Setting the optimal balance between metabolite supplementation and deprivation in cancer therapy (METABALANCANCER)

The goal of this proposal is to explore combinations of targeted metabolite supplementation and global nutrient restriction as a new strategy to reprogram tumor metabolism, to halt tumor progression and to improve response to treatments. Preclinical and clinical studies published by our group and by others showed that global nutrient restriction, in the form of cyclic fasting or fasting-mimicking diets (FMDs), produces desirable metabolic and immunologic effects that result in reduced tumor progression and in the prolongation of animal/patient survival. Of note, our unpublished results indicate that the supplementation of specific amino acids or fatty acids has in vitro and in vivo antitumor effects, which are strongly enhanced when metabolite supplementation is combined with nutrient starvation. By employing canonical cell biology and biochemical experiments, polysome/ribosome profiling, isotope tracing experiments and integrated omics (transcriptomic, proteomic, metabolomic) analyses in in vitro and in vivo murine and human tumor models, here we propose to: - identify the cell-autonomous and immune-mediated mechanisms at the basis of the antitumor effects of targeted metabolite supplementation in combination with global nutrient restriction; - identify the most effective metabolite supplementation-restriction strategy to be tested in a first-in-human clinical trial in patients with advanced triple-negative breast cancer. While the basic cancer research and medical oncology communities are engaged in a historical scientific and clinical diatribe on the use of nutrient deprivation vs. supplementation approaches to halt tumor progression and to improve patient survival, we will exploit our unprecedented ability to conduct parallel preclinical and clinical experimentation in the field of cancer metabolism to identify new and effective combinations of balanced metabolite supplementation and restriction, with relevant scientific and translational implications.