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Stanford University School of Medicine

Double agent: Anti-tumor drug already in human trials may combat atherosclerosis

double agentHere's an attention-getting twofer for you: A signal tumor cells display on their surfaces to protect themselves from being devoured by the immune system also plays a role in enabling atherosclerosis, the process underlying heart attacks and strokes.

An injectable drug that can block this so-called "don't eat me" signal is already being tested in clinical trials in cancer patients, so safety data obtained from those trials can be used to advance the drug's evaluation for combating cardiovascular disease, the world's biggest killer.

In a study published in Nature, Stanford cardiologist and vascular surgeon Nick Leeper, MD, and his colleagues found that the "don't eat me" signal - actually a cell-surface protein scientists call CD47 - is oddly abundant in atherosclerotic plaques. These are composites of fatty substances and dead and dying cells that accumulate at various places inside most people's arteries and eventually restrict blood flow or, if they rupture, hive off clots that can clog these vessels, suddenly cutting off blood supply to the heart, brain or other organ.

While writing a news release on the study, I asked Leeper to give me some background. He did:

Even a perfectly healthy body turns over more than 100 billion cells a day, every day... One of the several jobs performed by immune cells called macrophages -- from the Greek words for 'big eater'-- is to come and gobble up those dead and dying cells, which might otherwise begin releasing substances that can foster inflammation.

Many cells in the body feature CD47 on their surfaces to tell the immune system, "Hey! I'm alive, going strong,  and part of this person's healthy tissue." That keeps macrophages from attacking them.

But in the late 1990s and early 2000s, Stanford developmental biologist and stem-cell reseacher Irv Weissman, MD, and his colleagues identified CD47 as being overrepresented on tumor cells, which helps them evade destruction by macrophages. Weissman's group went on to show that blocking CD47 with monoclonal antibodies that bind to and obstruct the protein on tumor cells restores macrophages' ability to devour those cells. Phase-1 clinical safety trials of CD47-blocking antibodies in patients with solid tumors and blood cancers are now underway.

In the new Nature study, Leeper's team found that these same antibodies can prevent and even reverse the buildup of atherosclerotic plaque in several strains of laboratory mice that are particularly predisposed to develop cardiovascular disease.

If what's worked so well in mice winds up working in people, the rare example of a single agent (the anti-CD47 antibodies) that can effectively treat both cancer and atherosclerosis in one shot, as it were (making it, of course, a "double agent"), could someday become a reality. What's especially tantalizing is that this drug would fight cardiovascular disease by targeting not mere risk factors, such as high cholesterol or high blood pressure, but the actual atherosclerotic plaques directly responsible for the disorder.

Previously: Glucose-guzzling immune cells may cook up coronary artery disease, Stanford study finds, Widely prescribed heartburn drugs may heighten heart-attack risk and Single antibody shrinks or eliminates tumors in mice at Stanford
Photo by AJC1

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