SEPTEMBER 25, 2025, NEW YORK – A joint University of Zurich-Ludwig Cancer Research study has demonstrated that combining an existing cancer drug with a dietary intervention dramatically improves the efficacy of the therapy and greatly extends survival time in mouse models of neuroblastoma, a frequently lethal pediatric cancer.
But as researchers including Ludwig Princeton Director Joshua Rabinowitz, Associate Director Eileen White and postdoc Sarah Cherkaoui with Raphael Morscher of the University of Zurich and Michael Hogarty of the University of Pennsylvania report in the current issue of Nature, the proposed intervention does not, like most therapies, treat the malignancy by killing cancer cells.
“Our rationally devised tweak to the diet of mice with neuroblastoma synergized with the cancer drug to instruct tumor cells to stop dividing and instead turn into healthy tissue,” said Morscher. “The discoveries we’ve made here have important implications for the clinical management of this childhood cancer, which is often very difficult to treat, and perhaps several others.”
Neuroblastoma stems from the arrested development of immature nerve cell precursors, which proliferate uncontrollably to form tumors—typically in the adrenal glands at the top of the kidneys, though not infrequently in other parts of the body—instead of differentiating into healthy neural tissue.
The tumors are known to depend on certain metabolites, polyamines, which can be made by their constituent cells or supplied by the blood. A drug recently approved by the U.S. Food and Drug Administration to prevent neuroblastoma relapse, DMFO, targets that dependency by inhibiting an enzyme in cells that makes polyamines.
Morscher, Rabinowitz, Cherkaoui and their colleagues conducted sophisticated studies in mouse models of neuroblastoma to trace the metabolic pathways favored by the tumors to make molecular precursors of polyamines. They discovered that the metabolism of two dietary amino acids—arginine and proline—were notably altered in the mice and disproportionately fed into the sequential biochemical reactions that generate the polyamine precursor ornithine.
When mice engineered to develop neuroblastoma were kept on a diet devoid of these two amino acids, their cancer cells began differentiating into normal neural tissue, arresting tumor growth. This new enthusiasm for differentiation was not, however, caused by changes in the genes expressed by the neuroblastoma but by a glitch in turning certain genetic instructions—those favoring cancer—into protein in the nutrient-stressed state caused by the diet-drug combination.
“We found that the diet-drug combination disrupts the neuroblastoma cell’s ability to make certain proteins that drive the uncontrolled proliferation of neuroblastoma cells,” said Cherkaoui.
Exploring the phenomenon, the researchers identified a subtle quirk in the genetic code in gene transcripts, which the cell’s protein manufacturing machinery reads as it strings amino acids together to make proteins. That quirk is disproportionately associated with the transcripts that drive cell division, but not those that orchestrate the differentiation of neural precursors into nerves. In the absence of polyamines, the protein-making machinery stalls when it comes across the quirk—disproportionately arresting the production of proteins that propel cell division.
Analogous quirks, the authors suggest, may be exploited to treat other pediatric cancers, as the one identified in this study is probably representative of many such mechanisms that have evolved to regulate cellular responses to metabolic stress.
“By changing both what a tumor eats and how it processes these nutrients, we may be able to reprogram other deadly childhood cancers like neuroblastoma to stop growing,” said Rabinowitz.
The next step, he said, will be to evaluate this intervention—or something like it—as a treatment for neuroblastoma. Though dietary interventions sound pretty straightforward, they can be very difficult to implement, as anyone trying to lose weight will attest.
An alternative would be to reduce arginine or ornithine levels using an enzyme, much as the enzyme asparaginase is currently used to treat leukemia, said Rabinowitz.
He, Morscher and their colleagues are now evaluating such strategies.
This study was supported by the Ludwig Institute for Cancer Research, the U.S. National Institutes of Health, U.S. Department of Defense, Swiss National Foundation, European Cooperation in Science and Technology (COST), NOMIS Foundation, Alex’s Lemonade Stand Foundation for Childhood Cancer, Hyundai Hope On Wheels.
Aside from his post as Director of the Princeton Branch of the Ludwig Institute for Cancer Research, Joshua Rabinowitz is Professor in the Department of Chemistry & Lewis-Sigler Institute for Integrative Genomics and Member of the Rutgers Cancer Institute.