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.?
?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.