Metformin Mimics Exercise Benefits in Prostate Cancer Patients Through Metabolic Pathway Activation

A groundbreaking study from Sylvester Comprehensive Cancer Center has revealed that metformin, a widely prescribed diabetes medication, may replicate key metabolic benefits of exercise in prostate cancer patients by activating specific biological pathways associated with energy balance and weight control.

The research, published in EMBO Molecular Medicine, demonstrates that metformin significantly increases levels of N-lactoyl-phenylalanine (Lac-Phe), a naturally occurring molecule that typically rises during intense physical activity and is linked to appetite regulation and weight management.

Targeting Exercise-Associated Metabolic Pathways

The study focused on Lac-Phe, a compound produced when lactate—a substance that accumulates during exertion—combines with phenylalanine, a basic building block of protein. Scientists first identified Lac-Phe because its levels spike after intense exercise, coinciding with shifts in energy use and appetite regulation.

"From a clinical standpoint, seeing a metabolic signal that mirrors what we associate with intense exercise was striking," said Dr. Marijo Bilusic, genitourinary medical oncologist and professor of medicine at the University of Miami Miller School of Medicine. "For patients whose treatments or symptoms limit physical activity, that kind of effect could be especially meaningful."

The research team analyzed serum samples from non-diabetic, overweight or obese patients with hormone-sensitive prostate cancer participating in the BIMET-1 trial. Participants received either bicalutamide alone or in combination with 1,000 mg of metformin twice daily.

Consistent Metabolic Response Across Patient Populations

Metformin treatment consistently and significantly increased serum Lac-Phe levels in prostate cancer patients, regardless of age, body mass index, disease stage, or treatment regimen, including androgen deprivation therapy (ADT). Notably, the Lac-Phe concentrations achieved with metformin were comparable to those reported after strenuous exercise, occurring even when patients were not exercising at the time of blood collection.

The effect persisted after hormone therapy began and was confirmed across an expanded cohort of 25 additional men with various stages of prostate cancer, including metastatic hormone-sensitive, biochemically recurrent, and metastatic castration-resistant disease.

"All BIMET-1 trial participants in the metformin-treated arm demonstrated a marked rise in Lac-Phe from baseline," the researchers reported, while patients who did not receive metformin showed no significant changes in serum Lac-Phe concentrations.

Weight Management Benefits During Hormone Therapy

The study revealed that metformin-treated patients showed improved weight management during anti-androgen therapy. Most treated individuals maintained or lost weight over six months, unlike controls who typically experience weight gain during hormone treatment.

While metformin also raises growth differentiation factor 15 (GDF15), a stress hormone associated with appetite suppression, the study found that Lac-Phe was more closely tied to weight changes. The two molecules didn't rise together, suggesting metformin affects weight through multiple pathways, with Lac-Phe playing a more significant role.

Clinical Implications for Cancer Care

Higher Lac-Phe levels were not associated with anti-tumor response to metformin and did not correlate with changes in prostate-specific antigen (PSA), a standard marker used to monitor prostate cancer. This distinction suggests that Lac-Phe reflects how the body manages energy, weight, and metabolic strain during treatment rather than direct anticancer effects.

"Cancer therapy often affects the body in ways that go beyond the tumor," said Dr. Priyamvada Rai, co-leader of the Tumor Biology Program at Sylvester. "Supporting metabolic health can influence how patients tolerate treatment and how they feel over time, even if it doesn't directly change tumor growth."

The findings are particularly relevant for prostate cancer patients receiving hormone-based therapies, which are known to disrupt metabolism and contribute to weight gain, insulin resistance, and cardiovascular risk—precisely when fatigue and other side effects often limit physical activity.

Broader Metabolic Understanding

The research represents a collaborative effort across Sylvester's Tumor Biology, Cancer Epigenetics and Translational & Clinical Oncology programs, utilizing targeted metabolic profiling through ultra-high-performance liquid chromatography coupled with tandem mass spectrometry to quantify lactate and Lac-Phe levels.

"Metabolism is involved in everything cells do," said Dr. David B. Lombard, co-leader of the Cancer Epigenetics Program. "These findings suggest Lac-Phe may be a very informative signal for understanding how metformin affects metabolism in prostate cancer patients."

The study also observed that patients receiving other metabolism-modifying interventions showed elevated Lac-Phe levels, suggesting this metabolite may reflect a 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," said 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."