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BRAF mutations in childhood brain tumours

Research that we funded nearly 20 years ago laid the foundations for last week’s approval of dabrafenib and trametinib to treat childhood gliomas.

The approval of this treatment marks the first new treatment in decades, and the first targeted treatment for children.

This new treatment has the potential to improve survival and quality of life for children diagnosed with low and high-grade gliomas with a BRAF V600E mutation. 

We are delighted with this news, and proud of the vital role we played in BRAF mutation research over the last 20 years.

Funding from the Samantha Dickson Brain Tumour Trust  

Dr David Jones – now leading the EVEREST Centre in Germany – started his PhD in 2005 with funding from us nearly 20 years ago.  

His findings were remarkable and laid the foundations for better understanding of low-grade brain tumours and also brought life to a research field that was so understudied.   

The knowledge that he and his colleagues gained about BRAF mutations laid the foundations for new drug discoveries.  

In 2005, David’s project used (then) new technology to study childhood pilocytic astrocytoma.   

An understudied field of research  

Back then, only very few researchers focussed on low-grade research into brain tumours. The Samantha Dickson Brain Tumour Trust saw so much potential in this research – to ensure that children diagnosed with low-grade brain tumours had the best care and quality of life – that they provided funding towards David’s PhD project.   

His research focussed on understanding what drives the growth of pilocytic astrocytoma in children. At the time most of what researchers knew about BRAF mutations was in other cancers such as melanoma and lung cancer. But little was known about what drives pilocytic astrocytoma growth during childhood.   

Understanding BRAF mutations in low-grade childhood brain tumours  

David’s research identified, for the first time, that a BRAF mutation drives pilocytic astrocytoma growth.    

He discovered that a fusion between a gene known as KIAA1549 and the BRAF gene was common in paediatric low-grade brain tumours such as pilocytic astrocytoma. And that this fusion created a hybrid gene which causes abnormal function in the BRAF signalling pathways that are important for cell growth and multiplication.   

At this point in his PhD, no one in the world knew his discovery and so David had found something completely novel that underpins paediatric low-grade tumour research. This BRAF fusion gene is today considered an important diagnostic marker for paediatric low-grade brain tumours.  

It is important to acknowledge that while this was my PhD project, this work could not have been achieved without the collaboration between researchers both in the laboratory I worked in at the University of Cambridge, and other experts in the field. Paediatric cancer research has to be a collaborative effort as the numbers of children diagnosed are relatively small. Therefore, the scientific community must work together to understand this complex group of brain tumours and improve treatment options for children – and this is how the EVEREST Centre was born."

Dr David Jones

20 years on  

Now, nearly 20 years later, we know that mutations in the BRAF gene are implicated in other low-grade (and high-grade) brain tumours in children, and there are several different types of mutations that may lead to tumour growth.   

One of them is the BRAF fusion that David discovered during his PhD. Another is the BRAF V600E mutation which is being targeted by the drugs dabrafenib and trametinib.  

Angela and I are so pleased our brave decision in the early 2000’s to fund research for both low-grade tumours in children and adults has paid off. Before we started, funding for research into these tumours was almost non existent. David’s research was amazing for such a young researcher. We are so pleased he has remained in the brain tumour research field and now leads our Everest Centre in Heidelberg. He is one of the leading experts in the world in this field.

Neil Dickson, Founder of The Brain Tumour Charity

What are BRAF mutations?  

A BRAF mutation is a change in the DNA of the BRAF gene.  

The normal BRAF function gives cells signals to grow, multiply and perform specialist functions in the body.  

A mutation in this gene can lead to the wrong signals being given. This can cause cells to multiply and grow uncontrollably, which results in tumour formation and growth.   

There are different types of BRAF mutation that can be targeted with different drugs to stop the cells dividing. These include the BRAF V600E mutation – this is where dabrafenib and trametinib become important.   

There are other mutations such as a BRAF fusion which also causes uncontrolled cell growth but can be targeted with different drug combinations.   

How do dabrafenib and trametinib work?  

Dabrafenib and trametinib block a pathway known as the MAPK pathway. This pathway is important for cell growth. By using these drugs in combination, the MAPK pathway is blocked at two different points – making the combination treatment more effective.   

Dabrafenib specifically inhibits the V600E-mutant version of the BRAF gene. This mutation allows cells to grow uncontrollably. So, by blocking it, dabrafenib can stop or slow the growth of the mutated tumour cells.  

Trametinib is known as a MEK inhibitor and inhibits proteins which are important in cell growth and multiplication. Inhibiting these proteins leads to reduced cell growth and increased cell death.  

This combination treatment has only been approved for brain tumours with a BRAF V600E mutation as dabrafenib is targeted to this specific DNA mutation.