Researchers led by Ludwig Princeton’s Sarah Cherkaoui, Raphael Morscher of the University of Zurich and Michael Hogarty of the University of Pennsylvania with Ludwig Princeton Director Joshua Rabinowitz and Associate Director Eileen White reported in a September publication in Nature that, in mouse models, a dietary intervention improves the anti-cancer efficacy of difluoromethylornithine (DFMO), a drug approved for the childhood cancer neuroblastoma. The combination arrests tumor growth not by killing cancer cells but by inducing their differentiation. Neuroblastoma cells depend on polyamines, and DFMO inhibits an enzyme that makes these metabolites via a pathway starting from the amino acids arginine and proline. A diet devoid of those amino acids depletes polyamines and synergizes with DFMO. The mechanism of action of the combination involves altered translation of particular gene transcripts into proteins due to ribosome stalling at codons that have an adenosine in the third position, apparently because polyamines are required for efficient translation of such codons. Such transcripts are selectively enriched in cell cycle genes and low in neuronal differentiation genes. Impaired translation of the former favors a pro-differentiation proteome in the cells, inducing the observed therapeutic effect. 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 responses to metabolic stress.
Reprogramming neuroblastoma by diet-enhanced polyamine depletion
Nature, 2025 September 24