A new commentary highlights preclinical evidence that inhibiting key amino acids in combination with polyamine inhibitors can cause aggressive neuroblastoma cells to mature rather than proliferate.
Commentary: Rewire your cancer by changing your diet. Image credit: Nemes Laszlo / Shutterstock
Recently published explanatory articles New England Medical Journal Highlights how targeted dietary manipulation can reprogram tumor biology.
The possibility that diet may improve cancer treatment outcomes is of great interest across researchers, clinicians, and the patient community. Mechanistic studies have shown that some dietary manipulations can affect tumor metabolism and the tumor microenvironment, enhancing response to conventional treatments such as radiation and chemotherapy. Nevertheless, knowledge gaps still limit its application to clinical practice.
Most dietary intervention trials are short-term, small-scale, and focus on non-specific outcomes rather than cancer endpoints. Therefore, to establish nutritional guidelines for cancer treatment, it is paramount to go beyond dietary recommendations and rigorously test specific dietary elements in long-term studies with sufficient power. Nevertheless, well-designed preclinical studies remain valuable for identifying and refining clinical research questions.
MYCN-driven metabolic targeting in neuroblastoma
For example, recent work in the MYCN-driven neuroblastoma mouse model discussed in this commentary showed that precise dietary manipulation can reprogram cancer biology. Dietary restriction of specific amino acids combined with pharmacological inhibition of polyamine metabolism was effective in this preclinical model through a novel mechanism. In other words, the reprogrammed cancer cells stopped proliferating and differentiated into more mature cells.
Neuroblastoma caused by MYCN is one of the deadliest childhood cancers and, like other cancers, is highly dependent on polyamines, which are essential for cell proliferation and growth. Eflornithine is a drug that inhibits polyamine synthesis by binding to ornithine decarboxylase (ODC). Despite showing clinical promise and receiving prior approval to reduce the risk of recurrence in neuroblastoma, eflornithine has limited efficacy as monotherapy.
Therefore, eflornithine was combined with a diet lacking the amino acids proline and arginine, which are metabolized to the polyamine precursor ornithine. The study found that although proline levels are abnormally elevated in neuroblastoma tumors, polyamine synthesis remains dependent on circulating ornithine and arginine. Proline can be converted to ornithine, but the enzymes involved in this conversion have low activity in neuroblastoma caused by MYCN.
As a result, dietary restriction depleted ornithine from tumors, while eflornithine inhibited the conversion of ornithine to polyamines. In particular, polyamine depletion unexpectedly impaired hypusination of eukaryotic translation initiation factor 5A (eIF5A), for which the polyamine spermidine is an essential precursor. The researchers tested whether the treatment effect was due to a reduction in hypusinated eIF5A.
Codon-selective translation and differentiation-promoting proteome
Polyamine depletion caused ribosome stalling depending on codon identity, particularly codons containing adenosine in the 3rd position. As a result, when polyamines were depleted, ribosomes struggled to translate cell-cycle proteins rich in adenosine-terminal codons, but continued to translate differentiated proteins with fewer such codons. This selectivity resulted in a pro-differentiation proteome, guiding neuroblastoma cells to exit the cell cycle and differentiate into more mature cells.
Remarkably, genetic ablation of hypusination did not reproduce these effects, indicating that polyamine depletion, but not hypusination, promoted this reprogramming. These findings have important implications. First, as a proof of concept, this study showed that metabolic intervention can induce differentiation in childhood cancers. Second, cellular programs have evolved different preferences for codon usage, suggesting regulatory mechanisms linking metabolism and cell fate.
Additionally, these principles may be applicable beyond neuroblastoma. The ability of metabolic stress to alter translation based on codon composition may create new therapeutic opportunities across cancers. Overall, this study showed that dietary restriction of specific amino acids can synergize with drugs to induce cancer differentiation and provided a roadmap for clinical research. However, whether this approach would benefit children with neuroblastoma requires further investigation.
