In Barrett's esophagus, the normal stratified epithelium of the esophagus is replaced by an intestinal-type epithelium owing to chronic gastroduodenal reflux. Although the condition is not cancerous in itself, it is a warning sign that potentially cancerous tissue transformations are in progress. Usually the condition can be stabilized, but potentially cancerous tissue remains. For this reason, researchers at the Hubrecht Institute (Utrecht, The Netherlands) have been searching for new drugs able to return Barrett's esophagus tissue back into the healthy, normal lining of the esophagus.

Researchers reported in the January/February 2010 issue of the journal Disease Models & Mechanisms that an intact and activated Notch signaling pathway was present in metaplastic Barrett's esophagus epithelium, but not in the normal human esophagus. To inactivate Notch signaling they decided to utilize an experimental drug, DBZ, a gamma-secretase inhibitor that is under evaluation as a potential treatment for Alzheimer's disease. The link between gamma-secretase and Notch signaling was the basis for the decision to apply a gamma-secretase inhibitor in Barrett's esophagus. Gamma-secretase plays a critical role in developmental signaling by the transmembrane receptor Notch, freeing the cytoplasmic tail of Notch to travel to the cell nucleus to act as a transcription factor.

In a rat model DBZ converted the proliferative Barrett's epithelial cells into terminally differentiated (noncancerous) goblet cells while having no effect on normal esophageal tissue. This observation led the investigators to conclude that, "The local application of gamma-secretase inhibitors may present a simple therapeutic strategy for this increasingly common premalignant condition."

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Hubrecht Institute