Immune cell migration throughout the human body creates “cellular highways,” which cancer cells use to hitch a ride to other locations. Under a collaboration with Roche, researchers at the Paul Scherrer Institute have deciphered the structure of a membrane protein that’s key to guiding this migration of immune cells—a finding they believe could lay the foundation for the development of drugs to stop certain cancers from metastasizing.
The protein is called chemokine receptor 7 (CCR7), which is among 20 G protein-coupled receptors that help orchestrate immune cell movement. With the new information on CCR7’s structure, the researchers were able to screen for drugs that block its signaling. During that process, they found a match in a drug that Merck & Co. is already testing in people, navarixin (MK-7123). They published the discovery in the journal Cell.
White blood cells either randomly patrol our body or move toward specific tissues as needed. When CCR7 interacts with certain signaling molecules, it triggers a cascade of reactions that direct B cells, T cells and antigen-presenting dendritic cells to lymph nodes throughout the body.
Cancer cells can take advantage of CCR7 by following the same signals to break away from their original tumor site and into the lymphatic system. That allows them to form metastases in other tissues.
In the study, the Roche-PSI team first used X-ray crystallography to determine the structure of CCR7. With this information, the researchers were able to block the receptor, stopping "the chain reaction that leads to cell migration from getting started,” co-author Steffen Brünle, a researcher at the Paul Scherrer Institute, said in a statement.
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Brünle and his colleagues were surprised to discover that Merck's navarixin could target CCR7, because it is actually designed to bind to a different receptor called CXCR2. The drug is now being tested alongside Merck's blockbuster PD-1 inhibitor Keytruda in a phase 2 trial in patients with non-small cell lung cancer, prostate cancer and colorectal cancer.
“Considering the role of CCR7 in metastasis, it is not difficult to imagine that part of the navarixin anticancer effects are due to silencing CCR7 instead of it acting solely via CXCR1/CXCR2,” the authors wrote in the study.
Metastatic cancers are hard to treat and often linked to increased mortality risk for patients, which is why many research groups are looking for new ways to stop tumors from spreading. A team led by the Garvan Institute of Medical Research in Australia recently found that some pancreatic tumors overproduce a protein called perlecan to help them escape their original cellular environments. Researchers at Duke University discovered that cancer cells can spread by building a large protrusion that they use to smash their way out of a matrix of proteins.
Brünle and colleagues hope their findings offer inspiration for developing drugs that prevent the spread of certain cancer cells via the body’s lymphatic system. During the study, they used computer simulation to screen millions of molecules in a database at Roche, and they found five additional compounds that they believe could hold promise in stopping cancer metastasis.