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Medical First: Targeted Therapy Prevents Esophageal Cancer in Local Study 

For the millions of people throughout the world who suffer from gastroesophageal reflux disease (GERD), a new study published in the Annals of Surgery suggests that a targeted drug therapy may one day be the key to reducing their risk for esophageal cancer.
Led by Blair Jobe, MD, one of the nation’s foremost esophageal disease experts and Director of the Institute for the Treatment of Esophageal and Thoracic Disease at the West Penn Allegheny Health System (WPAHS), the groundbreaking pre-clinical study is the first to demonstrate the potential of a targeted drug therapy for preventing esophageal cancer in a high risk population.
Gastroesophageal reflux occurs when the amount of gastric fluid (acid and bile from the stomach) that refluxes into the esophagus (the tube that carries food from the mouth to the stomach) exceeds the normal limit, causing a variety of possible symptoms, such as heartburn, chest pain and pulmonary distress.  It is estimated that 25-40% of healthy adult Americans experience symptomatic GERD on a monthly basis and approximately 10-20% suffer from it daily.
In some cases, chronic GERD causes mucosal injury to the inner lining tissues of the esophagus, which can lead to a premalignant condition called Barrett’s esophagus.   Barrett’s is a potentially serious complication in which the squamous cells that normally line the esophagus are replaced by gland cells that resemble those found in the linings of the stomach and small intestine which are more resistant to the harsh gastric fluids. 
“The abnormal presence and proliferation of these gland cells in the esophagus substantially increases the risk of developing an invasive cancer called adenocarcinoma, so our current strategy is to perform surveillance endoscopy, treat more advanced Barrett’s with ablation procedures or remove diseased tissue with an endoscopic procedure,” Dr. Jobe said. 
“What we have shown in this study is that there may ultimately be a better way to prevent esophageal cancer using a targeted medical therapy that simply disables the molecular switch that puts the process of developing this condition into motion,” he said.
Dr. Jobe and his team focused their investigation on a molecular pathway - called the hedgehog pathway - that is associated with the growth of epithelial tissues in the stomach and upper digestive tract during development of the foregut.   It is believed that Barrett’s is an aberrant expression and activation of this pathway that takes place in the esophagus in response to excessive exposure to gastric juices.
To disrupt the hedgehog pathway, the team used an investigational drug developed by Bristol Meyers Squibb that inhibits a protein central to the pathway’s function – called smoothened (Smo).
After surgically inducing GERD in a large sampling of rats, the Smo inhibitor drug was administered orally to half of them over a period of 28 weeks.   Among subjects randomized to receive the drug, there was a 36% lower risk of Barrett’s esophagus and a 62% relative risk reduction for developing esophageal cancer compared to the control group.
“Overexpression of Smo with resultant activation of the hedgehog pathway has been identified previously as a factor in several cancer types, including esophageal cancer.  In our study, there was a highly significant risk reduction in the development of both Barrett’s esophagus and esophageal cancer in animals treated with the Smo inhibitor, indicating that this therapy may have the potential to prevent cancer associated with reflux disease,” Dr. Jobe said.
“To our knowledge, this is the first demonstration of the prevention of esophageal adenocarcinoma in an in vivo [living organism] model of this cancer type.”
Dr. Jobe said the next step is to further evaluate the hedgehog pathway in both the preclinical and clinical setting to more definitively prove the preventive effect of Smo inhibition and better understand the precise mechanism of action.
Editors Note:  This research was conducted by Dr. Jobe while he was on staff at the University of Pittsburgh.


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