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Scientists link 2 cancer-promoting pathways in esophageal cancer
Date:3/19/2012

mor samples to demonstrate how Hedgehog and mTOR, both implicated in esophageal and a variety of cancers, converge on Gli1.

Slipping Gli1 into the nucleus

Gli1 is a transcription factor - a protein that moves into the cell nucleus where it binds to and activates other genes. Gli1 normally is held out of the nucleus by a protein called SuFu, which binds to it at a specific region.

Hung said the Hedgehog pathway frees Gli1 by activating a signaling protein called Smoothened (SMO), which blocks SuFu binding, allowing Gli1 to move into the nucleus and activate a variety of genes, including Hedgehog activators.

GDC-0449, approved in January by the FDA for treatment of metastatic basal cell carcinoma, inhibits SMO. Basal cell carcinoma is driven by mutations in the Hedgehog pathway, Hung said, but resistance to SMO 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," Hung said.

How mTOR helps Gli1

Hung and colleagues started with Tumor Necrosis Factor Alpha (TNFa), an inflammatory protein connected to development of esophageal cancer. In a series of experiments, they found that TNFa triggers Gli1 through the mTOR pathway by:

  • Activating the kinase S6K1, which attaches a phosphate group to Gli1 rendering the phosphorylated Gli1 unable to bind to SuFu.
  • With SuFu thwarted, the phosphorylated version of Gli1 moves into the nucleus and activates genes.
The team developed an antibody to identify the presence of phosphorylated Gli1, providing a possible biomarker of cancer resistant to Hedgehog inhibitors, Hung said.

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 percent. Together, they reduced tumor volume by 90 percen
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Contact: Scott Merville
smerville@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert  

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