Results Published in The Journal of Clinical Investigation

A new study has identified an FDA approved cancer drug, crizotinib, as a possible new coating for drug-eluting stents. Researchers found that crizotinib in mice helped prevent the narrowing of blood vessels after stenting without affecting the blood vessel lining. Results of this study were published today in The Journal of Clinical Investigation.

To find a more effective drug to use on stents, researchers used a computational biology or “big data” approach to better understand the genetic pathways of re-narrowing that occurs in stented vessels or in-stent stenosis. Caused by the buildup of scar-like tissue in the inner walls of heart vessels, the disease can often lead to the return of symptoms or heart attacks.

“This study features an innovative approach to research – the opportunity to take big data to identify non-obvious mediators of disease and then investigate them as potential therapeutics. We identified a prospective candidate for drug-eluting stents that inhibits in-stent stenosis without affecting the endothelium,” said Ziad A. Ali, MD, DPhil, lead author of the paper. Dr. Ali was a cardiovascular fellow at Stanford University during the first years of the study. He was also the first person to publish a mouse model of angioplasty and stenting in the Journal of Arteriosclerosis, Thrombosis, and Vascular Biology in 2007 allowing for the investigation of therapeutic targets for stent injury and restenosis in genetically modified mouse strains. He is now the Associate Director of Translational Science at Columbia University Medical Center and a Physician Contributor at the Cardiovascular Research Foundation.

The most common treatment for a blocked artery is balloon angioplasty and placement of a stent, a metal scaffold used to keep the artery open. More than one million procedures are performed annually in the United States. A limitation of this procedure is in-stent stenosis, the re-narrowing of the blood vessel by scar-like tissue leading to restricted blood flow. To combat this, drug-eluting stents are used to block the growth of this scar-like tissue around the stents. However, current agents used in drug-eluting stents also inhibit the regrowth of the endothelium (or lining of the blood vessel) which can increase the risk of blood clots and heart attacks. As such, patients treated with drug-eluting stents require treatment with blood thinners to prevent stent blockage from a blood clot. Thus, treatment with drug-eluting stents can be less desirable for people with bleeding problems or those who need surgery after a stent is placed.

Researchers combined a text analysis of medical literature with data from large-scale genetic studies in humans to develop a theory that they then tested in the laboratory with a genetically modified mouse model. Using a gene network analysis of coronary artery samples collected from 89 patients in Germany, they identified the gene GPX1, a naturally occurring antioxidant, as associated with cardiovascular events. They tested this by studying mice with atherosclerosis in which the gene had been knocked out. Plaque increased significantly in the arteries of mice with knocked out GPX1.

In further gene interaction analyses, researchers also found that there was an increased risk of the disease from interaction between GPX1 and ROS1, a gene previously found to be important in cancer. Researchers then used crizotinib, a chemotherapy drug used as a personalized medicine treatment for certain lung cancers, to test whether the inhibition of ROS1 could help reduce the damage to blood vessels. The drug was used in mice with atherosclerotic disease surgically implanted with stents. Researchers found that the drug reduced in-stent stenosis without impairing the endothelium growth.

“These findings highlight the need for targeted rather than broad-spectrum therapies and can affect how we treat future patients,” said Euan Ashley, MD, senior author of the study and Associate Professor of Cardiovascular Medicine and Genetics at the Stanford University School of Medicine. “These results indicate that patients who receive drug-eluting stents with crizotinib may someday no longer be required to take blood thinners after balloon angioplasty and stenting.”

The study was funded by the National Institutes of Health (grants 4R00HL109256, R00HL089413, DP2OD004613 and R01 HL105993) among others.

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