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Penn researchers find targeted therapy combination overcomes treatment resistance in liver cancer
April 14, 2008SAN DIEGO -- Researchers at the University of Pennsylvania School of Medicine and Abramson Cancer Center reported today at the annual meeting of the American Association for Cancer Research that combining two targeted therapies overcomes treatment resistance in liver cancer cell lines. The team is currently designing a trial to test the combination in patients.
Liver cancer is resistant to many chemotherapies and to cell-death inducing agents. Last year, however, the U.S. Food and Drug Administration approved sorafenib (Nexavar®) as a treatment for liver cancer after a clinical trial showed that the targeted agent prolonged survival in some patients.
Unfortunately not all patients respond to sorafenib and the drug does not cure the disease.
Therefore, Wafik El-Deiry, MD, PhD, Professor of Medicine, Genetics, and Pharmacology, and co-Program Leader of Radiation Biology in the Abramson Cancer Center, and colleagues have tested other targeted agents in combination with sorafenib.
They found that treating liver cancer cells with sorafenib and an antibody or the natural ligand that stimulates programmed cell death via the TRAIL pathway, dramatically increases the rate of cell death.
"Sorafenib by itself causes a little cell death, but not that much," Dr. El-Deiry said. "Now you combine sorafenib and TRAIL, and all of the sudden you get massive cell death. It is a real synergistic interaction. It is very profound killing."
The combination works regardless of whether the researchers use a monoclonal antibody that stimulates the TRAIL receptor, which resides on the surface of the cancer cells, or the receptor's natural ligand, a small protein called TRAIL. Both the antibody and the TRAIL ligand are currently being tested as single agents in patients.
Within the next several months, Dr. El-Deiry's team expects to announce the details for a trial testing the combination in patients.
In a healthy individual, the immune system uses the TRAIL pathway to rid the body of unwanted cells, including precancerous ones. Once cancer develops, however, the cells often become less responsive to TRAIL activation, in part because of an overabundance of a protein called Mcl-1, according to Dr. El-Deiry. His team found that sorafenib reduces the amount of Mcl-1 in the cancer cells, restoring their sensitivity to TRAIL-induced cell death.
Although the Penn investigators focused their current report on liver cancer, they discovered that the sorafenib-TRAIL combination also kills colon cancer cell in vitro and in animal models.
University of Pennsylvania School of Medicine
Therefore, Wafik El-Deiry, MD, PhD, Professor of Medicine, Genetics, and Pharmacology, and co-Program Leader of Radiation Biology in the Abramson Cancer Center, and colleagues have tested other targeted agents in combination with sorafenib.
They found that treating liver cancer cells with sorafenib and an antibody or the natural ligand that stimulates programmed cell death via the TRAIL pathway, dramatically increases the rate of cell death.
"Sorafenib by itself causes a little cell death, but not that much," Dr. El-Deiry said. "Now you combine sorafenib and TRAIL, and all of the sudden you get massive cell death. It is a real synergistic interaction. It is very profound killing."
The combination works regardless of whether the researchers use a monoclonal antibody that stimulates the TRAIL receptor, which resides on the surface of the cancer cells, or the receptor's natural ligand, a small protein called TRAIL. Both the antibody and the TRAIL ligand are currently being tested as single agents in patients.
Within the next several months, Dr. El-Deiry's team expects to announce the details for a trial testing the combination in patients.
In a healthy individual, the immune system uses the TRAIL pathway to rid the body of unwanted cells, including precancerous ones. Once cancer develops, however, the cells often become less responsive to TRAIL activation, in part because of an overabundance of a protein called Mcl-1, according to Dr. El-Deiry. His team found that sorafenib reduces the amount of Mcl-1 in the cancer cells, restoring their sensitivity to TRAIL-induced cell death.
Although the Penn investigators focused their current report on liver cancer, they discovered that the sorafenib-TRAIL combination also kills colon cancer cell in vitro and in animal models.
University of Pennsylvania School of Medicine
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Liver Cancer Current Events and Liver Cancer News RSSTargeting Tumor Behavior May Lead To New Liver Cancer Drugs
Ohio State University cancer researchers have used computational and genomic methods to identify possible anti-cancer agents that may block a particular kind of tumor behavior.
Improved method developed to test carcinogen risk
Researchers at Oregon State University recently completed the largest animal study ever done in the field of toxicology, and the findings challenge some basic concepts about how to determine what level of a cancer-causing compound can be considered safe.
Good news for some hard-to-treat hepatitis C patients
In a multi-center trial led by a Saint Louis University researcher, investigators found that a new combination therapy of daily consensus interferon and ribavirin helps some hepatitis C patients who have not responded to previous treatment.
DKK-3 and WIF-1: Proteins related to liver cancer development?
Liver cancer is one of the most fatal human malignancies and the third most frequent cause of tumor-related death, about half a million people globally each year.
Low-fat diet helps genetically predisposed animals avoid liver cancer
In a study comparing two strains of mice, one susceptible to developing cancer and the other not, researchers found that a high-fat diet predisposed the cancer-susceptible strain to liver cancer, and that by switching to a low-fat diet early in the experiment, the same high-risk mice avoided the malignancy.
Stem cell protein offers a new cancer target
A protein abundant in embryonic stem cells is now shown to be important in cancer, and offers a possible new target for drug development, report researchers from the Stem Cell Program at Children's Hospital Boston.
Study indicates cancer preventive effect for statins
The commonly used prescription statin drugs may have a protective effect in the prevention of liver cancer and lead to a reduction in the need for gallbladder removals, according to two studies published in Gastroenterologyiption statin drugs may have a protective effect in the prevention of liver cancer and lead to a reduction in the need for gallbladder removals, according to two studies published in Gastroenterology.
Targeted agent shows promise in biliary cancer study
An experimental agent has shown promising results in people with advanced biliary cancer, according to a multi-institutional clinical trial led by cancer researchers at the Ohio State University.
Long-term L-carnitine supplementation prevents development of liver cancer
A study will be published on March 21, 2009 in World Journal of Gastroenterology addresses the question. A research group in King Saud University, Kingdom of Saudi Arabia investigated, for the first time, the role of carnitine, a naturally occurring compound that is synthesized mainly in the liver, during the development of hepatocarcinogenesis.
Pitt vaccine to prevent colon cancer being tested in patients
Researchers at the University of Pittsburgh School of Medicine have begun testing a vaccine that might be able to prevent colon cancer in people at high risk for developing the disease.
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