Glioblastoma is regarded as the most malignant form of brain tumor. In many cases, neurosurgeons are not able to remove such tumors completely because of the risk of destroying too much brain tissue in the process. Moreover, it is often impossible to identify all the fine extensions by which the tumor spreads into surrounding healthy tissue. To at least slow down the growth of tumor cells that have remained in the head, almost all glioblastoma patients are treated by radiotherapy after surgery.
“Unfortunately, we can only delay cancerous growth in this way, but we cannot cure patients. The tumor cells, especially the cancer stem cells, are very resistant to radiation,” says Prof. Dr. Dr. Peter Huber, who is head of the Clinical Cooperation Unit ‘Radiation Oncology’ at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ).
Studies conducted in recent years found that response to radiation therapy in various cancers is better when certain types of cellular growth factors are blocked at the same time. Glioblastoma cells often produce large amounts of a growth factor called TGF-β (transforming growth factor beta). High levels of TGF-β in these tumors are correlated with particularly aggressive growth and a poor prognosis. In addition, the factor seems to support the self-renewal capability of glioblastoma stem cells. “We therefore suspect that blocking TGF-β signaling pathways slows down the self-renewal of cancer stem cells and, thus, may improve radiation treatment outcomes,” Peter Huber adds, explaining the background of the study now published.
In collaboration with colleagues from, among others, the Radiology Department of Heidelberg University Hospitals and a DKFZ department led by Prof. Dr. Ana Villalba, Huber’s team investigated the effect of a combination of radiation treatment and a newly developed substance called LY2109761. This substance blocks the signals that are transmitted into cells by the TGF-β receptor. The investigators first studied glioblastoma cells in tissue samples taken during surgical removal of the tumors. Irradiation combined with adding the substance reduced the self-renewal capability of tumor stem cells and delayed their growth significantly better than radiation treatment alone.
The group transplanted human glioblastoma cells into the brains of mice and found that these animals, after receiving the combination therapy, survived longer than those animals treated by radiotherapy alone. Tissue studies showed that, under the combination therapy, tumors grew more slowly and less invasively and showed a lower density of newly formed blood vessels. “Paradoxically, radiation therapy can provoke aggressive growth behavior in surviving tumor cells. LY2109761 seems to prevent this fatal effect,” says Huber, explaining how the drug seems to work.
Blocking of TGF-β signaling produced such promising results that researchers will now conduct a multicenter clinical trial to find out whether this mechanism may also slow down glioblastoma growth in patients more effectively than the current standard treatment. Led by Prof. Dr. Wolfgang Wick, who is head of a collaboration unit of DKFZ and the Neurology Department of Heidelberg University Hospitals, the combination therapy will be tested in Germany (Heidelberg), Spain, and the U.S.A.
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor. These tumors are often aggressive and infiltrate surrounding brain tissue. GBMs arise from glial cells, which are cells that form the tissue that surrounds and protects other nerve cells found within the brain and spinal cord. GBMs are mainly composed of star-shaped glial cells known as astrocytes. The general term glioma includes any type of brain tumor such as astrocytoma and oligodendroglioma that arise from glial cells.
Astrocytomas are classified according to a grading system developed by the World Health Organization (WHO). Astrocytomas come in four grades based upon how fast the cells are reproducing and that likelihood that they will infiltrate nearby tissue. Grades I or II astrocytomas are nonmalignant and may be referred to as low-grade. Grades III and IV astrocytomas are malignant and may be referred to as high-grade astrocytomas. Grade III astrocytomas are known as anaplastic astrocytomas. Grade IV astrocytomas are known as glioblastoma multiforme.
Mengxian Zhang, Susanne Kleber, Manuel Röhrich, Carmen Timke, Na Han, Jochen Tuettenberg, Ana Martin-Villalba, Jürgen Debus, Peter Peschke, Ute Wirkner, Michael Lahn and Peter E. Huber: Blockade of TGF-beta signaling by the TGFβR-I kinase inhibitor LY2109761 enhances radiation response and prolongs survival in glioblastoma. Cancer Research 2011, DOI:10.1158/0008-5472.CAN-11-1212
Most invasive type of glial tumor
Commonly spreads to nearby tissue
Includes distinct genetic subtypes
May be composed of several different kinds of cells (i.e., astrocytes, oligodendrocytes)
May have evolved from a low-grade astrocytoma or an oligodendroglioma
Common among men and women in their 50s-70s
More common in men than women
Accounts for 17 percent of all primary brain tumors
The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 2,500 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg where promising approaches from cancer research are translated into the clinic. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. The center is a member of the Helmholtz Association of National Research Centers. Ninety percent of its funding comes from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.
Dr. Sibylle Kohlstädt
Helmholtz Association of German Research Centres