Stopping pancreatic cancer before it starts

Written by 
Susan Gammon
Maria Diaz Mecco

Pancreatic cancer is relatively rare, but when it occurs it tends to be deadly—just 5 percent of patients survive five years or more past diagnosis.  A new study co-authored by Jorge Moscat, Ph.D., and Maria Diaz-Meco Ph.D., professors at SBP’s NCI-designated Cancer Center, looks at ways to detect and stop precursors of pancreatic cancer—premalignant lesions known as intraepithelial neoplasia 1 (PanIN1)—before they become cancer. PanIN1 lesions are relatively common, affecting 16 percent of healthy adults and 60 percent of people with chronic pancreatitis, or inflammation of the pancreas. 

Yet only 1 percent of PanIN1 lesions will lead to the most lethal form of pancreatic cancer—the challenge is predicting which people have the particularly insidious lesions.  There are several risk factors—having first-degree relatives with pancreatic cancer, chronic pancreatitis, obesity, diabetes, tobacco smoking and alcohol consumption, for example—but it’s not known how these risk factors trigger the conversion of a PanIN1 lesion to cancer.

The study, published in Cancer Cell and led by Michael Karin, Ph.D., distinguished professor of Pharmacology and Pathology at UC San Diego School of Medicine, discovered that in human cells and mice, interference with autophagy, a cell process that gets rid of faulty proteins and cell trash, worsens the damage to pancreatic cells that produce digestive enzymes. The disruption leads to the accumulation of a protein called p62/SQSTM1, which is typically elevated in chronic pancreatitis and PanIN lesions.

Moscat, an authority on p62 and cancer, explains that impaired autophagy can lead to a build up of p62/SQSTM1, helping precursor lesions advance to full-blown pancreatic cancer through specific molecular steps. First, p62 stimulates a protein in the cell nucleus called NRF2. Then NRF2 stimulates a protein MDM2. Elevated MDM2 converts cells that have certain cancer-causing gene mutations into rapidly multiplying pancreatic ducts cells. These duct cells in turn give rise to malignant pancreatic cancer.

According to Diaz-Meco, when the researchers used an investigational drug that targets MDMs, they were able to prevent cancer progression in mice, and even restore normal pancreatic cell identity.

These findings suggest that treatment of individuals who are at high risk of pancreatic cancer may benefit from treatment with MDM2 inhibitors,” explains Diaz-Meco. “MDM2 inhibitors may prevent PanIN lesions from becoming cancer, reducing the toll of this currently incurable malignancy.”

The story is based on a UCSD Health Sciences report.