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Targeted attack against brain cancer

No. 20 | 26/05/2015 | by Koh

With the goal of enhancing the treatment of glioblastoma, the most aggressive type of brain cancer, scientists at the German Cancer Research Center (DKFZ) have been searching for specific structures that could lend themselves as drug targets. The researchers have now discovered an enzyme that drives the growth of these tumors. Agents that block this enzyme have already been approved as drugs and may consequently be utilized to halt the growth of these brain tumors.

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Kinases, which make up a large family of enzymes, are among some of the promising targets for advanced, customized anticancer drugs. They are the switchboards of cellular signaling pathways. Many mutations found in cancer cells lead to higher-than-normal activity of these signaling pathways and drive the growth of cancer cells. Substances that inhibit kinases block the transmission of such signals, thus slowing down uncontrolled cell division. A number of these substances have already been approved for use in cancer treatment.

“Particularly in the treatment of cancer types with extremely aggressive growth behavior such as glioblastoma, promising targets for attack by targeted drugs have not yet been discovered,” says Professor Peter Lichter from the German Cancer Research Center (Deutsches Krebsforschungszentrum – DKFZ). “Therefore, we have focused on searching for treatment strategies for this dangerous disease.”

The researchers, headed by Lichter, wanted to find out how the loss of these enzymes impacts the cell. To this end, they used specific RNA probes to turn off each of the kinase genes individually in glioblastoma cell samples obtained from patients. It turned out that about 80 of these enzymes are indispensable for the viability and growth of glioblastoma cells.

Based on specific characteristics of the tumors, the scientists assigned them to two distinct subgroups called mesenchymal and proneural gliomas. They found that each of these two tumor types depends on a specific set of kinases for survival.

All twelve samples studied from the mesenchymal group, which is particularly aggressive, robustly overproduced a kinase called AXL, a finding the scientists did not observe in proneural gliomas or in healthy brain cells.

When AXL is turned off, glioblastoma cells of the mesenchymal subtype are more susceptible to cell death by apoptosis and form fewer daughter colonies. These effects were not observed in cancer cells of the proneural subtype. 

Agents targeting AXL are already being tested in clinical trials to treat blood cancer. Study head Violaine Goidts and her team have now found out that in the Petri dish, mesenchymal glioblastoma cells respond well to treatment with these substances. 

For the cell culture experiments, the scientists used so-called “neurospheres.” To obtain these, cells from a patient’s tumor are cultured in vitro using specific growth factors. In the culture medium, the cancer stem cells present in the cell mixture form 3D tissue-like structures that are similar in composition to the original tumor. Therefore, they are particularly well-suited for testing the effectiveness of drugs or combinations of substances without using animals.

Experimental mice that had received glioblastoma transplantations survived longer without cancer symptoms if AXL had been silenced in the cancer cells. However, after about one month, the animals eventually developed cancer. This indicates that the kinase regulates cancer growth, but does not regulate carcinogenesis.

The researchers analyzed molecular databases and also found cases of AXL overexpression in other types of brain cancer as well as in cancers of the pancreas, bowel and ovaries. Most of these cases were associated with a poor prognosis.

“Our results suggest that it may be worthwhile to test the AXL inhibitor against glioblastomas of the mesenchymal group in clinical trials,” Lichter says. “In this case, it might be useful to combine it with other agents in order to prevent the development of resistance right from the start.”

Peng Cheng, Emma Phillips, Sung-Hak Kim, David Taylor, Thomas Hielscher, Laura Puccio, Anita Hjelmeland, Peter Lichter, Ichiro Nakano and Violaine Goidts: Kinome-wide shRNA Screen Identifies the Receptor Tyrosine Kinase AXL as a Key Regulator for Mesenchymal Glioblastoma Stem-like Cells. Stem Cell reports 2015, DOI: 10.1016/j.stemcr.2015.03.005

The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institution in Germany. More than 1,300 scientists at the DKFZ investigate how cancer develops, identify cancer risk factors and search for new strategies to prevent people from developing cancer. They are developing new methods to diagnose tumors more precisely and treat cancer patients more successfully. The DKFZ's Cancer Information Service (KID) provides patients, interested citizens and experts with individual answers to all questions on cancer.

Jointly with partners from the university hospitals, the DKFZ operates the National Center for Tumor Diseases (NCT) in Heidelberg and Dresden, and the Hopp Children's Tumour Center KiTZ in Heidelberg. In the German Consortium for Translational Cancer Research (DKTK), one of the six German Centers for Health Research, the DKFZ maintains translational centers at seven university partner locations. NCT and DKTK sites combine excellent university medicine with the high-profile research of the DKFZ. They contribute to the endeavor of transferring promising approaches from cancer research to the clinic and thus improving the chances of cancer patients.

The DKFZ is 90 percent financed by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg. The DKFZ is a member of the Helmholtz Association of German Research Centers.

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