Patients who have had their arteries unblocked using stents or balloon angioplasty can find that their arteries become obstructed again, sometimes after only a few months. Researchers at Stanford University School of Medicine have used big data to repurpose a marketed cancer drug. This has potential to create a better way to stop the new obstruction, known as in-stent restenosis (ISR) or stent disease. The results were published in the Journal of Clinical Investigation.
Arteries blocked by plaque can be opened using balloon-tipped catheters (balloon angioplasty), often in combination with stents (small mesh tubes). However, this process can damage the artery lining, triggering cell regrowth and vascular remodelling, which blocks the artery once again. Drug-eluting stents can be used to block this growth; however, by inhibiting the regrowth of the endothelium, these can also delay arterial healing and increase the risk of blood clots and heart attacks. To avoid blood clots, patients will therefore have to be treated with anticoagulants for around a year, which can be risky for those at risk of bleeding problems or who might require surgery during that time.
“Even though we’ve made drug-eluting stents, still 10% of stents block up,” says lead author Ziad Ali, MD, PhD. “A lot of our patient population is on the elderly side with bad hips or diabetes. Once you get a drug-coated stent, you can’t have surgery for a year. And if you stop the blood thinners for any reason, you’re at risk of a stent clotting off. And that actually causes a heart attack. Stent thrombosis has a high mortality rate. Our idea was to find a novel therapeutic that would stop the regrowth while not affecting the endothelium of the vessels.”
The researchers started by getting a better understanding of the genetic pathways of coronary artery disease (coronary atherosclerosis), the leading cause of death worldwide. They carried out a gene network analysis of coronary artery samples collected from 89 patients in Germany. This analysis linked the GPX1 (glutathione peroxidase-1) gene with cardiovascular events. GPX1 is part of the body’s antioxidant defence mechanism. They validated the findings by creating GPX1 knockout mice, which developed increased levels of atherosclerosis.
In the next step, the team carried out gene variant pair analysis, looking into gene interactions from a US meta-analysis of genome-wide data for stent disease, and another study carried out in Japan, and found an increased risk of the disease linked with regulatory interplay between GPX1 and a tyrosine kinase receptor gene, ROS1.
“[ROS1] hadn’t been studied in cardiovascular diseases. We knew it was an important gene in cancer,” says Euan Ashley, MD, associate professor of cardiovascular medicine and genetics.
This connection with a cancer-linked gene led the team to look into the chemotherapeutic crizotinib, a tyrosine kinase inhibitor that targets ROS1, and that has been approved for specific subtypes of lung cancer. In mice with coronary artery disease and surgically implanted stents, crizotinib stopped stent disease and did not damage the endothelium.
“The major finding of the study is that artery stent disease acts surprisingly like a tumour in the blood vessel wall,” says Ashley. “Inhibiting it with nonspecific pharmaceutical agents, as we do now, leads to heart attacks from clots caused by lack of endothelial lining on the stent, whereas targeting it with the drug we use here, crizotinib, acts much more specifically and inhibits the disease without affecting the endothelium.”
The researchers combined data from large-scale genetic studies in humans with text analysis of medical literature, and used computational biology to identify novel mediators of disease. However, these finding s are only theoretical, as explains: “The computational biology approach can give you a good hypothesis, but then you need to prove it in the lab,” Ashley added. “The marriage of the two is what makes this study really special.”
The team found that in studies in mice, crizotinib, an approved cancer drug, was able to prevent stent disease.
“Crizotinib not only reduced stent disease but also protected the endothelium of the blood vessels. The implications are that, down the road, patients who receive drug-eluting stents with this new drug may no longer be required to take blood thinners after their procedure,” concludes Ashley.