Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Scientists link 2 cancer-promoting pathways in esophageal cancer

Hedgehog and mTOR converge; Findings suggest new combination therapy

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 tumor 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 percent.

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.

Earlier research by other labs indicates that the AKT and MAPK/ERK also activate the Hedgehog pathway. Hung and colleagues show that AKT and ERK, which both activate the mTOR pathway, appear to activate Gli1 via phosphorylation of S6K1 and Gli1.

Co-authors with Hung and first author Yan Wang, Ph.D., are Qingqing Ding, M.D., Ph.D., Chia-Jui Yen, M.D., Ph.D., Weiya Xia, M.D., Jing-Yu Lang, Ph.D., Chia-Wei Li, Ph.D., Jennifer Hsu, Ph.D., Stephanie Miller, Ph.D., Dung-Fang Lee, Ph.D., Jung-Mao Hsu, Ph.D., Longfei Huo, Ph.D., Adam LaBaff, Dong-Ping Liu, Ph.D., and Tzu-Ksuan Huang, Ph.D., of MD Anderson's Department of Molecular and Cellular Oncology; Julie Izzo, M.D., MD Anderson Department of Experimental Therapeutics; Jaffer Ajani, M.D., MD Anderson's Department of Gastrointestinal Medical Oncology; Xuemei Wang of MD Anderson's Department of Biostatistics; Yun Wu, M.D., Ph.D., and Huamin Wang, M.D., Ph.D., of MD Anderson's Department of Pathology; Chien-Chen Lai, Ph.D., of the Graduate Institute of Chinese Medical Science and the Institute of Molecular Biology, National Chung Hsing University, Taiwan; Fuu-Jen Tsai, M.D., Ph.D., Department of Medical Research, China Medical University, Taiwan; Wei-Chao Chang, Ph.D., of the Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University; Chung-Hsuan Chen, Ph.D., Genomics Research Center, Academica Sinica, Taipei, Taiwan; Tsung-Teh Wu, M.D., Ph.D., Department of Anatomic Pathology, Mayo Clinic, Rochester, MN; Navtej Buttar, M.D., and Kenneth Wang, M.D., Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.

Funding for this research was provided by grants from the National Cancer Institute, including MD Anderson's Cancer Center Support Grant; The Kadoorie Charitable Foundation; Susan G. Komen for the Cure; the Sister Institution Fund of China Medical University and Hospital and MD Anderson; the Department of Health Cancer Research Center of Excellence, Taiwan; MD Anderson's Center for Multidisciplinary Research Program, and the Delmer Dallas Endowed Research Fund in Gastrointestinal Cancers; Mr. and Mrs. Raymond P. Park, Dr. Abdul Aziz Sultan, Susan J. Smith and Carlos Cantu family funds, the River Creek Foundation, Schecter Family Foundation and the Kevin Frankel and Gary W. Frazier Funds.

About MD Anderson

The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. MD Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For eight of the past 10 years, including 2011, MD Anderson has ranked No. 1 in cancer care in "Best Hospitals," a survey published annually in U.S. News & World Report.

Scott Merville | EurekAlert!
Further information:

More articles from Health and Medicine:

nachricht Resolving the mystery of preeclampsia
21.10.2016 | Universitätsklinikum Magdeburg

nachricht New potential cancer treatment using microwaves to target deep tumors
12.10.2016 | University of Texas at Arlington

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

Im Focus: New Products - Highlights of COMPAMED 2016

COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.

In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...

Im Focus: Ultra-thin ferroelectric material for next-generation electronics

'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.

Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Resolving the mystery of preeclampsia

21.10.2016 | Health and Medicine

Stanford researchers create new special-purpose computer that may someday save us billions

21.10.2016 | Information Technology

From ancient fossils to future cars

21.10.2016 | Materials Sciences

More VideoLinks >>>