A Diabetes Drug May Mimic Exercise to Help Prostate Cancer Patients Stay Healthier

Hormone therapy for prostate cancer is, metabolically speaking, a kind of managed catastrophe. Within months of starting androgen deprivation treatment, men begin gaining weight, losing muscle, accumulating fat around the abdomen. Blood sugar climbs. Cardiovascular risk rises. The treatments work, often very well, but the body they work in pays a substantial price. And here is the particular cruelty of it: the one intervention most reliably shown to blunt these effects, regular strenuous exercise, becomes harder to do precisely when it matters most. Fatigue is pervasive. Pain is common. Sometimes the disease itself makes sustained activity impossible.

Which is why a finding from researchers at the Sylvester Comprehensive Cancer Center at the University of Miami has attracted attention. Metformin, a cheap and widely prescribed diabetes drug, appears to raise blood levels of a molecule that the body normally produces only during intense physical exertion, and it does so at concentrations comparable to those seen after strenuous exercise, even in men who are sedentary.

The molecule in question is N-lactoyl-phenylalanine, known to researchers as Lac-Phe. It’s not a household name, but it has been generating considerable interest since a 2022 study in Nature first identified it as a kind of exercise signal, a molecule whose levels spike after vigorous activity and that appears to play a role in appetite suppression and weight regulation. The basic chemistry is fairly elegant: Lac-Phe forms when lactate, the substance that builds up in muscles during exertion, combines with phenylalanine, an amino acid. In gut cells, an enzyme called CNDP2 catalyses the reaction. Exercise floods the bloodstream with lactate; lactate drives Lac-Phe production; Lac-Phe, in turn, seems to tell the brain to eat less and burn more.

Then came a separate and intriguing observation. People taking metformin, even without exercising, also showed elevated Lac-Phe. The same pathway, apparently, can be activated pharmacologically.

Marijo Bilusic, a genitourinary medical oncologist at Sylvester and the first author of the new study, and his colleagues decided to find out whether this held true in men with prostate cancer, a population where the metabolic stakes are particularly high. They drew on two patient groups: one from BIMET-1, a prospective clinical trial that had enrolled overweight and obese prostate cancer patients on a controlled metformin regimen, and a second, broader cohort of men across the disease spectrum who were taking metformin for metabolic reasons. Serum samples were analysed using high-precision mass spectrometry, with the researchers blinded to which patients were on which treatments. When the data were unblinded, the signal was unambiguous. Metformin-treated patients showed substantially elevated Lac-Phe compared to those on no metabolic drugs, and the levels clustered, remarkably, in the same range reported after strenuous exercise in healthy individuals.

Bilusic described the response as striking. “Seeing a metabolic signal that mirrors what we associate with intense exercise…” in men who were not exercising at the time of blood collection was not what the team had necessarily expected to find so consistently. The effect persisted after patients began androgen deprivation therapy, the hormone-suppressing treatment that typically accelerates metabolic decline. “That kind of effect could be especially meaningful,” Bilusic said, for patients whose treatments or symptoms limit physical activity.

“Cancer therapy often affects the body in ways that go beyond the tumor,” said Priyamvada Rai, co-leader of Sylvester’s Tumor Biology Program and a senior author on the paper. Her point is worth sitting with. Hormone therapy extends lives, but the metabolic syndrome it induces, weight gain, insulin resistance, elevated cardiovascular risk, is itself associated with worse long-term outcomes. Finding a way to blunt that syndrome without requiring patients to run on a treadmill would be clinically significant, even if it had nothing to do with shrinking the tumor.

And that distinction matters quite a bit here. The study, published in EMBO Molecular Medicine, is careful not to oversell what Lac-Phe elevation actually means. When researchers looked at PSA levels, the standard marker used to track prostate cancer progression, they found no relationship between Lac-Phe concentrations and whether metformin was controlling the cancer. “The result isn’t a new cancer biomarker, but a clearer understanding…” as Bilusic put it, of how the drug might support metabolic health during treatment. Lac-Phe is not telling you whether the tumor is shrinking. It may be telling you something about whether the patient is, in some metabolic sense, holding steady.

Weight data from the BIMET-1 trial offer tentative support for that interpretation. Among patients who received metformin before and during androgen deprivation therapy, only one of seven gained weight over the trial period. In the control arm, weight gain was far more common, which is roughly what you’d expect from hormone therapy alone. The correlation between Lac-Phe elevation and weight management was stronger than the correlation with a second molecule, GDF-15, that had previously been thought to be metformin’s main mechanism for appetite regulation. The two molecules didn’t rise together, suggesting metformin works through multiple metabolic routes, with Lac-Phe possibly doing more of the heavy lifting for weight control than had been assumed.

“Metabolism is involved in everything cells do,” said David Lombard, co-leader of Sylvester’s Cancer Epigenetics Program and another senior author. That might sound like an obvious thing to say, but it speaks to a broader shift in how oncologists think about cancer care. The tumor is not the only thing that matters. A patient who emerges from treatment metabolically wrecked, insulin resistant, 15 kilograms heavier, and at elevated risk of a cardiac event, has not been served well, even if their PSA is in the right range. Treatments that address both the cancer and the body’s broader metabolic response to that treatment are, at least in principle, better medicine.

There are real limitations to acknowledge. The patient numbers here are small: a dozen BIMET-1 participants and 25 in the broader biomarker cohort. The study includes only men, so it’s genuinely unknown whether the metformin-Lac-Phe link operates in female cancer patients. And the causal direction, while plausible, remains suggestive rather than definitively established: Lac-Phe is elevated in metformin-treated patients, and those patients manage their weight better, but whether Lac-Phe is the mechanism doing that work or simply a correlate of some other process is still being worked out. Larger, prospective studies would be needed to know for certain.

What the research does, perhaps most usefully, is connect a clinical observation (metformin helps cancer patients manage weight during hormone therapy, as the large STAMPEDE trial separately confirmed last year) to a specific molecular candidate that might explain why. If Lac-Phe is genuinely part of the mechanism, it becomes a measurable signal, something that could one day be used to calibrate dosing, to identify which patients are likely to benefit most, or to test other drugs that might achieve similar effects through the same pathway. The GLP-1 agonists tirzepatide and semaglutide, after all, also elevated Lac-Phe in the secondary cohort, suggesting this particular metabolic node may be a point of convergence for several very different weight-management interventions. That could matter considerably as oncologists try to figure out whether the anti-obesity drugs now reshaping medicine might also reshape cancer care.

DOI / Source: https://doi.org/10.1038/s44321-026-00408-6