Vera P. Krymskaya, PHD

American Lung Association/LAM Foundation Career Investigator Award 2005-2008

Lymphangioleiomyomatosis (LAM) is a rare genetic disorder of unknown origin, which primarily affects women of childbearing age. LAM is characterized by the unusual growth of smooth muscle cells in the interstitium, the supportive tissue between the air sacs of the lungs. These smooth muscle-like LAM cells invade the tissue of the lungs. Their growth destroys lung tissue and obstructs the airways and blood and lymph vessels.

In recent years, a connection has been found between LAM and the loss of function or the mutation of the tumor suppressor gene TSC2. However, there is still much that is not known about how the disruption in the signaling pathway of tumor suppressor genes causes the abnormal growth, proliferation and migration of LAM cells in the lung.

Dr. Krymskaya found that “turning on” the signaling pathway regulated by this gene can stop this LAM cell migration. With her Career Investigator Award, she studied the mechanisms by which TSC2 regulates LAM cell invasive growth. She found that TSC2 plays a critical role in regulating cell migration and invasiveness, which may contribute to the development of LAM. She also found that TSC2 regulates the activity of a protein called Rho GTPase, a discovery that led to a larger grant from the National Heart, Lung, and Blood Institute.

The NHLBI grant has allowed Dr. Krymskaya to conduct a study using a novel combination of two drugs—rapamycin and simvastatin—as a potential treatment for LAM. Dr. Krymskaya previously found that rapamycin inhibits LAM cell growth. The drug is currently being tested in clinical trials as a treatment to slow or stop the growth of LAM cells in the lung. However the drug will not kill LAM cells, and some people will experience side effects from the drug or become resistant to it. Simvastatin, which is well known as a cholesterol lowering drug, and also shows promise as an anti-cancer drug, fights LAM in a different way than rapamycin. It inhibits the activity of Rho GTPase. Unlike rapamycin, which slows or stops the growth of LAM cells, simvastatin appears to kill abnormal LAM cells.

In a recently published study, Dr. Krymskaya has found that mice with LAM-related flank tumors treated with both rapamycin and simvastatin lived longer than those treated with either drug alone. The rapamycin dose used in the combination treatment was much lower than the equivalent human dose being tested as a stand-alone LAM treatment. Many of the mice receiving the combination drug treatment for 50 days survived for a year or more with no recurrence of LAM.

Plans are underway for a clinical trial of the combination rapamycin/simvastatin treatment for LAM.