From cancer to cardiovascular disease, AstraZeneca oncology hopeful could slow atherosclerosis

An AstraZeneca drug once studied for use in cancer could have a new lease on life slowing the progression of hardened arteries, new study results suggest. 

In an article published June 8 in Nature Cardiovascular Research, scientists from the New York University Grossman School of Medicine reported that the drug saracatinib was able to reduce signs of atherosclerosis in mice. The findings were backed up by additional results from experiments in rabbits as well as human plasma and tissue samples. 

“Our findings provide new insight into the inflammatory mechanisms in atherosclerosis and suggest for the first time that saracatinib may offer an effective therapy in cases where standard therapy, in the form of statins, fails to help,” study co-lead Letizia Amadori, Ph.D., said in a press release. 

Statins are the go-to treatment for atherosclerosis, a condition where plaques composed of fats, cholesterol, waste from cells and other substances build up along artery walls. The resulting stiffening and inflammation can lead to heart attacks and strokes if left untreated. Statins combat this by inhibiting cholesterol formation in the liver, stabilizing the plaques so they don’t grow larger or break apart. 

But the drugs aren’t enough to reverse the inflammation in some patients, leaving them at risk of heart attacks and strokes. Data on anti-inflammatory medications, like immunosuppressants, have shown mixed results. They also come with the potential for serious side effects, including cancer. 

The researchers wondered whether any existing drugs might solve the problem. To find out, they started by analyzing blood plasma samples from 34 patients with atherosclerosis, all of whom were on statins. They compared these samples with others from 24 healthy donors. The patient samples had higher levels of inflammatory signals than the ones from healthy people, confirming previous findings about inflammation in atherosclerosis. 

Reasoning that a candidate drug would be able to downregulate the genes involved in the production of the many inflammatory proteins that constitute chronic inflammation, the team created data sets from the National Institutes of Health’s Library of Integrated Network-Based Cellular Signatures, an enormous repository of information on how approved therapeutic compounds impact human cells. Saracatinib emerged as a potential contender, as it was able to block the expression of target genes. 

The researchers then conducted a series of experiments on diseased tissue and blood samples to better understand saracatinib’s mechanism of action. They found that the drug specifically blocked genes involved in the production of interleukin-1 beta and interleukin-6, a pair of proteins that are known biomarkers for predicting cardiovascular events. Besides downregulating genes for inflammatory molecules, saracatinib also increased the activity of genes that make proteins that help clear out plaque deposits in the arteries. 

Next, it was time to see whether these findings held up in animals. The team started by feeding mice a high-fat diet akin to the standard Western diet for 16 weeks. Some mice received either saracatinib or atorvastatin—trade name Lipitor—or a combination of the two drugs in their food, while others received no medication. The researchers found saracatinib alone reduced plaques by a greater degree than atorvastatin alone and that it also reduced the number of macrophages within the plaques. Though saracatinib wasn’t able to lower levels of circulating inflammatory molecules by itself, it was able to do so in combination with atorvastatin. 

The scientists then investigated whether saracatinib could work in advanced atherosclerosis, too. Using a rabbit model of the condition that develops plaques very similar to the ones seen in human disease, they found that saracatinib given at doses equivalent to ones given to clinical trial participants reduced inflammation within the plaques and prevented them from growing over time. While the team didn’t find any additional improvement in inflammation levels by combining atorvastatin with the drug, they did see that the combination was better able to control lipid levels in the plaques than was atorvastatin alone. 

“By acting through different pathways, saracatinib has the potential to be used as an anti-inflammatory treatment for patients who are already treated with lipid-lowering drugs,” the researchers concluded in their paper. 

AstraZeneca, which wasn’t involved in the research, originally developed saracatinib for use against solid tumors. While it failed to perform in clinical trials for breast cancer, the drug later showed to have some efficacy in idiopathic pulmonary fibrosis, for which the U.S. Food and Drug Administration granted it orphan-drug status. It’s also being tested in Alzheimer’s disease.