Experimental viro-and genetherapy of malignant glioma

XIAP-expression contributes to the resistance of cancer to apoptosis. We have shown that a nearly complete knockdown of XIAP protein after infection of glioma and several other tumor cell lines with an adenovirus encoding XIAP antisense RNA (Ad-XIAP-as) promoted apoptosis whereas non-neoplastic cells resisted these effects. Ad-XIAP-as gene therapy induced cell death in orthotopic glioma xenografts, prolongs survival of tumor-bearing mice and collaborates with Apo2L/TRAIL in vivo. Using a Sp1-transcription factor inhibitor to partially knockdown XIAP expression by blocking the transcription of the XIAP gene, we could demonstrate that this incomplete downregulation of XIAP was not sufficient to directly induce cell death, but sensitized glioma cells to Apo2L/TRAIL-induced apoptosis. Altogether these data reinforce the possible role of XIAP as a therapeutic target in human glioma.

Supported by: German Cancer Council

(Contact person: Dr. U. Naumann)

The development of oncolytic adenovirus for glioma virotherapy is another focus of interest. Viruses are known as inductors of disease. But not every virus induces sickness in man. For this, so called “oncolytic viruses” could be used to fight against cancer. These viruses identify and solely replicate in tumor cells. Non-neoplastic cells were infected, but the virus does not replicate. As a consequence of replication, the tumor cell is killed. In our studies we are testing an adenovirus (Ad-DELO) which exclusively replicates in chemoresistant tumor cells. As a side effect, infection of the cells with Ad-DELO leads to enhanced sensitivity towards chemotherapy. Armament of Ad-DELO with a shRNA against a DNA repair enzyme, MGMT, further sensitizes infected cells to chemotherapy. Treatment of glioma bearing mice showed prolonged median survival of mice having a combinatorial therapy with Ad-DELO and temozolomide, a chemotherapeutic drug. Experiments were done as a joint research project in cooperation with the University of Munich (Klinikum Rechts der Isar) and the Institute for Pathology of the Charité in Berlin.

Supported by: Federal Ministry of Education and Research (Contact persons: Dr. U. Naumann, Tübingen; Prof. Dr. M. Weller, Zurich, Swiss)