Cholesterol Therapies Could Slow Tumor Growth in Melanoma Patients with BRAF V600E Mutation

Cholesterol Therapies Could Slow Tumor Growth in Melanoma Patients with BRAF V600E Mutation

Cancer cells usually rely on blood sugar to grow, but melanomas with the BRAF V600E mutation prefer burning fat to get their energy, even when glucose is abundant.

Although this makes low-carb diets useless for patients whose cancers are driven by the mutation, new research suggests they might benefit from lipid-lowering drugs, such as statins. Lipids are a complex fat containing nitrogen and frequently phosphorus or sulfur.

The study, “Prevention of Dietary-Fat-Fueled Ketogenesis Attenuates BRAF V600E Tumor Growth,” was published in Cell Metabolism.

Evidence indicates that most cancers consume a lot of glucose, a phenomenon known as the Warburg effect. A low-carb diet has shown promise in limiting tumor growth in these cancers.

This suggests that understanding how metabolic alterations occur in cancer may help in the development and design of diets that can lower cancer risk and improve treatment. Metabolic alteration refers to changes in the way cancers use energy.

Prior work at Emory University’s Winship Cancer Institute had suggested that cancer cells with the BRAF V600E mutation obtained their energy by burning fat, through what is called the ketogenesis pathway. Cells with the mutation are found in more than 60 percent of all melanomas and in some colorectal cancers and multiple myelomas.

One of the molecular products of the ketogenesis pathway is acetoacetate. Researchers led by Jing Chen discovered that this metabolite could bind to mutated BRAF, promoting tumor activity.

When the researchers fed mice a diet whose caloric content was 90 percent fat, V600E melanoma cells grew much faster than in mice on a normal diet — in fact, twice as large over four weeks. In tumors with other tumor-promoting mutations, this effect was not observed.

Giving mice cholesterol-lowering therapies, such as Lescol (fluvastatin), niacin, or fenofibrate, slowed tumor progression, even when the mice were on a normal diet. But when the researchers injected acetoacetate into the mice, the tumors starting growing at a faster pace again.

“Limiting dietary fat intake and monitoring circulating acetoacetate levels might be beneficial in patients with BRAF V600E melanoma or other related cancers,” Chen, a professor of hematology and medical oncology at the Winship Cancer Institute, said in a press release. “At this point, we can’t be specific about diet suggestions, because we need to know more about what types of dietary fat trigger acetoacetate production.

“Lipid lowering agents may have a role in cancer prevention or supplemental treatment approaches to reduce cancer progression or improve clinical outcomes in the BRAF V600E-positive pre-malignancy and cancer settings,” added Chen, the study’s senior author.

The team found that dehydroacetic acid, a chemical that structurally resembles acetoacetate, also could inhibit BRAF’s effects on tumor growth. The chemical, used in cosmetics, generated low toxicity in the mice. But further studies are required to understand if it could be used as a cancer therapy.


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