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A Sweet Surprise: Targeting Sugar-coated Proteins to Treat Pancreatitis

A Sweet Surprise: Targeting Sugar-coated Proteins to Treat Pancreatitis content piece image
Pancreatic lineage immunofluorescence (IF) of the whole body, R;F CA19-9 mouse model. Credit: CSHL
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CA19-9 – a complex sugar structure that coats many proteins, has now been linked to the transformation of pancreatitis to pancreatic cancer, according to a new study published in Science.   

Using a mouse model, Dannielle D. Engle and colleagues have shown that elevated levels of CA19-9 causes inflammation to occur in the pancreas. Without a subsequent reduction in the levels of CA19-9, wound healing is hindered, causing a transformation in the pancreas that can fuel the development of pancreatic cancer.

Findings from the study indicate that in future it may be possible to therapeutically target CA19-9, by blocking the complex sugar molecule’s activity.

“Even though elevated levels of CA19-9 is bad, it represents a unique opportunity for a new therapeutic target,” explains Engle, in a recent video highlighting their research.

Dannielle D. Engle discusses the team's CA19-9 research. Credit: CSHL

What is pancreatitis?

Pancreatitis is a condition with limited treatment options, that involves inflammation of the pancreas – a gland located in the upper abdomen. There are different types of pancreatitis – acute, chronic and hereditary.

Pancreatitis causes

Pancreatitis occurs when cells within the pancreas become irritated as a result of premature activation of digestive enzymes inside the pancreas, causing inflammation.

There are several causes of pancreatitis, including:
  • Excessive, long-term alcohol consumption
  • Gallstones
  • Surgery or injury to the abdomen
  • Smoking cigarettes
  • Medications (drug-induced pancreatitis)
  • A family history of the condition
  • Hypercalcemia
  • Infections
  • Hypertriglyceridemia
  • Pancreatic cancer

Investigating the role of CA19-9

CA19-9 is in the serum of 10–30% of patients with pancreatitis and 75% of patients with pancreatic cancer. Whilst CA19-9 is known to be a clinically useful biomarker for these conditions, until now knowledge of its exact role in pancreatic cancer and pancreatitis has been limited. Engle and team set out to gain a deeper understanding of CA19-9’s function, however their first task was to develop a model capable of recapitulating the elevated CA19-9 observed in humans. Wild-type mice naturally lack the enzyme required to generate CA19-9, therefore the team created a mouse model that could produce CA19-9, in addition to organoid models of pancreatic disease. The mice producing CA19-9 subsequently developed pancreatitis.

The team found that they were able to reverse CA19-9-mediated pancreatitis, and by using CA19-9 blocking antibodies it’s activity could be suppressed. “By targeting CA19-9 with antibodies in animal models, we were able to reduce the severity of pancreatitis and even prevent it from occurring,” says Engle, in a recent press release.

“Pancreatitis is required for developing pancreatic cancer, and we might be able to prevent that transition in patients with pancreatitis by targeting CA19-9,” says Engle. CA19-9 cooperates with the KrasG12D oncogene to produce aggressive pancreatic cancer.

The paper notes that: “Fully human CA19-9 antibodies have passed Phase 1A clinical trials PET-imaging of pancreatic cancer,” indicating that with the support of future studies it could be possible to rapidly translate CA19-9 targeted therapy to the clinic for the treatment of pancreatitis.

“It is a way of treating pancreatitis that we really never had before and represents a way of not just treating existing pancreatitis, but theoretically preventing it from occurring in patients at risk.” concludes Engle.

Types of pancreatitis

Acute pancreatitis has a mortality rate of ~10%. Diagnosis is usually challenging and therefore treatment can often be delayed due to the inaccessibility of the pancreas.
Chronic pancreatitis involves inflammation of the pancreas that is unable to heal, the condition worsens and ultimately leads to permanent damage , impairing the functionality of the gland and impacts its ability to make pancreatic hormones.
Hereditary pancreatitis is a genetic condition. It is estimated that 65–80% of those with this form of pancreatitis have mutations in the PRSS1 gene. The PSS1 gene encodes a cationic trypsinogen enzyme that is prematurely converted to trypsin whilst still in the pancreas. The remaining 35–20% of cases are caused by a mutation in other genes. Patients with hereditary pancreatitis have a 40% lifetime risk of developing pancreatic cancer.

Reference: Dannielle D. Engle, et al. The Glycan CA19-9Promotes Pancreatitis and Pancreatic Cancer in Mice. Science (2019)