Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scientists link 2 cancer-promoting pathways in esophageal cancer

20.03.2012
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:
http://www.mdanderson.org

More articles from Health and Medicine:

nachricht Study suggests possible new target for treating and preventing Alzheimer's
02.12.2016 | Oregon Health & Science University

nachricht The first analysis of Ewing's sarcoma methyloma opens doors to new treatments
01.12.2016 | IDIBELL-Bellvitge Biomedical Research Institute

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: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

Im Focus: Molecules change shape when wet

Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water

In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...

Im Focus: Fraunhofer ISE Develops Highly Compact, High Frequency DC/DC Converter for Aviation

The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.

Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

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

14.10.2016 | Event News

 
Latest News

UTSA study describes new minimally invasive device to treat cancer and other illnesses

02.12.2016 | Medical Engineering

Plasma-zapping process could yield trans fat-free soybean oil product

02.12.2016 | Agricultural and Forestry Science

What do Netflix, Google and planetary systems have in common?

02.12.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>