HOUSTON - Identification of a non-traditional pathway for spiriting a cancer-promoting protein into the cell nucleus points to a possible combination therapy for esophageal cancer and indicates a mechanism of resistance for new drugs that attack the Hedgehog pathway.
A team of researchers at The University of Texas MD Anderson Cancer Center reports in the March 20 Cancer Cell that the mTOR molecular pathway promotes the activity of the Gli1 protein in esophageal cancer development and progression.
"The Hedgehog pathway is the established, or canonical, pathway for activating Gli1. We've shown a clear-cut mechanism to link all non-canonical activation of Gli1 through a single pathway, TOR," said senior author Mien-Chie Hung, Ph.D., vice president for basic research, professor and chair of MD Anderson's Department of Molecular and Cellular Oncology.
"Crosstalk between these two pathways is a challenge, but our experiments showed a combination of the mTOR inhibitor RAD-001 (Everolimus) and the Hedgehog inhibitor GDC-0449 (Erivedge) steeply reduced the tumor burden in a mouse model of esophageal adenocarcinoma," Hung said.
Both drugs have been approved by the U.S. Food and Drug Administration for use in other types of cancer.
Both pathways active in aggressive human cancer
An analysis of 107 tissue samples of human esophageal cancer tumors showed that 80 (74.8 percent) had a marker of mTOR promotion of Gli1 and 87 (81.3 percent) had the version of Gli1 activated by Hedgehog.
Esophageal cancer is one of the most aggressive forms of cancer, with fewer than 20 percent of patients surviving for five years, the study notes. And it has become more frequent in the United States by 5 to 10 percent annually since the 1980s. Inflammation and obesity are thought to be driving factors in this increased incidence, Hung said.
The researchers used experiments with cell lines, mouse models and human tu
|Contact: Scott Merville|
University of Texas M. D. Anderson Cancer Center