09:44pm Tuesday 02 June 2020

Therapeutically Targeted Gene Mutation May Cause Subset of Pancreatic Cancers

Dustin Deming

Dustin Deming

“My lab is interested in what the mutation profiles are in cancers,” said Dustin Deming, MD, assistant professor of medicineat UWCCC. “Nearly ninety percent of pancreas cancers have a mutation in the KRAS gene, but there is currently no successful drug therapy to target those mutations, making pancreas cancer one of the more difficult cancers to treat.”

“The idea behind this study was to ask if there is potentially any other mutation in the remaining cases that can be targeted,” Deming said.

He and his research team searched through publicly available datasets of pancreas cancer mutation profiles to see if they could identify a gene other than KRAS that appeared with some frequency.

“We found that, though uncommon, there appears to be a small percentage of pancreas cancers that have a mutation in the PIK3CA gene, a gene we know from our work in colon cancer that we can target therapeutically, and target it pretty well,” Deming said.

In fact, it was Deming’s work on the treatment of different genetic subtypes of colorectal cancer that recently earned him one of only 28 V Scholar grants from the V Foundation for Cancer Research. According to the foundation, the $200,000 V Scholar grants are “designed to identify, retain and further the careers of talented young investigators.”

PIK3CA encodes a protein, called PI3K, that is responsible for activating many downstream targets that promote cell growth, and mutant forms of the gene can lead to persistent, uncontrollable signaling of these targets. PIK3CA mutations have been implicated in many human cancers including colorectal and breast, and an estimated three to five percent of pancreas cancers have mutations in this gene.

To directly assess the role of PIK3CA mutations in pancreas cancer development, Deming and his team generated mouse models where the mutant gene was expressed only in pancreatic cells but no other tissue types. They then performed histology and pathology tests on pancreas sections from these mice and found several hallmarks of pancreas cancer development were present.

“We were able to show that this mutation can initiate pancreas cancer in mice, and therefore the idea that it initiates pancreas cancers in humans, though more uncommonly than KRAS mutations, might be valid,” Deming said.

Next, they wanted to see if drugs that inhibit PI3K, like those used with some success to treat colorectal cancers, could reduce the pancreas cancer burden in these genetically altered mice. They administered a dual inhibitor drug that targets both PI3K and one of its downstream targets, and found that nearly all of the cancer hallmarks previously seen in the untreated mice were not present in the treated group.

“Our next goal is to find patients who have this mutation, look at their clinical characteristics and try to figure out if there is some way, other than genotyping everyone’s cancer for this mutation, to predict who might benefit,” Deming said. “We are excited that this work might have identified a more treatable subtype of pancreatic cancer that could respond to drugs that are already in clinical development.”

The study was published in the journal Oncogenesis.

University of Wisconsin School of Medicine and Public Health

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