Taking advantage of cancers’ abnormal metabolism could lead to a new way to ‘starve’ tumours

Cancer cells need energy and nutrients to carry on growing. And, because they often multiply rapidly, cancer cells have a high demand for fuel.

One tempting idea for treating cancer that’s emerged over the years is trying to cut off this fuel supply and ‘starve’ the tumour.

But there’s a hitch.

Healthy cells rely on the same sources of energy and nutrients as cancer cells. So any treatment that deprived cancer cells of fuel would also stop our cells and organs from working properly, leaving us in serious trouble.

Scientists are a persistent bunch though, and don’t give up easily. Over the last decade there’s been a renewed interest in finding out exactly how cancer cells get the nutrients they need to grow.

Now our researchers at the Beatson Institute and the University of Glasgow might have found a way to shut down cancer cells’ fuel supply, while at the same time leaving healthy cells unaffected.

And the potential treatment uncovered by the researchers, led by Professor Karen Vousden and Dr Oliver Maddocks and published in the journal Nature, might be surprisingly simple – a specially made diet for cancer patients undergoing therapy.

Cancer and abnormal metabolism

Cells rely on a family of molecules called amino acids to grow. They are the building blocks of life, working like Lego bricks that build up into the proteins that help cells function and give our bodies their shape, structure and strength.

We need to get some amino acids through protein in our diet – for example meat and dairy are rich sources of amino acids – but others can be made by our cells including 2 amino acids called serine and glycine.

Healthy cells use a series of chemical reactions in small ‘batteries’ called mitochondria to make the energy they need to function. “If they are running short of serine and glycine, cells can divert molecules from energy production and use them to make these amino acids,” says Maddocks.

And this is where it gets interesting when it comes to cancer cells.

Back in the 50s a scientist called Otto Warburg first noticed that cancer cells use a different chemical process to turn fuel into energy than normal cells. This re-wired metabolism was named after him: the Warburg Effect.

Cancer cells have higher demands for nutrients and are less adaptable than normal cells when facing nutrient starvation.

– Dr Oliver Maddocks

“Cancer cells frequently re-wire their metabolism to support their rapid growth,” says Maddocks.

The Warburg Effect is where cancer cells bypass the specialist mitochondria that normal cells use to generate energy, meaning they produce energy less efficiently, but much more rapidly. But it comes at a cost.

“Their re-wired metabolism often means that cancer cells have higher demands for nutrients and are less adaptable than normal cells when facing nutrient starvation,” says Maddocks.

This vulnerability sparked an idea. The researchers wanted to try and exploit this weakness and starve cancer cells by cutting off the supply of serine and glycine from the diet.

“Four years ago we had our first glimpse that this approach to starve tumours might work. We simply removed serine and glycine from the food we gave mice with tumours, and the tumours grew more slowly than those in mice fed a control diet,” says Vousden.

“We were surprised that diet alone could have such a clear effect. And so we’ve taken the research to the next step.”

Can diet alone slow cancer growth?

This time the team studied mice with faulty genes that develop cancers in a similar way to people.

“We studied one group of mice that are genetically predisposed to develop bowel cancer, and another group predisposed to lymphoma,” says Maddocks. “We introduced the diet after tumours had begun to grow, and we saw the same results as before – mice on a diet lacking serine and glycine survived longer.”

“Even if we used the special diet on mice with more advanced tumours there was still a positive effect,” he says. “And this more closely mimics treating people with cancer.”

Their experiments suggest that starving the cancer cells is more effective when the cells are under something called ‘oxidative stress’, which is caused by an imbalance of molecules called reactive oxygen species (ROS).

It’s a really exciting time for cancer metabolism. Interest in the field has re-ignited, and we’re seeing some exciting potential treatments.

– Professor Karen Vousden

These molecules are produced naturally in cells and are vital for our health; they are needed for a healthy immune system and help cells communicate with each other. But too many can cause damage within cells and lead to cell death.

“Many cancer treatments, including chemotherapy and radiotherapy, lead to a big increase in the levels of reactive oxygen species,” says Vousden. “So we wanted to find out if starving cancer cells of serine and glycine would be more effective if we put cancer cells under oxidative stress.”

Using mice that were genetically engineered to develop lymphoma and were missing a protein that lowers ROS in cells, the researchers showed that the serine and glycine free diet had an even bigger impact on survival.

But it’s not all good news. The team found that a faulty gene that is frequently found in several types of cancer, including pancreatic cancer, can overcome the effect of the diet, suggesting that not all cancers would be susceptible to diet treatment.

“The faulty version of the KRAS gene helps cancer cells make their own serine and glycine, and overcome the effects of taking them out of the diet, but this knowledge could help us select which type of tumours to treat,” says Vousden.

Don’t try this at home

These are promising early findings from the lab, but the researchers are quick to emphasise that their research has a long way to go.

It certainly isn’t grounds for altering normal diet.

“We’re interested in this as a possible treatment. A special, carefully formulated diet replacement to give cancer patients for short periods while they are having other forms of therapy, like chemotherapy or radiotherapy,” says Maddocks.

“Like any new treatment, the next step would be a clinical trial to see if a special diet is safe for patients and if it does have any benefit for people. This would be carried out by doctors and nutritionists in the clinic, where patients could be carefully monitored to make sure they are getting all the other nutrients they need and weren’t being harmed by the diet.”

Our diet is complex and it’s impossible to cut out serine and glycine without excluding other amino acids vital to our health too, so there is no way to do this safely with a DIY home-made diet plan.

The other potential avenue researchers are exploring is finding drugs that mop up serine and glycine from our bodies, starving the cells in the same way but without needing a special diet.

“It’s a really exciting time for cancer metabolism,” says Vousden. “Interest in the field has re-ignited, and we’re seeing some exciting potential treatments. Now we want to take these ideas forward and see if they could help patients.”

Emma