Researchers from Heidelberg University in Germany have found that anticoagulant drugs that inhibit thrombin (an enzyme used for clot formation) reduce the number of brain metastases (cancerous growths in the brain) in mice.
Brain metastases are a deadly complication in advanced cancers. They cannot be surgically removed and have no long-term response to treatment. As such, ways of preventing them from occurring would be extremely helpful for patients with cancers likely to develop brain metastases, such as those with melanoma (occurring in around half of all cases) and breast and lung cancer.
Prior to the present study, earlier research from observational studies had found that antithrombotic drugs used to inhibit blood clotting can improve the prognosis of certain cancers. As such, the researchers were curious whether these drugs could influence the development of metastases.
To see whether this was the case, they conducted some experiments on mice injected with melanoma or breast cancer cells. Using a microscopic technique know as in vivo multiphoton laser-scanning microscopy, they observed how these tumor cells soon began to arrest in the fine blood capillaries of the brain and that clots frequently formed around them. In particular, they noted that those with clots around them were then able to penetrate the capillary wall, ultimately forming metastases, whereas those without clots were not.
Further study indicated that the cancer cells were able to promote the formation of these clots, which then helped them penetrate through vessel walls and into the brain. In particular, they were noted to promote the formation of enzyme thrombin, a key factor in the formation of blood clots.
Given the key role of thrombin in the formation of clots, the researchers hypothesized that a drug that inhibits its production would suppress metastasis by preventing tumor cells from getting into brain tissue. And they were right; mice given thrombin inhibitor dabigatran, an already approved drug, developed significantly fewer metastases than mice left untreated.
The researchers also noted that inhibiting another blood clotting factor (known as von Willebrand factor) with certain antibodies resulted in reduced blood clot formation in mice, and thus brain metastases too.
“Our goal is to identify drugs for the prevention of brain metastases in high-risk patients,” says Frank Winkler, one of the study’s authors.
“The studies in mice are a first step toward understanding exactly how theses substances can prevent tumor cells from colonizing the brain. In the long term, we then want to test these substances in clinical trials. To do this, we first need to better understand for which cancer subtypes this mechanism is particularly important, and also whether we can even better identify patients with a particularly high risk of brain metastases.”