brain cancer kills more children than any other disease in Australia – is largely that not enough money has been invested in research. Cure Brain Cancer is doing things differently to improve outcomes for patients and one of things that makes us different is our approach and outlook. Our question is not ‘why?’ but ‘why not?’ and – more importantly – ‘how can we?’ Perhaps this is the more pertinent question here; not why brain cancer kills these children, but how are we going to change this

Research into paediatric brain tumours has come a long way already. Yes, there is a long way to go; survival rates for brain cancer have hardly improved for 30 years. But that’s not because nothing has been done. However, the number of clinical trials for children and access to these trials is limited; with a disease of such low incidence, the clinical research has historically tended to follow what has been done in adult trials, but this is changing.

Professor Stewart Kellie, a paediatric neuro-oncologist & oncologist at The Children’s Hospital at Westmead, says there have already been huge advances, but says global collaboration is key to success when it comes to paediatric clinical trials and research. By pooling resources, answers can be arrived at more quickly.

“I think the biggest change that I’ve seen in my professional career has been the incorporation of research – and particularly clinical trials – into the frontline treatment of children”.

– Prof. Stewart Kellie

Back in April, four international studies made breakthroughs simultaneously in a fatal form of brain cancer, Diffuse Intrinsic Pontine Glioma (DIPG). All of them focused on mutations in the ACVR1 gene. (We published an article at the time looking in more detail at these studies.) Discovering these links between ACRV1 and DIPG opens up many more questions, but that’s not necessarily a bad thing, because it also opens up many more possibilities. One of those studies, led by scientists at the Institute of Cancer Research in London, identified recurrent activating mutations in the ACVR1 gene in DIPG, but also found that those mutations are identical to ones found in people with the congenital childhood developmental disorder fibrodysplasia ossificans progressiva (FOP). What this means is that they can start to investigate whether drugs that have already been developed for FOP could be repurposed to treat DIPG. By discovering common gene mutations between paediatric brain cancer and other diseases or cancers, new treatment options present themselves. This discovery was made possible in part because of international collaboration.

Access to children’s tissue samples to facilitate research is also vital, not just because it can provide insights into that particular patient’s tumour, but because developing tissue banks enables researchers to compare and cross reference data from across brain tumours and across other cancers and diseases. In a recent blog for Cure Brain Cancer, Barrie Littlefield, whose own daughter died from glioblastoma in 2011, said he thinks quick and accurate tumour pathology and up-to-date genetic testing should happen regardless of whether there are clear clinical implications, as the information may be useful at a later stage if not immediately. Tissue banks are invaluable resources when it comes to developing new therapies and understanding the molecular biology of brain tumours. Just last week, a study using data from The Cancer Genome Atlas (a large scale genomic sequencing project) suggested that 1 in 10 cancers could be diagnosed more accurately based on genetic makeup, rather than where they occur in the body. The researchers genetically profiled and compared 3,500 samples of tumor tissue and identified 12 sub-types of cancer, only five of which correlated with their tissue-of-origin classifications. The other seven were newly identified genetic subtypes of cancer which affect more than one type of tissue. They say it ultimately provides the biologic foundation for a new era of personalized cancer treatment, in which cancers are diagnosed based on genetics rather than tissue of origin.

As you can see, many questions remain regarding childhood brain tumours. We don’t know why brain cancer occurs. But crucially we need to answer the question ‘how?’ How do we treat this disease? How do we improve survival, as investment in research has done for other diseases such as leukaemia and breast cancer? How do we give children diagnosed with brain cancer a more hopeful prognosis? The urgency and focus is on finding new treatments but epidemiological advances (which have been hampered by low incidence in children thus far) could ultimately be critical, and this too could be unlocked through further research investment and collaboration. Research will answer these big questions. All that’s required is funding.

Don’t let kids fight brain cancer alone
Henry Sapiecha

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