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SAN 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 sorafenibterm (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 antibodyterm 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.â€
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.
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True Synergy
In hematologic neoplasms (leukemia, lymphoma, multiple myeloma), true synergy is very common. In cases where drugs are only additive and not synergistic, nothing is learned by testing the drugs in combination over what is learned by testing them separately. So drugs in combination are only tested in cases where there is the realistic possiblity of seeing true synergy.
The best combinations are those in which there is true synergy and in which the toxicities of the drugs in the combination are non-overlapping, so that full doses of each drug may be given safely.
The theory behind combination chemotherapy is that you can't give full doses of all drugs when you give them together. They have overlapping toxicity, which means you need to cut the doses when you give them together, so you get down to "homeopathic" dose levels.
Pharmaceutical companies have been attracted to studies looking at the maximum tolerated dose of any treatments. Cancer sufferers have been taking doses of expensive and potentially toxic treatments that are possibly well in excess of what they need.
Many of the highly expensive targeted cancer drugs may be just as effective and produce fewer side effects if taken over shorter periods and in lower doses. The search for minimum effective doses of treatments should be one of the key goals of cancer research.
Molecular testing methods detect the presence or absence of selected gene mutations which theoretically correlate with single agent drug activity. Tests are performed using material from dead, fixed or frozen cancer cells.
Cell culture methods assess the net effect of all inter-cellular and intra-cellular processes occurring in real-time when cells are exposed to anti-cancer agents. Tests are performed using intact, living cancer cells plated in microclusters.
Cell culture methods allow for testing of different drugs within the same class and drug combinations to detect drug synergy and drug antagonism.