Safety, Feasibility and Metabolic Effects of the Fasting Mimicking Diet (FMD) in Cancer Patients

Tumor and normal cells display differential sensitivity to nutrient and growth factor deprivation. Due to high proliferation rates, most tumor cells depend on continuous energy and metabolic replenishment to renew and duplicate their intracellular components, such as lipid membranes, organelles, DNA and proteins; moreover, as a consequence of constitutive activation of oncogenic pathways, they are unable to halt their proliferation during starvation. This exposes them to acute energetic and anabolic crisis when nutrients (e.g. glucose, amino acids) and growth factors (e.g. insulin) in the extracellular environment are scarce. Starvation-induced toxicity is even higher when tumor cells are exposed to cytotoxic compounds, such as DNA damaging agents. Indeed, repair mechanisms that are essential to survive damage induced by cytotoxic chemotherapy require energy (in the form of ATP units) and metabolic precursors (e.g., nucleotides) that are potentially reduced at the tumor site during nutrient deprivation.

Conversely, cells of healthy tissues are more capable of adapting their proliferation and metabolism to the metabolic contexture. In conditions of nutrient and growth factor deprivation, most normal cells enter a quiescent proliferative status, thus reducing energy- and metabolite-requiring processes, such as DNA, lipid and protein synthesis; they also activate catabolic processes, such as autophagy, which provide the minimal amount of metabolites to survive starvation. Proliferative quiescence not only prevents the occurrence of damage to intracellular structures and orgenelles, but also favors their repair by sparing energy units and essential metabolites.

This differential response to starvation by cancer and normal cells could be potentially exploited to selectively target in vivo human cancers, while sparing healthy tissues. Cyclic fasting or a plant-based, calorie-restricted, low-carbohydrate low-protein diet known as fasting mimicking diet (FMD), are two approaches that have emerged in recent years to selectively target the metabolic vulnerabilities of malignant cells. Indeed, they are capable of inducing meaningful modifications in systemic metabolism, such as reduction of blood glucose insulin and insulin-like growth factor (IGF-1) in both mice and healthy volunteers.

Studies performed in preclinical models of several cancers have demonstrated that cyclic fasting/FMD produce synergistic anticancer effects when combined with cytotoxic chemotherapy, while protecting normal tissues and stimulating antitumor immunity. So far, only a few studies have tested the effects of fasting/FMD in healthy volunteers or cancer patients.

In healthy volunteers, three consecutive cycles of FMD have been shown to be safe and associated with meaningful changes in risk factors for chronic diseases. In cancer patients, a few small studies have demonstrated that short-term fasting (1-3 consecutive days every 3-4 weeks) is feasible and safe in combination with standard chemotherapy, including platinum-based chemotherapy. However, the effects of the FMD in cancer patients have not been investigated so far.