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Why don’t brain tumours respond to drugs?

Malignant brain tumours do not often respond to promising new drugs. Researchers from Heidelberg have now uncovered a mechanism and a tumour marker that are linked to the development of this resistance. A “death receptor” might possibly indicate the chances of success of chemotherapy at the same time as providing new approaches for developing a new therapy for the successful treatment of brain tumours.

Dr. Wolf Müller, Chief Consultant in the Department of Neuropathology at the Institute of Pathology at the University of Heidelberg, and his team have been able to show that certain brain tumours (astrocytomas) can cripple a protein on their cell surface, the so-called death receptor. Drugs can dock to this receptor resulting in the death of the cells. An intact “death receptor” can therefore serve as tumour marker for assessing the success of a therapy. The study was carried out with funds from the Heidelberg/Mannheim Tumour Centre and published in the journal “Clinical Cancer Research”.

Primary brain tumours that develop from brain cells, in particular malignant glioblastomas, often have a bad prognosis. Although many therapies are used to full capacity, patients with a glioblastoma generally die within two years of being diagnosed with the tumour. Therefore, the team of researchers are working hard to obtain deeper insights into the biology of these tumours with the aim of developing more efficient therapies.

"Death receptor” can be switched on and off

The Heidelberg scientists examined different primary brain tumours (astrocytomas, including glioblastomas) and found out that the gene encoding the death receptor DR4 was switched off in up to 75 per cent of cases by what is known as “promoter methylation”. Methylation refers to the attachment of methyl groups to a specific gene segment that have a decisive effect on its activity (expression). The methylation of the promoter prevents the transcription of the gene.

The DR4 death receptor is an attractive target for receptor-specific therapies. Fortunately, the drug Mapatumumab, an antibody protein that binds directly to the receptor and can induce apoptosis, is available for such therapies. This drug is currently being tested in a number of clinical trials (phase II) for its effect on solid tumours such as lung cancer.

New approach for the specific therapy of brain tumour cells

The use of Mapatumumab for the treatment of gliomas seems particularly promising since the death receptor is generally only found on tumour cells, and not on other brain cells. Gliomas are highly invasive tumours that intermingle with healthy brain tissue, making complete surgical removal impossible and rendering chemotherapy very difficult. Chemotherapy with Mapatumumab has the potential to target all tumour cells and promote their apoptosis while leaving healthy brain cells that do not have this particular receptor unaffected.

In cell culture experiments, the researchers have already been able to reverse methylation and restore the function of the “death receptor” with the result that the tumour cells reacted to the drugs and died. The cells became resistant to the drugs when the transcription of the gene was once again repressed.

“It is still not possible to exclusively treat individual genes through such manipulations. However, knowledge of the tumour markers might be a good starting point for the development of new therapies involving the manipulation of these genes,” explains Dr. Wolf Müller. Specific investigations of the tumour tissue prior to such a therapy might help identify patients with intact death receptors. Such patients would then stand a good chance of benefiting from this promising therapy while patients without intact death receptors could at least be spared the side effects of a futile therapy.

Literature:
Epigenetic Silencing of Death Receptor 4 Mediates Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Resistance in Gliomas. Agnes Elias, Markus D Siegelin, Albert Steinmüller, Andreas von Deimling, Ulrike Lass, Bernhard Korn, Wolf Mueller, Clinical Cancer Research, 2009, Epub ahead of print.

 

Further information:
Dr. med. Wolf C. Müller
- Chief Consultant -
Department of Neuropathology/Institute of Pathology
University Hospital of Heidelberg
Im Neuenheimer Feld 220
69120 Heidelberg
Tel.: +49 (0)6221 / 56 39 912
Fax: +49 (0)6221 / 56 45 66
E-mail: Wolf.Mueller(at)med.uni-heidelberg.de
Website address: https://www.gesundheitsindustrie-bw.de/en/article/press-release/why-don-t-brain-tumours-respond-to-drugs