The underlying molecular mechanisms of DHG were first characterized a good ten years ago. Due to these specific characteristics, DHG is now listed as an independent brain tumor type. However, it has not yet been possible to translate this knowledge into more efficient treatment options. The current research work led by Johannes Gojo (Department of Pediatrics and Adolescent Medicine) and Walter Berger (Center for Cancer Research) was able to show that the tumor cells use a special mechanism to become "immortal". However, this mechanism is associated with elevated stress due to increased damage to genetic material (DNA). The research group identified this "vulnerability" as a new therapeutic approach and showed that the targeted triggering of further DNA damage with simultaneous inhibition of DNA repair represents a promising therapeutic approach for this aggressive type of brain tumor.
The study was conducted as part of a TRANSCAN-2 EU project investigating the potential of so-called PARP inhibitors for pediatric solid tumors. PARP inhibitors have revolutionized the treatment of breast, ovarian and prostate cancers with defective DNA strand break repair mechanisms, also known as "Breast Cancer" (BRCA) gene-mutated tumors. The pan-European project builds on preliminary international studies showing that certain pediatric tumors have mutations in genes that can lead to defective DNA damage repair, similar to BRCA-mutated tumors in adults.
Combination therapy increases the stress pressure on tumor cells
Histones are protein molecules that structure the position and function of DNA and are therefore involved in the functionality and regulation of gene expression. In collaboration with Christian Lehmann in the group of Jürgen Knoblich (MedUni Vienna/Vienna General Hospital/IMBA), stem cells were modified so that they exhibit the same mutations as in the rare brain tumor DHG. The results showed that typical molecular changes of the brain tumor again trigger a mechanism to lengthen the telomeres (the protective caps of the chromosomes) in the stem cells. This leads to a kind of "immortality", but also to increased DNA damage. "The tumor cells depend on a combination of mutations that enables them to survive, but at the same time creates novel vulnerabilities for therapies," says study leader Walter Berger. Together with international partners, it was shown that tumor cells respond to a combination therapy with PARP inhibitors. "These drugs block the repair of DNA damage - a mechanism on which the tumors depend. In addition, a so-called topoisomerase inhibitor was used, an agent that causes DNA breaks and increases the stress on the tumor cells. This combination leads to irreparable damage, so that tumor cells die or their growth is stopped," says first author Anna Lämmerer, explaining the essential part of the therapy.
The therapy strategy developed here has already been successfully applied to a patient with a particularly aggressive DHG. "The tumor, which was previously resistant to radiation, responded to this new therapy. Our findings provide the basis for further international studies on PARP inhibitor combinations in childhood brain tumors," adds study leader Johannes Gojo.
These important results with high clinical relevance were obtained in collaboration with several different disciplines at the Comprehensive Cancer Center of MedUni Vienna and Vienna General Hospital as well as national and international collaboration partners.
Publication: Neuro-Oncology
Alternative lengthening of telomere-based immortalization renders H3G34R-mutant diffuse hemispheric glioma hypersensitive to PARP inhibitor combination regimens
Anna Laemmerer, Christian Lehmann, Lisa Mayr, Katharina Bruckner, Lisa Gabler, Daniel Senfter, Philipp Meyer, Theresa Balber,Christine Pirker, Carola N. Jaunecker, Dominik Kirchhofer, Petra Vician, Michelle Griesser, Sabine Spiegl-Kreinecker, Maria T. Schmook, Tatjana Traub-Weidinger, Peter Kuess, Franziska Eckert, Aniello Federico, Sibylle Madlener, Natalia Stepien, Bernhard Robl, Alicia Baumgartner, Johannes A. Hainfellner, Karin Dieckmann, Christian Dorfer, Karl Roessler, Nina S. Corsini, Klaus Holzmann, Wolfgang M. Schmidt, Andreas Peyrl, Amedeo A. Azizi, Christine Haberler, Alexander Beck, Stefan M. Pfister Julia Schueler, Daniela Loetsch-Gojo, Jürgen A. Knoblich, Walter Berger*, Johannes Gojo*
doi: 10.1093/neuonc/noae228