Diabetes drug decreases lung cancer tumors in mice with gene mutation
While there's been mounting evidence over the past 10 years suggesting a link between cancer and metabolism, there has been little attempt to research metabolic drugs and their effect on cancer cells.
In 2003, Reuben Shaw, an associate professor at the Salk Institute for Biological Studies, discovered that a gene altered in lung cancer regulated an enzyme used in therapies in diabetes. For a decade, Shaw has wondered if drugs designed to treat metabolic diseases could also be effective at combating cancer.
In a new study, Shaw and his team found that phenformin, a derivative of the widely used oral Type 2 diabetes drug metformin, decreased the size of lung tumors in mice and increased the animals' survival. The study was published in the journal Cancer Cell.
In previous research, Shaw discovered that cells lacking a normal copy of the LKB1 gene fail to activate the metabolic enzyme AMPK in response to low energy levels. The result is that cells with mutated LKB1 run out of energy and undergo apoptosis, or programmed cell death, while cells with normal LKB1 are alerted to the crisis and re-correct their metabolism.
"When cells lack this gene they don't know if they have enough energy or not. This is not a disaster to not have the gene, but it did suggest a therapeutic window," Shaw explained to FierceBiotechResearch. "If we could find a way to lower the energy levels of cells, normal cells would cope with that just fine whereas the tumors will have no idea that this drug is able to get in there and it would cause the cells to die."
Just like a car with a fuel gauge on empty, Shaw's team observed that the cells with mutated LKB1 shut down.
Researchers tested phenformin, a more potent form of metformin, in mice with lung cancer cells and observed tumor reduction in mice lacking the fuel gauge sensor--the LKB1.
"So to translate this to humans in the clinic, you'd want to treat lung cancer patients who have tumors that have alternations in that gene," Shaw said.
The findings may eventually provide a more personalized approach to treatment for the nearly 30 percent of patients with non-small cell lung cancer whose tumors lack LKB1.