Paving the way: How biopsies are offering hope to children with aggressive brain tumours

“Our motivation for studying it is because there haven’t been any new effective treatments for decades.” 

Overall, survival for children’s cancers in the UK has more than doubled since the 1970s. Today around 8 in 10 children diagnosed with cancer will survive. We have come a long way. But for some cancer types, progress has been stunted.  

Professor Chris Jones, based at the Institute of Cancer Research (ICR), studies a type of brain tumour known as Diffuse Intrinsic Pontine Glioma (DIPG). DIPG occurs almost exclusively in children, when they’re about 6 to 8 years old.  

“It’s found in the brainstem and because of where it’s found, you can’t operate. Cutting the tumour out isn’t possible at all. So for that reason, and the fact they spread throughout the brainstem and the central nervous system, they’re essentially incurable.”  

The average survival for a child diagnosed with this type of brain tumour is just 9 months. And because studying DIPG has its challenges, sadly this figure has shown little improvement over the years. 

But the tide may slowly be turning.   

Decades in the making 

For decades, clinical trials of DIPG were based on work done using samples from adult brain tumours that looked similar to DIPG down a microscope. None of these studies were able to provide answers and because of the lack of actual DIPG samples, there was a gap in our understanding of the biology of the disease.  

“It wasn’t until about 10 years ago that we started collecting biopsies in the clinic” explains Jones. And it’s this change in practice that’s led us to where we are today. 

This surge in taking biopsies happened around the same time on both sides of the Atlantic. In Europe, namely Paris, researchers began introducing a minimally invasive form of surgery for biopsies. “And so from both Europe and the USA, we soon had a sufficient quantity and quality of material to start doing the molecular work that we’re building on now.”

The samples used by Jones came from the Biological Medicine for DIPG Eradication trial, known as the BIOMEDE trial. It’s a Europe-wide, phase 2 trial that started in Paris. The UK arm of the trial, co-funded by us and The Brain Tumour Charity, was led by Professor Darren Hargrave.  

What researchers saw when they first studied the samples changed our understanding of DIPG.  

“It’s unlike any other form of cancer, it’s completely different to the similar looking tumours that occur in elderly adults, driven by different genes, different pathways,” Jones explains. “So it was no wonder that all the trials that had been done for so many years failed, because although it looked similar down a microscope, the underlying biology was completely different.” 

The samples have already proved invaluable, revealing that DIPG is totally biologically unique. 

A promising discovery

The team began by testing drugs on tumour samples grown in the lab. A subset of cells seemed to be very responsive to a group of drugs known as MEK inhibitors, which block signals from a protein called MEK that tell cells to divide and grow. 

But when they tested the MEK inhibitor trametinib in mice with DIPG, the effects fell short.  Tumour cells quickly became resistant to the drug. 

“It didn’t seem to work on its own, which got us thinking, what do we know about this drug and this pathway?” 

While this class of drugs can be very effective in some tumour types, these cancers can develop resistance to them, through a number of mechanisms. So the team went back to the drawing board to try and figure out why the tumour cells were becoming resistant.

“When we began looking into the biology,” explains Jones, “they all came back with essentially the same mechanism.” 

The cells were developing mutations in MEK. And with these small changes, they were no longer susceptible to the effects of the drugs. 

Now the researchers had an idea of how the cancer cells were developing resistance to the MEK inhibitors, they were prepared to find a way to circumnavigate the resistance, by trialling different drug combinations. 

The team went back to analyse their initial data and found that the samples that became resistant to MEK drugs were sensitive to one of the very first trial drugs used for the children with DIPG, dasatinib. “Essentially, if you’re resistant to one drug, you’re sensitive to the other and vice versa.” 

Trametinib in combination with dasatinib managed to cut growth in mice with DIPG by over 60%. 

“They have the potential to be a very promising combination in children with DIPG with this particular molecular signature.” 

A catalyst for change 

Jones emphasises that none of this would be possible without the advocacy of the parents.  

“Imagine you get a terrible diagnosis like this and told your child isn’t going to make it. When parents asked what can be done, they were told nothing, because no one is studying it.”  

The parent community was fundamental in catalysing this change, “partly through their advocacy and, opening up of samples, but also by funding it directly, and bringing researchers into the field and working together”. 

As well as being co-funded by us, this particular project was funded by a number of cancer charities, including Christopher’s Smile, Abbie’s Army, Islastones Foundation, the CRIS Cancer Foundation, Children with Cancer UK, and the Ollie Young Foundation. 

The benefit for patients 

The samples we now have thanks to the BIOMEDE trial provide a valuable resource for researchers all over the world to continue making strides for DIPG. “If anybody wanted samples for more in depth, functional studies and other molecular studies that, it’s an enormous resource of the community to understand this disease in more detail.”  

While, the novel combination showed great success in early trials in the lab, further research is still needed until we can see a real difference for patients. 

Nevertheless, Jones is excited about what the future holds. “One of my PhD students, also funded by Cancer Research UK, is taking the research to the next stage, by looking at mathematical modelling of what the best treatment schedule would be. 

“Eventually we hope to take our findings to a clinical trial, and show improvement in survival for these children, which we haven’t been able to show yet. The growing interest in the field has given me hope. I am really optimistic that between us all, we are going to start to see these results filtered through to benefits for the patients.”  

Lilly