Diabetes drug holds promise for patients with lung cancer
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 may give hope to the nearly 30% of patients with non-small cell lung cancer (NSCLC) whose tumors lack LKB1 (also called STK11).
Cancer and metabolism are connected. This has fueled hopes that drugs originally designed to treat metabolic disease could also work against cancer.
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. A previous study demonstrated that cells lacking a normal copy of the LKB1 gene fail to activate AMPK in response to low energy levels. LKB1-dependent activation of AMPK serves as a low-energy checkpoint in the cell. Cells that lack LKB1 are unable to sense such metabolic stress and initiate the process to restore their ATP levels following a metabolic change. As a result, these LKB1-mutant cells run out of cellular energy and undergo apoptosis, or programmed cell death, whereas cells with intact LKB1 are alerted to the crisis and recorrect their metabolism.
"The driving idea behind the research is knowing that AMPK serves as a sensor for low energy loss in cells and that LKB1-deficient cells lack the ability to activate AMPK and sense energy loss," says David Shackelford, PhD, a postdoctoral researcher at the Salk Institute in La Jolla, California, who spearheaded the study in the laboratory of Reuben Shaw, PhD. This study was published in Cancer Cell (2013; 23:143-158).
Further testing on mice with earlier stage disease used cutting-edge imaging technologies just like those used on lung cancer patients in the clinic. Early phenformin treatment resulted in increased survival and slower tumor progression in tumors lacking LKB1, but no significant benefit was seen for tumors with alterations in other lung cancer genes. This specificity in treatment fits with an emerging approach in cancer treatment nationwide, known as personalized medicine, in which the therapies for each patient are selected based on the genes altered in their tumors.
"This study is a proof-of-principle that drugs of this chemical type cause energy stress and lower ATP levels to where it kills LKB1-deficient cells without damaging normal, healthy cells," said Shaw.
The FDA took phenformin off the market in 1978 due to a high risk of lactic acid buildup in patients with compromised kidney function, which is not uncommon among people with diabetes but less of an issue for most patients with cancer. The issue of kidney toxicity would also be bypassed in cancer patients because the treatment course is much shorter, measured in weeks to months compared to years of treatment for diabetes.