Decoy protein helps to fight cancer in mice by stopping muscle breakdown.
Researchers have created a molecule that, in mice, can fully reverse the devastating muscle loss that often accompanies advanced cancer — and thereby increase the lifespan of animals with the disease.
The molecule blocks the activity of a key muscle-limiting protein called myostatin by acting as a decoy. Instead of myostatin binding to its normal receptor and triggering muscle wastage, it is 'mopped up' by binding to the decoy molecule instead.
Muscle wasting — called cachexia — is thought to account for about 30% of deaths in patients with cancer, but how exactly cachexia is spurred by cancer — or indeed exactly how it leads to a patient's decline — isn't known. It is thought that several molecular pathways work in tandem, "activating an axis of evil to control muscle mass in a negative way", says H. Q. Han, lead author of the study and scientific director of the metabolic disorders division at Amgen, a biotechnology company in Thousand Oaks, California.
Han and his group wanted to find the dominant pathway responsible for cancer cachexia, and then design a way to block it in order to treat patients. Several studies have shown that blocking the myostatin pathway can promote muscle growth, says Han, and some have shown that a molecule closely related to myostatin, called activin A, becomes more abundant in patients with some cancers.
"We examined a large random collection of cancer cell lines in vitro, and found that one-third of them secreted large amounts of activin A," says Han. "This led us to believe that activin A must have some systemic function when overproduced in a cancer setting."
The researchers created a soluble version of the activin A receptor — which is thought to affect both myostatin and activin A signalling — by fusing a piece of human activin receptor to an antibody. This decoy mopped up the ligands that usually bind to the real receptor, thus blocking receptor activation.
There's really an overwhelming amount of data now showing the benefits of targeting this pathway. ,
A single injection of the soluble receptor into normal mice boosted their muscle mass by 25% or more in a week or two. When it was given to mice implanted with colon cancer cells, their muscle mass returned to normal, even though their tumours continued to grow. Strikingly, all of the animals that did not receive the soluble receptor were dead 40 days after cancer cells were implanted, but more than half of the treated animals survived to this point. The study will be published tomorrow in the journal Cell1.
Han's group isn't the first to try to manipulate the myostatin pathway to treat muscle wasting. "There's really an overwhelming amount of data now showing the benefits of targeting this pathway," says Se-Jin Lee, a molecular biologist at Johns Hopkins University in Baltimore, Maryland, who co-discovered the myostatin gene and its role in regulating skeletal muscle mass in 19972.
The fact that disrupting the myostatin pathway caused such strong muscle regrowth isn't so surprising, says Lee, because other studies have shown that this pathway has an extremely negative effect on muscle growth.
Ken Fearon, a surgical oncologist at the University of Edinburgh, UK, who has studied cancer cachexia, agrees. "They've antagonized one of the main in vivo brakes" to muscle growth, he says. "If you take the brakes off a car, it'll keep going down the road."
What is most exciting is that the treatment prolonged survival, according to Lee and Fearon, because few treatments for cancer cachexia currently exist. "The reason that oncologists don't bother measuring — let alone treating — cachexia is that they feel their options are so limited outside of treating the cancer," Fearon says.
Despite the molecule's powerful effect in mice, "does blocking this pathway in humans also cause muscle to grow?" asks Lee. "That question has not been answered yet."
It is also still unclear whether the myostatin pathway plays a causative role in regulating the condition, he says, and the study doesn't provide all the answers. "The fact that you can prevent the muscle loss doesn't say that it's due to overactivity in this pathway," he notes.
Several pharmaceutical and biotech companies have begun clinical trials to test compounds that target the myostatin pathway. In the only such study published so far, researchers from Johns Hopkins University and drug firm Wyeth (now part of Pfizer) used an antibody to block myostatin in an attempt to treat the muscle-wasting disease muscular dystrophy3. "Those results were quite wishy-washy," Lee says.
Other trials, including on testing a similar form of the soluble activin A receptor by pharmaceutical company Acceleron, based in Cambridge, Massachusetts, are still in progress. Unlike many of the other compounds being tested, says Lee, this particular compound can bind not just to myostatin and activin but also to many other related molecules. This could make it more potent, he notes, "but of course it might also be the downfall" if this lack of specificity leads to unwanted side effects in patients.
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Katsnelson, A. Drug flexes muscle against cancer. Nature (2010). https://doi.org/10.1038/news.2010.419