They divide and divide, and no natural border can stop them. Tumours such as the Ewing sarcoma, a bone cancer that occurs predominantly in teenagers, grow incessantly, making treatment difficult. A few years ago, Prof. Dr. Udo Kontny and his team from the University Hospital in Freiburg discovered a way to stop the growth of this particular tumour by activating a switch on the surface of cells which induces cellular death. Can physicians learn to use this particular switch?
Ewing sarcoma is the second most frequent bone cancer in children and young adolescents. Up until the 1960s, practically all Ewing sarcoma sufferers died from the tumour that can occur anywhere in the body, but is most common in the proximal long tubular bones of the upper and lower legs. The reason for the fatal outcome is the tumour's tendency to metastasise. Although chemotherapy, which exerts its effect on the whole body, is available to complement localised surgery and radiotherapy, such treatments are often started too late. If the tumour has already formed metastases at the time it is diagnosed or if the tumour recurs, then the disease is often deadly. "Therefore, we are looking for new therapies," said Prof. Dr. Udo Kontny from the Department of Haematology and Oncology at the Children's Hospital in Freiburg. Kontny and his team are concentrating on the cellular suicide programme (apoptosis) which is installed by default in all cells.
Apoptosis is a kind of a control mechanism in the body. During development and also throughout the entire lifespan of an organism, defective cells or cells that are no longer needed must be removed from the body. If a liver cell has become too old or if the body no longer needs the large number of immune cells it produces to fight off unwanted intruders, then certain signals will spark off specific signalling cascades in the cells. A higher quantity of caspase enzymes will be produced, cutting the cells up in small pieces which are then removed by the macrophages. This type of cellular death is induced by an external stimulus received by a death receptor located on the membrane of all cells. The apoptosis signal is transmitted to the cell where caspases are switched on. “We are concentrating on two particular questions,” said Kontny. “One, can we stimulate this apoptosis pathway and make the cancer cells undergo suicide? Two, can we repair the apoptosis pathway when it is defective?”
Many years ago, researchers found out that the cells of the Ewing sarcoma have a death receptor that reacts to TRAIL (editor's note: tumor necrosis factor (TNF)-related apoptosis-inducing ligand; member of the TNF family of cytokines that promotes apoptosis). Experiments carried out by Kontny and his team on cancer cells in the test tube showed that TRAIL induces apoptosis in around 80 per cent of all tumour cells. In contrast to the molecule Fas ligand (FasL), which also switches on death receptors, TRAIL does not lead to so many side effects in other body tissues like the liver. It seems that TRAIL can be directed specifically against tumour cells. "This makes the molecule very attractive for our research into the improvement of cancer treatment," said Kontny explaining that TRAIL might soon be used as part of a combined chemotherapy to treat Ewing sarcoma. But why is TRAIL only effective in about 80 per cent of tumour cells? Kontny and his team discovered that some of the cancer cells had a defective signalling pathway downstream of the death receptor. In other words, these TRAIL-resistant tumour cells lack caspase 8 and are unable to cleave cancer cells. Can this problem be solved?
“The problem can be solved with interferon γ,” said Kontny. Interferon γ is a signalling molecule in the human body that plays an important role in the activity of immune cells during infection. The failure of the molecule has already been linked with a number of autoimmune diseases. The scientists from Freiburg have shown that the quantity of caspase 8 increases in apoptosis-resistant cancer cells when they are exposed to interferon γ. The molecule does something akin to repairing the signalling pathway that induces apoptosis. “This has important implications for the potential application of TRAIL as a drug,” said Kontny. “When treating Ewing sarcoma, TRAIL should always be used in combination with interferon γ; the administration of TRAIL alone does not make sense if the entire signalling pathway is not intact.” Interferon γ is well tolerated by patients and can therefore be combined with TRAIL. In addition, it has another advantage: Kontny and his cooperation partners at the National Cancer Institute in Bethesda, USA, carried out experiments on mice. They injected tumour cells into the lower legs of the mice and found that interferon γ reduced the probability of metastasis. The Freiburg scientists are currently investigating why this happens.
In another project, Kontny and his team are investigating another substance that might be able to stop the growth of Ewing sarcoma. The substance in question is known as treosulfan, and has been shown to be an effective alternative to busulfan, the currently used drug. Treosulfan and busulfan can intercalate into the DNA of tumour cells, thereby inhibiting DNA replication. This kind of damage also induces the cellular apoptosis programme. The Freiburg scientists were able to show in mice and in the test tube that treosulfan was more effective than busulfan. In contrast to busulfan, treosulfan does not lead to the lung problems that are often experienced by patients undergoing radiotherapy. "In a new study, we will test treosulfan in patients from the high-risk group, i.e. patients who require radiotherapy," said Kontny. Kontny and his team might potentially be able to detect much earlier than is currently possible whether tumour cells are responding to drugs such as TRAIL or treosulfan. Working in cooperation with radiologists, Kontny and his team have developed an imaging technique that indicates whether a therapy is successful even before the tumour has started to reduce in size. Previously, tumours had to show growth differences before a statement could be made as to whether the patient was responding to treatment or not.