Molecular Networks Engage in Harmful Talk; Two Drugs Interrupt
Researchers have caught two molecular signaling networks engaged in "crosstalk" that undermines attempts to successfully target cancer-promoting abnormalities in esophageal cancer. Writing in the March 20 edition of the journal Cancer Cell, the team shows how the mTOR and Hedgehog pathways converge on the activity of a single protein, called Gli1, and how this conversation can be interrupted with a combination of drugs already approved by the U.S. Food and Drug Administration for certain types of cancer.
"Crosstalk between these two pathways is a challenge, but our experiments showed a combination of the mTOR inhibitor RAD-001 (Afinitor®å) and the Hedgehog inhibitor GDC-0449 (Erivedge®å) steeply reduced the tumor burden in a mouse model of esophageal adenocarcinoma," says senior author Mien-Chie Hung, Ph.D., MD Anderson vice president for basic research and chair of the Department of Molecular and Cellular Oncology.
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 tumor samples to demonstrate how Hedgehog and mTOR activate Gli1 in different ways to promote esophageal cancer development and progression.
The two drugs together reduced the tumor burden of mice with esophageal cancer by 90 percent, suggesting that the combination merits testing in human clinical trials, Hung said.
The Hedgehog inhibitor GDC-0449 was approved by the FDA in January for basal cell carcinoma. Basal cell carcinoma is driven by mutations in the Hedgehog pathway, Hung says, but resistance to these inhibitors has emerged in clinical trials to treat other cancers, such as ovarian and pancreas. "We now believe the mTOR pathway is one source of this resistance."