Drug Targets For Aggressive Pancreatic Cancer Identified

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Microscopic image of mitochondrial stained pancreatic cancer cells
Mitochondrial staining (red) and nuclear staining (blue) of abnormal pancreatic ducts from a mouse model of human pancreatic ductal carcinoma. Mitochondrial shape changes occur throughout the progression of pancreatic cancer and the machinery that reg

Researchers have identified mutations specific to an aggressive type of pancreatic cancer, called adenosquamous cancer of the pancreas, that could be used as targets for new drugs to treat this often fatal disease.

As well as finding a number of genetic variants that are also found in other cancers, the team, led by Michael Barrett, Ph.D., a senior researcher at the Mayo Clinic in Arizona, found three variants specific to patients with the more aggressive cancer.

Notably, they also identified an inhibitor that could target one of the genetic mutations specific to adenosquamous pancreatic cancer (ASCP), which they tested in the lab.

“ASCP currently has no effective therapies,” said Barrett, who was corresponding author on the study which was published in the journal Cancer Research.

“Our study has shown that ASCPs have novel ‘hits’ (mutations and deletions) in genes that regulate tissue development and growth… As a consequence, cells within the tumor have the ability to revert to a stem-cell-like state that includes changes in cell types and appearance, and the activation of signaling pathways that drive the aggressive nature of ASCP.”

Overall, around 57,600 people in the US will be diagnosed with pancreatic cancer this year and, of those, it is predicted that only around 10,000 will survive. This makes finding new treatment options a high priority.

All pancreatic cancer is associated with a poor outcome. But, the rarer (1-4% cases) ASCP type, where more than 30% of the cells in the tumor are squamous or ‘skin-like’, has an even worse outcome than the more widespread pancreatic ductal adenoma that affects around 85% of patients with the disease.

Barrett and colleagues analyzed samples taken from 15 ASCP tumors, including five that had been expressed in a mouse model. They found genetic variants in the samples that are common in more widespread pancreatic cancers including mutations in the genes TP53, KRAS and MYC, all of which are commonly linked to cancer formation.

They also found genetic variation specific to ASCP in the gene SMYD2 and RORC, as well as a fusion of the FGR1-ERLIN2 genes in one sample.

The team also experimented with targeting the new targets they discovered and assessed the impact of inhibiting the activity of the FGR1 gene on ASCP cells with the FGR1-ERLIN2 fusion mutation that were grown in the lab. Cancer cell growth was inhibited, which makes the researchers hopeful that this could be a potential drug target for future ASCP treatments.

The genetic information collected in this study suggests that some of the variants discovered in ASCP tumors could make good drug targets either for new or repurposed drugs. For example, variation in FGR1 is implicated in other cancers and there are already drugs in the market that inhibit its activity such as dovitinib and brivanib, used to treat some types of liver and kidney cancer. The researchers also think RORC inhibition could be a promising way to target ASCP.

 

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