A non-traditional pathway for spiriting a cancer-promoting protein into the cell nucleus points to a possible combination therapy for esophageal cancer, researchers from The University of Texas MD Anderson Cancer Center reported in the latest issue of Cancer Cell.
The mTOR molecular pathway promotes the activity of the Gli1 protein in esophageal cancer development and progression, they noted in the report (CC, March 20, 2012).
The so-called "Hedgehog" pathway is the established pathway for activating Gli1, according to senior author Mien-Chie Hung, PhD, professor and chair of MD Anderson's Department of Molecular and Cellular Oncology.
"We've shown a clear-cut mechanism to link all non-canonical activation of Gli1 through a single pathway, TOR," Hung said in a press release. "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."
The team treated mice with esophageal cancer with RAD-001, GDC-0449, or both. The mTOR inhibitor RAD-001 alone had almost no effect. The Hedgehog inhibitor GDC-0449 alone reduced tumor volume by 40%. Together, they reduced tumor volume by 90%.
Clinical trials of the combination for esophageal and other cancers could be guided by the antibody for phosphorylated Gli1 and the presence of plain Gli1, Hung said, which would indicate a need to use both drugs.
