BOSTON, Mass. — Millions of people around the world take the drug metformin to help control their diabetes. While studies have discovered this medication may also treat other conditions, its predecessor could hold the key to fighting cancer. A new study finds an older diabetes drug, phenformin, promotes stronger cancer-fighting activities in the body than metformin.
Researchers from Massachusetts General Hospital say combining the 70-year-old drug with current immunotherapies shows promise in creating a new anti-cancer agent. The findings come from work examining how both phenformin and metformin work alongside immune checkpoint inhibitors, which enable T cells to attack and kill cancer cells. Some may find the results surprising, especially since physicians stopped using phenformin to treat diabetes 50 years ago!
Why did doctors stop prescribing phenformin?
Before the creation of metformin, phenformin was the prescription of choice, starting in the 1950s. However, by the late 1970s, officials withdrew the medication from use over the risk of patients developing lactic acidosis. This is a potentially dangerous condition in which patients experience a buildup of lactic acid in their blood. It can disrupt the body’s pH balance, leading to confusion, yellowing of the skin, and even trouble breathing.
Both drugs are biguanides, a class of anti-diabetic drugs originating from compounds in the French lilac. Even in medieval times, healers were aware of this plant’s hypoglycemic properties.
Over the last decade, MGH researchers have discovered that both phenformin and metformin have anti-tumor properties. Now, phenformin is taking the lead in those trials and spurring efforts to repurpose the drug as a cancer fighter.
“While the outcomes of various clinical studies of metformin in cancer patients have been underwhelming, research from our laboratory and others suggests that phenformin may have greater potential, particularly in combination with immunotherapies,” says senior author Bin Zheng, PhD, in a media release. “We have found, for example, that phenformin, but not metformin, enhances the efficacy of BRAF inhibitors in suppressing the proliferation of BRAF-mutant melanoma cells and BRAF-driven tumor growth in animal models.”
Researchers explain that BRAF mutations are changes in DNA common in about half of all melanomas (skin cancers).
Moving into phase 1 trials
MGH is now partnering with Memorial Sloan Kettering Cancer Center to launch a clinical trial of their new cancer treatment. Researchers will evaluate how well patients with BRAF-mutated melanoma respond to phenformin and a combination of inhibitors (dabrafenib/trametinib).
“If the safety of phenformin is confirmed in this trial, combinations of phenformin with targeted immunotherapies such as anti-PD-1 (programmed cell death 1 antibodies, which stimulate anti-tumor immunity) could be explored for patients with various types of solid tumors,” Zheng explains.
A previous study discovered better clinical outcomes among patients with non-small-cell lung cancer who received a combination of metformin and immunotherapy in comparison to patients taking immune checkpoint inhibitors alone.
Gut health may play a major role in fighting cancer
As for why biguanides seem to help fight cancer, researchers say their impact on the gut microbiota is likely key. The gut microbiota is a collection of trillions of cells, bacteria, viruses, and fungi living in harmony within the gut. The study finds biguanides may help modulate gut microbiota, allowing anti-tumor therapies to be more effective. It’s similar to the way anti-diabetics lower blood glucose levels in diabetes patients by interacting with the human microbiome.
“Scientists have shown a tremendous interest in biguanides as potential anti-cancer agents, and we believe our work will help the field to focus on the most promising ways forward, particularly phenformin,” Zheng concludes. “Phenformin demonstrates more metabolic and pharmacologic potential than metformin, and its toxicity, which might be a problem for certain people with diabetes, is actually lower than some current chemotherapies.”
The study appears in the journal Trends in Cancer.