Sometimes, creativity means designing futuristic new tools. Sometimes, it’s finding a new way of thinking about the tools we already have – no matter how old they might be.

Steroids have been a vital part of glioblastoma care for more than 50 years. They can keep the brain from swelling, so doctors use them to manage the most difficult symptoms of brain tumours and limit the side effects of treatments like surgery and radiotherapy. But it’s one thing to protect someone’s quality of life and another to stop their cancer. It took extra creativity to uncover how steroids might expose a weak point in glioblastoma itself.

Researchers at the Cancer Research UK Scotland Institute helped make that leap. Their discovery has changed our understanding of how glioblastoma grows, and it could also lead to a treatment that uses diet to slow the disease down.

Getting curious about glioblastoma metabolism

So often, it starts with curiosity. In this case, the crucial connection came when the team asked how steroids affect the way glioblastoma cells make energy.

“This project started by connecting a couple of dots,” explains lead researcher Dr Saverio Tardito. “Steroids are often used in glioblastoma treatment, but they are also known for regulating glucose metabolism in many tissues.

“Our curiosity set the objective – do steroids affect glioblastoma metabolism and, if so, can we exploit this to benefit the patient?”

Let’s start with part one of that question.

Through their study, published in Science Advances, the team found that steroids dramatically alter how glioblastoma cells process vitamin B3 (also known as niacin or nicotinamide).

Even if we can’t point it out, we’re all very familiar with vitamin B3 – it’s abundant in chicken breast, salmon and peanuts, and it’s so important for our health that it’s commonly added to flour. All our cells use vitamin B3 to create energy and repair damage, but glioblastoma cells treated with steroids have a special relationship with it.

Using advanced techniques, the team tracked steroid-exposed glioblastomas as they became especially reliant on vitamin B3 and an amino acid called methionine to make energy. In effect, the steroids pushed the cells to set up new production lines for turning these ingredients into a specific metabolite, or fuel molecule, that’s rare in the rest of the brain.

This is where part two of Tardito’s question comes in. Treating cancer is about finding ways to stop cancer cells while minimising damage to healthy ones. The metabolite the team identified (N1-methylnicotinamide) is about seven times more common in glioblastomas treated with steroids than in healthy brain cells. At that point, it’s not just an energy source – it’s a target.

Catching up with glioblastoma

The team had found a trap steroids set for glioblastoma cells, but they still needed to work out the best way to spring it. 

“Once we identified this hidden vulnerability in glioblastoma tumours we had to think hard and stay focused on how to harness this mechanism for patient benefit,” Tardito explains. 

Once again, the team did so in two stages. 

First, they realised that high levels of N1-methylnicotinamide in glioblastomas could be used to “fingerprint” the cancer, making it easier to detect and monitor using brain scans. These scans would also work without steroids, but the drugs make the picture clearer, the way ink does for a fingerprint. 

Then the team began to think through what their findings could mean for treating glioblastoma. Here, they zeroed in on methionine. Though it’s also essential for our health, methionine is easier and safer to restrict than vitamin B3, and steroids make glioblastoma cells much more reliant on it than their healthy equivalents. 

In the team’s mouse models, steroids combined with an experimental low-methionine diet safely halved methionine levels in glioblastoma cells and showed signs of restricting tumour growth. 

On a human level, that kind of diet would need to be specially formulated and prescribed for each patient, but it’s an exciting new approach with the potential to shut or slow down glioblastoma cells’ energy production. In the research paper’s own words, it could help create “a brain-specific metabolic state with antitumour effects for glioblastoma”.

Crossing new boundaries

Creativity doesn’t always come smoothly. It took more than half a century before researchers had the tools, the clues and the opportunity they needed to take another look at what steroids do to brain tumours. And that was just the prologue. 

“It wasn’t a single eureka moment,” says Tardito. “It was the collective effort of a multidisciplinary team, crossing boundaries over several years.” 

This is still early-stage research, so there are more years ahead. Although the team has shown that steroids change how glioblastoma cells make energy, there’s still work to do before they can begin to test whether low-methionine diets could help treat people with glioblastoma. 

The goal for those diets would be to slow glioblastoma down. If they’re effective, they could give people more time with their loved ones before their cancer grows further, and even improve the chances other treatments will be able to cure them.

Thankfully, after so long, thanks to new connections and new ways of thinking, research into treating brain tumours is beginning to speed up.

The people behind the research

So far, this project has brought together radiochemists, biochemists, cancer biologists, and neurosurgeons working across Scotland, Austria, Norway, France, and Luxembourg. Without that combination, the team couldn’t have made the same creative connections, and they wouldn’t have been able to move so quickly from a discovery to a new treatment approach.

“Now, we have the ambition to test some of these applications in the real world,” says Tardito.

And Tardito’s following his research across borders and boundaries, too. He’s moved from our Scotland Institute in Glasgow to the Centre for Cancer Research at the Medical University of Vienna. From there, he’ll keep working with collaborators across Europe to unlock the true potential of steroids in glioblastoma care.