Multi-use drug could combat esophageal adenocarcinoma

by • February 14, 2018 • Academia, Feature Slider, Feature-Home, Featured-Slides-Home, Orphan drugsComments Off on Multi-use drug could combat esophageal adenocarcinoma460

Faculty of Medicine scientists at the University of British Columbia have discovered that a drug currently being tested for autoimmune disorders of the blood may also be a knight in shining armour for those with esophageal cancer.

Shane Duggan, a postdoctoral fellow in the division of gastroenterology, and Dermot Kelleher, dean of the faculty of medicine, found that fostamatinib reduced the growth rate of esophageal adenocarcinoma in mice by at least 70 per cent compared to the control growth.

Esophageal cancer has abysmal survival rates (only 14 per cent alive five years after diagnosis) and is a growing Canadian health concern.

The scientists published their discovery in Cellular and Molecular Gastroenterology and Hepatology explaining their search for possible treatment targets for esophageal cancer – the sixth-leading cause of cancer-related mortality and second-deadliest form of cancer.

Duggan and Kelleher conducted a screen of about 6,000 genes found in a cell that are known or emerging drug targets in a variety of diseases. They found about 300 druggable genes specific to esophageal cancer and using biopsies of esophageal cancer from Br

itish Columbia, the U.K., and Ireland, they narrowed that list to three primary candidates. It was then that they noticed something surprising – the genes were more associated with immune cells than with the epithelial cells of the esophagus.

Esophageal cancer is often preceded by a condition called Barrett’s esophagus, which results from gastroesophageal

reflux disease (GERD). The reflux causes the inflammation and induces the esophageal tissue to transform into intestinal-like tissue. The immune cells unleashed by GERD may never fully depart from the esophagus, causing low-level inflammation that continues undetected and without symptoms. The transformed esophageal epithelial cells, after prolonged exposure to inflammation, seem to produce and become driven by a protein called spleen tyrosine kinase (SYK).

 

“That is what is driving the growth of esophageal cancer cells,” Duggan says. “The epithelial cancer cells produce — and become dependent on — inflammatory signals to maintain their abnormal growth rate.”

Dermot Kelleher (Photo Credit: UBC)

Kelleher adds, “If you looked at the results of our study blindly, you might assume you are looking at a form of lymphoma rather than an epithelial tumour.”

 

Duggan and Kelleher then turned their attention to fostamatinib, an SYK inhibitor developed by San Francisco-based Rigel Pharmaceuticals Inc., which has shown promise in immune and lymphoproliferative disorders.

 

“We found several drug candidates, but fostamatinib stood out because it’s further along in clinical trials and approvals,” Duggan says. “This was the most prominent, low-hanging fruit.” He added that clinical trials have already demonstrated the drug’s safety in other conditions.

 

Proving them right, their study expressed that the drug was very effective at stopping the growth of esophageal cancer in vitro and in mice models that had been implanted with human esophageal cancer cells. While the tumours expanded rapidly in the mice in the control group, there was virtually no growth of the tumours in the mice given fostamatinib.

 

“Our arsenal of drugs to treat esophageal cancer is very limited, compared to other, more common cancers,” comments Kelleher. “The discovery of SYK’s role in cancer growth, as well as other factors, offers the possibility of new weapons that are far more precise and tailored to the particular traits of esophageal cancer than standard chemotherapy agents.”

 

The research was supported by a private gift from Michael Chan, in memory of his late wife Pauline Chan of Vancouver.

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