Saracatinib

Studies in mice showed that saracatinib could reduce the size of plaques by a greater degree than a leading statin and that it also reduced inflammatory molecules within the plaques. 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. 

"Reverse-Engineering" of Existing Compound Yields Potential New Therapy NEW YORK, June 8, 2023 /PRNewswire/ -- An experimental drug already tested as a potential treatment for cancer, lung, and Alzheimer's disease may slow the progression of atherosclerosis that leads to heart disease, a new study shows. Led by researchers at NYU Grossman School of Medicine, the study explored the mechanisms behind atherosclerosis, in which fatty deposits build up in blood vessels. As this buildup hardens into plaques and causes misplaced immune reactions (inflammation), it can block blood flow to cause heart attack or stroke. Publishing June 8 in the journal Nature Cardiovascular Research, the new study showed that plasma (the liquid part of blood) from patients with atherosclerotic disease triggers an usually high inflammatory signal in blood immune cells. Further experiments then showed that the drug saracatinib reduced this inflammation signaling by more than 90% in human blood samples and diseased 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," says study co-lead author Letizia Amadori, PhD, a senior research scientist at NYU Langone Health. Physicians prescribe statins to reduce harmful fats in the blood, but studies show that even with reduced plaque deposits, inflammation persists in many patients, who remain at high risk for heart attack. According to the study authors, the causes of this chronic immune response in patients are not fully understood, and anti-inflammatory treatments are sometimes ineffective in patient studies. For the study, the team analyzed blood samples from 34 men and women with the condition specifically termed atherosclerotic cardiovascular disease (ASCVD), all of whom were on statins, and compared them with samples from 24 healthy donors. To home in on saracatinib, the study authors explored 4,823 genes including 277 already known to play a role in inflammation and produce cytokines and other proteins that promote a chronic immune response. According to Amadori, the team reasoned that if a particular medication could stop all these molecules from being made, then it could calm the response. Rather than trying to create a suitable drug from scratch, the researchers instead turned to a list of pharmaceuticals already approved or being tested for other uses. Specifically, they searched a series of datasets from the National Institutes of Health called the Library of Integrated Network-Based Cellular Signatures, which contains hundreds of thousands of test results mapping the effects of various molecules, signaling proteins, and genetic changes on human cells. Because saracatinib was shown in this search to reverse the expression of target genes, the process by which genes are turned on to make proteins, the authors tested it in human cells, diseased tissue, and animal models to see if it could actually stop, slow, or reverse inflammation prompted by ASCVD. Among the findings, the results revealed that saracatinib blocks gene activity responsible for producing inflammatory proteins such as interleukin-1 beta and interluekin-6 that maintain ASCVD's immune reactivity. Notably, an inhibitor of interleukin-1 beta was shown to effectively prevent heart attack in an earlier trial. At the same time, the drug boosted genes known to make proteins that help clean up plaque deposits by transporting fat away from the arteries. Further experiments in rabbits revealed that saracatinib reduced plaque-based inflammation by about 97% compared with untreated animals. Meanwhile in mice, the same therapy prompted up to an 80% reduction in cells linked to inflammation in plaques and shrunk plaque deposits between 48% and 70%, depending on the dose of the medication, says Amadori. "Our reverse-engineering method of finding new uses for old drugs can in theory be harnessed to uncover therapies for practically any disease that involves inflammation," said study senior author Chiara Giannarelli, MD, PhD. "Since these chemicals have already been tested for safety, this technique offers a swift and cost-effective approach to pharmaceutical development." Giannarelli, an associate professor in the Departments of Medicine and Pathology at NYU Langone, says the study team next plans to use their same protocol to explore potential treatments for other inflammatory conditions linked to ASCVD, such as rheumatic arthritis or type 2 diabetes. That said, Giannarelli cautions that while saracatinib appears promising, it must still be clinically tested to ensure that the treatment actually works in patients. Funding for the study was provided by National Institutes of Health (NIH) grants UH2TR002067 and UH3TR002067. Additional support was provided by NIH grants R21TR001739, R01HL153712, T32HL007824, R35HL135799, P01HL131481, R01HL143814, R01HL140072, RC2DK131995, R01DK131525, OT2OD030160, and U54HL127624. Giannarelli is an inventor of a patent pending (Tech 160808G PCT/US2022/017777) for this therapeutic approach to treat ASCVD as well as for the team's drug development pathway. The terms and conditions are being managed in accordance with the policies and practices of the Icahn School of Medicine at Mount Sinai and NYU Langone Health. In addition to Amadori and Giannarelli, other NYU researchers involved in the study were Ravneet Kaur, MS; Swathy Sajja, MS; Roza Shamailova, MA; Yannick Cyr, PhD; Natalia Eberhardt, PhD; and Kathryn Moore, PhD. Other investigators involved in the study are Dawn Fernandez, PhD; Simon Koplev, MS; Nicolas Fernandez, PhD; Pauline Mury, PhD; Nayaab Kahn, PhD; Minji Jeon, PhD; Christopher Hill, BA; Peik Sean Chong, MS; Sonum Naidu, BSE; Ken Sakurai, PhD; Adam Ghotbi, MD, PhD; Raphael Soler, MD, PhD; Adeeb Rahman, PhD; Peter Faries, MD; Zahi Fayad, PhD; and Avi Ma'ayan, PhD; at the Icahn School of Medicine at Mount Sinai in New York City. Claudia Calcagno, MD, PhD, also at Mount Sinai, served as study co-lead author. Media Inquiries Shira Polan 212-404-4279 shira.polan@nyulangone.org