A 'sweet spot' for treating pancreatitis?
LA JOLLA, Calif.—In recent years, CA19-9 has been under scrutiny as a potential biomarker for pancreatitis and pancreatic cancer. A chemical structure comprised of complex sugar molecules, CA19-9 is elevated in pancreatitis and pancreatic cancer patients, hence the interest in it for diagnosis and disease monitoring. But some of the latest work out of the Salk Institute for Biological Studies by Assistant Professor Dannielle Engle, a former Cold Spring Harbor Laboratory (CSHL) Cancer Center postdoctoral fellow, has shown that rather than being a biomarker, CA19-9 is actually the cause of these issues. Engle and her team's results were published last week in Science in a paper titled “The glycan CA19-9 promotes pancreatitis and pancreatic cancer in mice.”
Pancreatitis is an inflammation of the pancreas, and those with hereditary pancreatitis are faced with a 40 to 50 percent lifetime risk of going on to develop pancreatic cancer. And that cancer type is associated with a bleak outlook—according to CSHL, median survival for pancreatic cancer patients is only six months, and the five-year survival rate hovers around 8 percent. Part of this is due to late diagnosis, because “pancreatitis, which is a benign inflammation of the pancreas … can look very similar to pancreatic cancer. Because there is no way to distinguish between pancreatitis and pancreatic cancer, there is no early detection test for pancreatic cancer,” according to Salk Institute. Compounding the issue is the nature of pancreatic cancer itself; as explained by Dr. David Tuveson, director of the Cancer Center at CSHL, in a 2017 news piece, “You can think of a pancreas tumor as a big raisin oatmeal cookie, with the raisins representing the cancer cells and oatmeal portion representing the dense stroma that makes up over 90 percent of the tumor.” The stroma, Salk Institute notes, both provides the necessary substances for cancer growth and impairs treatment efficacy.
Engle began investigating pancreatic cancer in Tuveson's lab at CSHL, which is when she focused on CA19-9. When exploring the enzyme in mice—once they were engineered to properly produce it—she found that they went on to develop severe pancreatitis. CA19-9 triggers the immune system to repair injuries from pancreatitis in mice, at which point it can also trigger a chain reaction of biochemical reactions via the release of certain digestive enzymes from the pancreas. This chain reaction opens the door for the potential of cancer development.
“Pancreatitis is required for developing pancreatic cancer, and we might be able to prevent that transition in patients with pancreatitis by targeting CA19-9,” explained Engle. “By targeting CA19-9 with antibodies in animal models, we were able to reduce the severity of pancreatitis and even prevent it from occurring.”
As the authors reported in the Science paper, “Notably, CA19-9 expression in mice resulted in rapid and severe pancreatitis with hyperactivation of epidermal growth factor receptor (EGFR) signaling. Mechanistically, CA19-9 modification of the matricellular protein fibulin-3 increased its interaction with EGFR, and blockade of fibulin-3, EGFR ligands, or CA19-9 prevented EGFR hyperactivation in organoids. CA19-9–mediated pancreatitis was reversible and could be suppressed with CA19-9 antibodies. CA19-9 also cooperated with the KrasG12D oncogene to produce aggressive pancreatic cancer. These findings implicate CA19-9 in the etiology of pancreatitis and pancreatic cancer and nominate CA19-9 as a therapeutic target.”
A pending patent application for the use of CA19-9 to treat and prevent pancreatitis, filed by CSHL, has been exclusively licensed to biotech company BioNTech.