The combination of metformin, a commonly prescribed antidiabetic drug, and vascular endothelial growth factor-A inhibitors increased suppression of tumour growth in melanoma tumours with BRAF mutations compared with treatment with the inhibitors alone, according to the results of a study published in Cancer Discovery.

“Our results were surprising because combining metformin and vascular endothelial growth factor-A (VEGF-A) inhibitors was much more effective at blocking tumour growth than would be expected given the effect of either drug on its own,” said Richard Marais, Ph.D., who was recently appointed professor of molecular oncology and director at The Paterson Institute for Cancer Research in Manchester, England.

Although recent research has suggested that metformin may have anticancer properties, few studies have evaluated how metformin might affect the growth of melanoma, the most aggressive form of skin cancer.

To examine this association, Marais and colleagues at the Institute for Cancer Research in London tested how metformin affected a series of patient-derived melanoma cells, specifically those with two of the most common genetic mutations, BRAF and NRAS. First, they tested metformin on NRAS-mutant and BRAF-mutant melanoma cells grown in culture.

“When grown in culture, metformin had little effect on the growth of BRAF-mutant melanoma cells because BRAF activated a protein called RSK that promotes metformin resistance,” Marais said.

Next, researchers grew BRAF-mutated melanoma tumours in mice. In this setting, they found that metformin caused BRAF-mutated cells to secrete increased levels of VEGF-A, a molecule that promotes blood vessel formation and increases tumour growth. This observation prompted the researchers to use an animal model to test metformin in combination with commonly used VEGF-A inhibitors.

Tumour growth increased twofold with metformin alone. However, when metformin was combined with axitinib, tumor growth was suppressed by 45 percent; when combined with bevacizumab, tumor growth was suppressed by 64 percent compared with 34 percent for bevacizumab alone.

“Our results suggest that care should be taken when prescribing metformin to patients with BRAF-mutant melanoma as it could potentially worsen their disease,” Marais said. “Most importantly, our findings regarding the effectiveness of the metformin/VEGF-A inhibitor combination could be directly tested in the clinic.”

Moving forward, Marais and colleagues plan to research the mechanism behind this combination blocking tumour growth.

“We wish to initiate a clinical trial testing the combination of metformin and VEGF-A inhibitors in patients with BRAF-mutant melanoma, with the hope that this becomes an effective treatment option for people suffering from this deadly disease,” Marais said.

This study was funded by the Association for International Cancer Research, Cancer Research U.K. and the Institute of Cancer Research.

Source: AACR