Sometimes, an innocent-looking chemical structure isn’t so innocent after all. One such structure, it appears, is carbohydrate antigen 19-9 (CA19-9), a protein-coating glycan that marks the presence of pancreatic disease. Although CA19-9 has long been recognized as a biomarker for pancreatic disease, it was never ascribed any particular function, and so the glycan was deemed to be a mere bystander. But now evidence has come to light implicating CA19-9 as a promoter of pancreatitis and pancreatic cancer.
This finding, uncovered by scientists based at Cold Spring Harbor Laboratory (CSHL), suggests that if CA19-9 could be targeted by new drugs, pancreatitis could be prevented, as well as the progression of pancreatitis to pancreatic cancer. To justify the shift from correlation to causation with regard to CA19-9, the scientists point to evidence they collected from experiments with transgenic mice.
The transgenic mice were engineered to express the human enzymes that add CA19-9 to proteins. Unlike ordinary mice, which lack the enzymes, the transgenic mice developed severe pancreatitis. And if the transgenic mice also harbored a Kras oncogene, they went on to develop pancreatic cancer.
Significantly, pancreatitis in the transgenic mice could be reversed by treatment with CA19-9 antibodies.
Details about these unexpected observations appeared June 21 in the journal Science, in an article titled, “The glycan CA19-9 promotes pancreatitis and pancreatic cancer in mice.” According to the article, these observations suggest new avenues for the treatment of pancreatic disease.
Pancreatitis, an inflammation of the pancreas, accounts for 275,000 hospitalizations in the United States annually. Also, as the Science article notes, patients with pancreatitis have an elevated risk (2.7- to 16.5-fold) of developing pancreatic ductal adenocarcinoma (PDAC), and individuals with hereditary pancreatitis have a 40–55% lifetime risk of developing pancreatic cancer.
“Therapeutic options for pancreatitis patients are now focused on treating the symptoms, and little can be done to facilitate the resolution of idiopathic pancreatitis or to prevent its recurrence, highlighting the need for new treatments,” the article’ authors observed. “Prophylactic intervention could be beneficial in the setting of recurrent or hereditary pancreatitis and after certain routine procedures for which pancreatitis is a common outcome.”
“This is one of those unique opportunities,” emphasized Dannielle Engle, PhD, the article’s lead author and a former (CSHL) postdoctoral fellow, “where prophylactic intervention of pancreatitis may lead to prevention of pancreatic cancer in at-risk patients.” Engle investigated pancreatic disease in David Tuveson’s lab at CSHL and recently accepted an appointment at the Salk Institute.
“By understanding whether and how CA19-9 contributes to disease,” she continued, “we are now poised to apply this knowledge to improve the utility of CA19-9 both as a biomarker, but also as a new treatment strategy.”
In mice, CA19-9 recruits the immune system to repair injuries from pancreatitis. “CA19-9 expression in mice resulted in rapid and severe pancreatitis with hyperactivation of epidermal growth factor receptor (EGFR) signaling,” the Science article detailed. “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.”
Essentially, the recruitment process instigated by CA19-9 can be accompanied by the release of deleterious digestive enzymes from the pancreas, as well as a cascade of biochemical reactions. This cascade can open a transformational gateway for cancer to develop.
“Pancreatitis is required for developing pancreatic cancer, and we might be able to prevent that transition in patients with pancreatitis by targeting CA19-9,” Engle said. “By targeting CA19-9 with antibodies in animal models, we were able to reduce the severity of pancreatitis and even prevent it from occurring.”
A pending patent application filed by CSHL covering use of CA19-9 antibodies for the treatment and prevention of pancreatitis has been exclusively licensed to BioNTech, a German-based biotech company.
The CSHL team’s research article was accompanied by a perspective article (“Hiding in Plain Sight“) contributed by the University of Michigan’s Christopher J. Halbrook and Howard C. Crawford. These scientists observed that to date, CA19-9 has been clinically useful as a biomarker of pancreatic cancer tumor burden during treatment, rather than for early detection, because serum CA19-9 is also increased in other diseases, including pancreatitis.
“Although the discovery of a new function of CA19-9 is exciting, Engle et al. have also potentially revitalized a role for CA19-9 in the early detection of pancreatic cancer,” write Halbrook and Crawford. “With their transgenic mouse model and the organoids (cells grown as three-dimensional cultures) derived from them, they have generated an optimal system with which to identify CA19-9–modified proteins that can distinguish the metaplastic epithelia found in pancreatitis from the cancerous epithelia of adenocarcinoma.”