By cutting off a tumour’s hidden backup fuel supply, researchers have shown in mice that a precisely engineered diet can dramatically amplify the effect of an existing cancer drug – pointing to a potential new strategy against a disease that still kills half the children who develop its most aggressive form.
Treatment for high-risk neuroblastoma already pushes young patients to their limits. Months of chemotherapy, surgery, radiation and stem-cell transplantation are often not enough. Now, a study published in Nature suggests a different way to attack the disease: not by adding yet another powerful drug, but by altering the metabolic environment the tumour depends on.
The researchers designed a specialised diet that removes two key building blocks required for tumour growth. In mice, combining the diet with the already approved drug difluoromethylornithine (DFMO) did more than slow tumour progression – it significantly improved survival.
“Our goal is to push this to the clinic this year or early next year,” says co-author Raphael Morscher, a paediatric cancer researcher at the University of Zurich in Switzerland.
The approach targets a shared vulnerability in tumour metabolism. Many cancers exhibit MYC-driven metabolic rewiring that increases their reliance on polyamines – small molecules essential for rapid cell division. Limiting access to these molecules may therefore offer a strategy that extends beyond neuroblastoma to other MYC-driven cancers as well.
When a growth switch gets stuck
Neuroblastomas generally arise in the first two years of a baby’s life. For many families, the first sign of trouble is a lump on their infant’s tummy. “When we hear ‘neuro’, we think about the brain, but neuroblastomas arise from nerve cells all over the body – including the ones that control blood pressure or control how the bowel moves,” explains Raphael Morscher, who treats children at the University Children’s Hospital Zurich in addition to his research on cancer metabolism.
“If there are very specific mutations – often involving a gene called MYC, which acts like a growth switch and rewires how cells use nutrients – those nerve cells start dividing uncontrollably and can spread to other parts of the body,” Raphael Morscher says.
For reasons scientists still do not understand, some neuroblastomas “just shrink away in the first weeks of life,” he says. Others continue to grow and spread. These high-risk tumours require the most intensive treatments available. Nevertheless, despite everything doctors can throw at the tumours, half of these children still die.
He outlines the gruelling course of treatment these one- or two-year-old patients face: “We need to give all the chemotherapy we have for half a year. Then you do surgery, take out what is left. Then you do radiation. Then you do a double stem cell transplant. Then you do maintenance therapy afterwards, with immunotherapy plus differentiation therapy,” he says. “It is just unimaginable what these kids have to go through – and even after all of that, 50% still do not survive.”
For the lucky half that do make it more than five years past diagnosis, the same treatments that saved their lives can have long-term health effects. Chemotherapy and radiation can permanently affect a child’s growth, fertility and brain development.
“We are really trying to think about ways to treat children that are both more effective and fully reversible, that do not render these long-term side-effects,” says lead author Sarah Cherkaoui, a postdoctoral fellow at Princeton University in the United States.
Shutting down cancer’s polyamine engine
To exploit that vulnerability, Sarah Cherkaoui focused on difluoromethylornithine (DFMO), recently approved by the United States Food and Drug Administration as a maintenance therapy for children with neuroblastoma.
“It is currently only given after all the other treatment is finished,” Raphael Morscher says. But Sarah Cherkaoui thought that with the right combination therapy, DFMO could potentially be moved earlier in treatment.
DFMO blocks the tumour’s ability to produce polyamines – small positively charged molecules that stabilise DNA and are essential for rapid cell division.
“By limiting how much polyamine there is in the tumour, we are telling the cells to stop growing and start differentiating” or turning into different, healthy cell types, Sarah Cherkaoui explains.
It works by inhibiting ornithine decarboxylase, a key enzyme that converts ornithine into the first step of polyamine production. But when tumours continued growing despite DFMO, it suggested that the cancer had another way to feed itself.
Cutting the tumour’s hidden second fuel line
Using metabolic tracing with labelled nutrients, they followed the carbon atoms through the animals’ metabolism and confirmed that the cancer cells were incorporating dietary amino acids directly into polyamine synthesis.
They identified two specific dietary amino acids – proline and arginine – as alternative substrates that can be converted into ornithine and feed the polyamine pathway. That discovery suggested a simple test: remove both the internal supply with DFMO and the dietary backup.
Sarah Cherkaoui and her team put the theory to the test, feeding mice with neuroblastoma a diet without proline or arginine (which the researchers dubbed the ProArg-free diet). The rodent feed had to be specially formulated, since individual amino acids cannot be excluded through normal food choices. Instead, proteins must first be broken down into their smallest components – individual amino acids – in a process called hydrolysation.
In mice, only the combination produced a dramatic effect: tumours grew more slowly, shrank and survival improved markedly. Neither the diet nor the drug alone was sufficient, confirming that tumour growth depends on a continuous supply of polyamines from both internal production and dietary sources—and that cutting off both routes amplifies the drug’s effect.
Because MYC-driven tumours in several types of cancer – including adenocarcinoma and melanoma – show elevated polyamine metabolism, the same dual-targeting strategy may apply beyond neuroblastoma.
From mouse model to medical trial
The team hopes to begin clinical testing of the ProArg-free diet together with DFMO by the end of the year – an unusually rapid step forward, although the current results have only been shown in mice. Raphael Morscher says the families of children with neuroblastoma are “so motivated” to participate; helping to find new ways to fight cancer is empowering at a time when it is easy to feel helpless.
Since the children in the paediatric ward will not be eating mouse chow, what would a ProArg-free diet look like for them? Comparable amino-acid-restricted medical formulas are already used for rare metabolic disorders and severe allergies. These usually take the form of shakes, and although their taste “takes some getting used to” right now, Raphael Morscher says that other scientists are working to make them more palatable.
The researchers stress that this is a medically engineered diet. Cancer patients should be wary of claims that “dietary changes” – such as eating more leafy greens or sipping apple cider vinegar – are natural ways to cure cancer. “We have tried for decades, and it is not possible to ‘starve’ cancer by avoiding one food group or favouring another,” Raphael Morscher says. “Especially with children, every family asks this: should we now stop eating sugar? Should we now stop eating this or that?”
“No supermarket diet has been clinically proven to improve cancer treatment,” Raphael Morscher notes.
