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Low Levels of Common Enzyme Key to Resistance in Ewing’s Sarcoma

A study from scientists at the University of Freiburg, Germany, and their collaborators at the National Cancer Institute (NCI), part of the National Institutes of Health, has pinpointed a potential mechanism for resistance of Ewing’s sarcoma, a type of bone cancer, to a protein that may be useful in fighting cancer — and a possible method for overcoming this resistance. The results appear online May 23, 2007, in the Journal of Pathology.

The protein, called TRAIL (tumor necrosis factor apoptosis-inducing ligand),has generated tremendous interest among scientists looking for new therapies that target cancer cells but spare normal dividing cells. TRAIL binds to receptors on the surface of cancer cells and sets off a series of signals that cause the cells to commit suicide. Almost all normal cells are unaffected by TRAIL. The cells of many solid tumors, including Ewing’s sarcoma, have shown extreme sensitivity to TRAIL in laboratory experiments, and investigators have started testing the protein in early clinical trials.

Ewing’s sarcoma is the second most common bone tumor in children and adolescents. For children who have metastatic or relapsed disease, their prognosis is poor. More effective treatments are needed for these patients.

The scientists who conducted the study, led by Udo Kontny, M.D. from the University of Freiburg, showed that Ewing’s sarcoma cells that express low levels of an enzyme called caspase-8, which plays a role in cell suicide (apoptosis), are resistant to TRAIL-induced killing. However, the addition of interferon-gamma, a protein produced by cells of the immune system, to treatment with TRAIL caused the resistant cells to produce more caspase-8, making them once again sensitive to TRAIL-induced death.

“This study is an excellent example of how modern molecular biology can help us unlock the detailed mechanisms driving the new, targeted therapies for cancer,” said NCI Director John E. Niederhuber, M.D. “If a targeted treatment that shows promise in the laboratory does not work as expected in clinical trials, we need to go back and understand what properties of the cancer cells might be driving resistance.”

“When you look in the test tube, it’s really quite remarkable how quickly and dramatically Ewing’s sarcoma is killed by TRAIL,” explained Crystal Mackall, M.D., from NCI’s Center for Cancer Research (CCR), whose laboratory headed the NCI portion of the investigation. “But the initial results in animal studies were just not as effective as we would have expected. So we ended up thinking that, however this tumor is becoming resistant, it must be really important, and we’re going to need to add something to improve the effectiveness of TRAIL treatment in the clinic.”

The scientists focused on caspase-8 because lack of the protein had been linked in laboratory studies to TRAIL resistance in Ewing’s sarcoma cells and the cells of other tumors. To see if caspase-8 expression is also limited in tumor tissues acquired from patients, the researchers measured the expression of caspase-8 in 54 tissue samples taken from 47 patients with Ewing’s sarcoma. They found that, while 50 out of the 54 samples expressed caspase-8, the number of cells within each sample that expressed the protein varied considerably. In 76 percent of the samples, caspase-8 expression was detected in 60 to 100 percent of the cells. In the other 24 percent of the samples, caspase-8 expression was detected in only 0 to 50 percent of the cells. Therefore, within any individual Ewing’’s sarcoma tumor, cells that lack caspase-8 could cause resistance to TRAIL.

The investigators next tested whether interferon-gamma, which has been shown in the laboratory to increase caspase-8 expression in cells, could sensitize Ewings’s sarcoma cells with low expression of caspase-8 to treatment with TRAIL. They found that doses of interferon-gamma, within the range easily tolerated by patients, increased caspase-8 expression in caspase-8-deficient cells. When the interferon-gamma-treated cells were treated with TRAIL, they underwent cell death, indicating restored sensitivity to TRAIL.

Because most patients with Ewing’s sarcoma undergo chemotherapy, the investigators also looked at whether chemotherapy alters the levels of caspase-8 in Ewing’s sarcoma tumors. Using samples from the same 47 patients, they compared the number of tumor cells expressing caspase-8 between tumor samples collected before and after chemotherapy. They did not find any significant difference between the samples, suggesting that chemotherapy does not select for tumor cells that lack caspase-8, which would make subsequent treatment with TRAIL less effective. Data indicated that caspase-8 does not influence the sensitivity of Ewing’s sarcoma tumors to chemotherapy.

The investigators confirmed these results in the laboratory. When cells with different levels of caspase-8 expression were treated with the chemotherapy drug doxorubicin, no differences in sensitivity to the drug were seen. Changing the levels of caspase-8 expressed by the cells, genetically or by adding interferon-gamma, did not alter their sensitivity to chemotherapy, indicating “that the combination of TRAIL and interferon-gamma with standard chemotherapeutics in Ewing’s sarcoma could be feasible,” stated the authors.

“I’d like to see a clinical trial in humans of interferon-gamma and TRAIL or an agent that interacts with the TRAIL receptor, because I do believe that adding interferon-gamma will make cells more susceptible to TRAIL-induced killing,” said Dr. Mackall. An early phase study will be particularly important, she explained, because it is possible that adding interferon-gamma to treatment with TRAIL might also increase the incidence of side effects.

Lissat A, Vraetz T, Tsokos M, Klein R, Braun M, Koutelia N, Fisch P, Romero ME, Long L, Noellke P, Mackall CL, Niemeyer CM, Kontny U. Interferon-gamma sensitizes resistant Ewing’s sarcoma cells to TRAIL-induced apoptosis by upregulation of caspase-8 without altering chemosensitivity. J Pathol. Published online May 23, 2007.

Researchers are from the Division of Pediatric Hematology and Oncology and the Institute of Pathology, University of Freiburg, Germany; and the Pediatric Oncology Branch and Laboratory of Pathology, CCR, NCI, Bethesda, Md.

For more information on NCI's Laboratory of Pathology, visit http://ccr.cancer.gov/labs/lab.asp?labid=106.

For more information about cancer, please visit the NCI Web site at http://www.cancer.gov, or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.


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