Metformin elevates anti-obesogenic metabolite Lac-Phe in prostate cancer

Metformin use in men with prostate cancer was associated with significantly increased serum levels of N-lactoyl-phenylalanine (Lac-Phe), a metabolite linked to exercise-induced metabolic regulation, according to findings from a prospective clinical analysis published in EMBO Molecular Medicine.¹

The results suggest a potential mechanistic basis for the drug’s observed effects on weight and metabolic parameters during androgen deprivation therapy (ADT).

In the study, investigators reported that metformin consistently raised Lac-Phe concentrations to levels comparable to those observed following strenuous physical activity.¹ Given that ADT is frequently associated with weight gain, insulin resistance, and reduced physical activity, these findings may have implications for supportive care strategies in prostate cancer, particularly among patients unable to maintain regular exercise.

“This study reflects what’s possible when laboratory science, metabolic biology, and clinical investigation are intentionally brought together for transdisciplinary studies,” said lead author, Marijo Bilusic, MD, PhD, genitourinary medical oncologist and professor of medicine and medical oncology at the Miller School of Medicine, Miami, Florida.² “By working across Sylvester’s Tumor Biology, Cancer Epigenetics and Translational & Clinical Oncology programs, we were able to link a well-defined molecular signal to real patient data. The result isn’t a new cancer biomarker, but a clearer understanding of how a widely used drug may support metabolic health during prostate cancer treatment—an outcome that matters to patients and clinicians alike.”

The analysis incorporated patients from the BIMET-1 prospective trial, as well as men receiving metformin for metabolic dysfunction. Serum Lac-Phe levels were evaluated across disease stages and treatment contexts, including patients undergoing hormone therapy.

Metformin exposure was associated with a significant increase in circulating Lac-Phe irrespective of disease stage, oncologic outcomes, or concurrent ADT. Notably, patients receiving metformin in BIMET-1 demonstrated improved weight management following 6 months of anti-androgen therapy compared with patients in the control arm. Metformin was also found to raise the stress hormone GDF-15, although Lac-Phe correlated more strongly with patient weight management.

“From a clinical standpoint, seeing a metabolic signal that mirrors what we associate with intense exercise was striking,” added Bilusic. “For patients whose treatments or symptoms limit physical activity, that kind of effect could be especially meaningful.”

However, Lac-Phe levels did not correlate with prostate-specific antigen (PSA) responses or other markers of tumor activity, indicating that Lac-Phe levels were not predictive of metformin’s antitumor efficacy in this cohort. According to the authors, there may be other benefits to understanding how treatments affect metabolic health.

“Cancer therapy often affects the body in ways that go beyond the tumor,” said Priyamvada Rai, PhD, co-leader of the Tumor Biology Program and professor of radiation oncology at the Miller School of Medicine.² “Supporting metabolic health can influence how patients tolerate treatment and how they feel over time, even if it doesn’t directly change tumor growth. This study was an opportunity to investigate molecular pathways that can be therapeutically activated for better outcomes to treatments that induce metabolic stress.”

The investigators also observed Lac-Phe elevation with other metabolic therapies, suggesting that this metabolite may represent broader metabolic response rather than a drug-specific effect.

“What’s encouraging about this work is that it reminds us cancer care isn’t only about targeting tumors—it’s also about supporting the whole patient,” concluded Rai. “By better understanding how treatments affect metabolism, we can begin to identify ways to help patients maintain strength, resilience, and quality-of-life throughout their care.”

REFERENCES

1. Bilusic M, Gannamedi DP, Challu B, et al. The anti-obesogenic metabolite, Lac-Phe, is elevated by metformin treatment in prostate cancer patients. EMBO Molecular Medicine. 2026. doi:10.1038/s44321-026-00408-6

2. Study: Diabetes drug, metformin, may echo the benefits of exercise in prostate cancer care. News release. Sylvester Comprehensive Cancer Center. April 6, 2026. Accessed April 6, 2026. https://www.newswise.com/articles/study-diabetes-drug-metformin-may-echo-the-benefits-of-exercise-in-prostate-cancer-care