Researchers in Germany have found evidence that ceritinib, a drug already approved for cancer treatment, inhibits a cloaking mechanism many tumors’ cells use to hide from the body’s immune system. The findings could pave the way for new anti-cancer drugs, including optimized versions of the therapeutic.
Cancer cells are known to surround themselves with a cloud of adenosine, a molecule that suppresses the immune system, stimulates formation of new blood vessels to support the growing tumor, and helps malignant cells migrate to other organs. Adenosine is produced from adenosine triphosphate (ATP), which tumors secrete in large amounts. Various enzymes on the tumor surface convert ATP to adenosine over the course of several steps. The first of these conversion steps is catalyzed by CD39, making it an attractive target for disrupting the process. "If CD39 is inhibited, hardly any adenosine is produced,” says Professor Dr. Christa Müller from the Institute of Pharmacy at the University of Bonn.
For this reason, pharmaceutical researchers globally are searching for an active ingredient that slows down CD39. "[Without adenosine], ATP would accumulate around the cancer cells, which would actually stimulate the immune response," Müller says. "So the body's own defenses would not be suppressed; on the contrary, they would be turned on extra sharp."
But the search for a CD39 inhibitor has been largely unsuccessful. The Bonn research group therefore pursued a new search strategy, focused on other enzymes in the body that also process ATP. "These include, for example, the so-called protein kinases,” says Laura Schäkel, who collaborated with Prof. Müller. “The nice thing is that there are already approved drugs that inhibit protein kinases. We now looked at whether they also work against CD39."
At the start of the study, there were a total of 50 different agents approved for certain diseases that inhibit protein kinases. The research group examined all of them. "One of the substances, ceritinib, also blocks the conversion of ATP by CD39," Schäkel says. "We were able to show this not only in the test tube, but also in cultures with so-called triple-negative breast cancer cells. These are extremely difficult to treat—they usually hardly respond to therapies."
But Müller does not think it makes sense to simply administer ceritinib as a CD39 inhibitor in certain cancers. "After all, the active ingredient is primarily directed against a different group of enzymes; it would therefore have undesirable side effects," she says. "We now want to modify it so that it hardly inhibits protein kinases at all and instead slows down CD39 even more."
Such an optimized active ingredient could also be combined with other therapeutic agents. "Classic cytostatics usually massively weaken the immune system; CD39 blockers, on the other hand, would activate it," says Müller. "In combination, therefore, the drugs could possibly have a significantly greater effect."
It could be possible to measure whether the cancer cells of affected patients carry a lot of CD39 on their surface before administering the drug. "Because only then would treatment with CD39 inhibitors make sense," says Müller. "So you would tailor the administration to the individual patient. This personalization of therapies for the purpose of enhancing efficiency is becoming increasingly important in medicine."
The findings were published recently in Journal for ImmunoTherapy of Cancer.