Roche's efforts to stop cancer metastasis lead unexpectedly to a Merck drug

The migration of immune cells through the human body creates "cellular highways", which cancer cells use to drive to other places. In a collaboration with Roche, researchers at the Paul Scherrer Institute have deciphered the structure of a membrane protein essential to guide this migration of immune cells. This discovery could lay the foundation for the development of drugs to prevent the metastasis of certain cancers.

The protein is called the chemokine receptor 7 (CCR7), which is part of the G-protein coupled receptors helping to orchestrate the movement of immune cells. With new information on the structure of CCR7, researchers have been able to detect drugs that block its signaling. During this process, they found a match for a drug that Merck & Co. was already testing in humans, navarixin (MK-7123). They published the discovery in the journal Cell.

White blood cells patrol our body at random or move to 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 the entire whole body's lymph nodes.

Cancer cells can take advantage of CCR7 by following the same signals to separate from their original tumor site and into the lymphatic system. This 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, blocking "the chain reaction that leads to cell migration," said co-author Steffen Brünle, a researcher at the Paul Scherrer Institute, in a statement .

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Brünle and her colleagues were surprised to discover that Merck's navarixin could target CCR7 because it is actually designed to bind to another receptor called CXCR2. The drug is currently being tested alongside Keytruda, the potent inhibitor of Merck's PD-1, in a Phase 2 trial in patients with lung cancer non-small cell, prostate cancer and colorectal cancer.

"Given the role of CCR7 in metastases, it is not difficult to imagine that some of the anticancer effects of navarixin are due to the silence of CCR7 instead of acting only via CXCR1 / CXCR2," write the authors of the study.

Metastatic cancers are difficult to treat and are often associated with an increased risk of mortality in patients. That is why many research groups are looking for new ways to prevent the spread of tumors. A team led by the Garvan Institute of Medical Research in Australia recently discovered that some pancreatic tumors overproduced a protein called perlecan to help them get out of their original cell environment. Researchers at Duke University have discovered that cancer cells can spread by building a large protrusion that they use to split a protein matrix.

Brünle and her colleagues hope that their discoveries will be a source of inspiration for the development of drugs that prevent the spread of certain cancer cells via the body's lymphatic system. During the study, they used a computer simulation to screen millions of molecules in a Roche database and found five other compounds that they thought could be promising for stopping cancer metastasis.