Enzyme presents drug target to rare lung disease
An enzyme called Src kinase may provide a new way to attack lymphangioleiomyomatosis (LAM), a rare lung disease that appears only in women either alone or in association with a genetic disorder known as tuberous sclerosis, said researchers from Baylor College of Medicine in a report that appears in the journal Cancer Research.
Tuberous sclerosis complex (TSC) is a rare genetic disease that affects many of the body’s organ system, causing tumors in the brain, kidneys, heart, eyes, lung and skin. Because it also affects the central nervous system, those who have it suffer seizures, developmental delay, behavior problems, skin abnormalities and kidney disease.
LAM, the major lung manifestation in TSC, is found in 35 percent of women with the disorder. The lung lesions that occur in women with LAM cause tumor-like growths with cells proliferating in and destroying lung tissue. LAM is a progressive cystic lung disease associated with collapsed lung (pneumothorax), leakage of a milky fluid made up of lymphatic fluid and lipids or fats into the chest cavity (chylous effusions), shortness of breath during exercise and respiratory failure. Sporadic LAM can develop in women who do not have TSC but have mutations in the gene associated with it.
Dr. N. Tony Eissa, professor of medicine –pulmonology, pathology & immunology and molecular and cell biology at Baylor, and his colleagues sought to find out where the errant cells in LAM were coming from and how they were activated to grow aberrantly.
“We had come to the point where people were beginning to think that these cells that destroy lung tissues might actually come from a place outside the lung,” he said.
These cells are tumor-like in that they are invasive and move quickly from one place to another, said Eissa.
Dr. Alexey Tyryshkin, a postdoctoral fellow in the Eissa laboratory, and Eissa became interested in a possible role of Src kinase, which is known to play a role in tumors and in activating a process that leads to cellular transition from being epithelial (layers of cells that cover the surfaces or cavities of the body) to becoming mesenchymal cells, which are more mobile and thus can be more prone to migration. Eissa and Tyryshkin also noted a recent study suggesting that Src kinase turnover is regulated by autophagy. The latter is a cellular degradation process known to be defective in LAM cells. They hypothesized that Src kinase might be hyperactive in LAM tissues
In studies of tissues from the lungs of normal people and people with LAM as well as in animals, Eissa and his colleagues made three new findings:
- Src kinase is activated in LAM cells.
- The enzyme contributes to the destruction brought by LAM cells by promoting the mesenchymal phenotype of cells and thus becoming more mobile and invasive.
- Inhibiting Src kinase can reduce the potential of LAM cells to migrate to the lung in animal model of LAM.
There are drugs under development that can inhibit Src kinase in cells, said Eissa. He and his colleagues found the drugs can change the activity of LAM cells in tissue culture and in a mouse model of LAM.
“The LAM cells are less likely to colonize the lung when treated with these drugs,” he said.
In the next few months, he and his colleagues will test such drugs in subjects with LAM.
While there are treatments for LAM, there is no cure and some patients do not respond to existing treatments.
“As a physician scientist, one of the most satisfying times is when you can move a study at the bench into the clinic. It is exciting for us to do clinical trials based on the work we have done in the laboratories,” he said.
His future work is being funded by a new National Institutes of Health program called Discovering New Therapeutic Uses for Existing Molecules that speeds the repurposing of existing drugs for new diseases. His was one of nine such programs funded in 2013.
Dr. Abhisek Bhattacharya of Baylor also took part in this work.
Funding for this research came from National Heart, Lung and Blood Institute (Grant R01 HL69033) and from the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director, and the National Center for Advancing Translational Sciences (Grant UH2 TR000961).