The anti-obesogenic metabolite, Lac-Phe, is elevated by metformin treatment in prostate cancer patients

Randomized clinical trials have highlighted the importance of weight control and exercise in improving cancer outcomes, yet the molecular mediators of these benefits remain poorly understood. Recent studies in Type 2 diabetic patients reported that the insulin-sensitizing drug, metformin, exerts its anorexigenic and anti-obesogenic effects through elevation of N-lactoyl-phenylalanine (Lac-Phe), a metabolite also reported to underlie the metabolic benefits of exercise in healthy individuals. Because metformin can be repurposed for oncology, we investigated whether the metformin/Lac-Phe link extends to cancer by profiling serum Lac-Phe levels in non-diabetic prostate cancer patients from BIMET-1, a prospective metformin trial, as well as those receiving metformin for metabolic dysfunction. Irrespective of disease stage, anticancer outcomes, or hormone therapy status, metformin treatment significantly and consistently increased serum Lac-Phe in these cancer patients to concentrations that approximated levels reported after strenuous exercise. Moreover, patients on the metformin arm of BIMET-1 exhibited improved weight management following anti-androgen therapy relative to those in the control group. By generalizing the metformin/Lac-Phe axis, our study provides a new molecular context for the metabolic benefits of repurposing metformin in cancer patients.