Diabetes drug could hold promise for lung cancer patients
Over the past decade, growing evidence that cancer and metabolism are connected has emerged from a number of laboratories, including that of Reuben Shaw. Although scientists are still working to identify what tumors might be most responsive and which drugs most useful, Shaw and a team of scientists have recently found that phenformin, a derivative of the widely used diabetes drug metformin, decreased the size of lung tumors in mice and increased the animals' survival. The findings, reported in Cancer Cell, may give hope to the nearly 30 percent of patients with non-small cell lung cancer (NSCLC) whose tumors lack LKB1 (also called STK11).
The LKB1 gene turns on a metabolic enzyme called AMPK when energy levels of ATP, molecules that store the energy we need for just about everything we do, run low in cells. Cells that lack LKB1 are unable to sense metabolic stress and initiate the process to restore their ATP levels following a metabolic change. As a result, they run out of cellular energy and undergo apoptosis, or programmed cell death, whereas cells with intact LKB1 are alerted to the crisis and correct their metabolism.
This knowledge led Shaw and his group to a class of drugs that lower cellular energy levels by attacking the power stations of the cell, called mitochondria. Metformin and phenformin both inhibit mitochondria; however, phenformin is nearly 50 times more potent. In the study, the researchers tested phenformin as a chemotherapy agent in genetically engineered mice that lacked LKB1 and had advanced-stage lung tumors. After three weeks of treatment, they saw a modest reduction in tumor burden in the mice.
In further testing on mice with earlier stage disease, Shaw, in collaboration with David Shackelford (a former postdoctoral researcher in Shaw's lab who is now at UCLA's David Geffen School of Medicine), found that early phenformin treatment increased survival and slowed the progression of tumors lacking LKB1. It had no significant benefit for tumors with alterations in other lung cancer genes, however.
The work provides proof of principle and a basis to initiate human studies. If enough clinicians who believe in investigating phenformin can be organized, then phenformin as an anti-cancer agent could be a reality in the next several years.