Diffuse hemispheric glioma (DHG) is a brain tumor in children, adolescents and young adults with an average survival prognosis of less than two years and limited treatment options. A research team from MedUni Vienna and Vienna General Hospital identified increased stress through targeted genetic material (DNA) breaks while simultaneously inhibiting DNA repair in the tumor cell as a promising therapeutic approach. The study was recently published in the journal “Neuro-Oncology”.
The underlying molecular mechanisms of DHG were first characterized about ten years ago. Due to these specific characteristics, DHG is now listed as a separate type of brain tumor. So far, this knowledge has not been translated into more efficient therapy options. The current research work led by Johannes Gojo (University Clinic for Pediatrics and Adolescents) 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 accompanied by increased stress due to increased genetic material (DNA) damage. The research group identified this “vulnerability” as a new therapeutic approach and showed that targeted triggering of further DNA damage while simultaneously inhibiting DNA repair represents a promising therapeutic approach for this aggressive type of brain tumor.
The study was carried out as part of a TRANSCAN-2 EU project, which is 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 Europe-wide project follows international preliminary studies that showed that certain pediatric tumors have mutations in genes that can lead to defective repair of DNA damage, similar to BRCA-mutant 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 Jürgen Knoblich’s group (MedUni Vienna/Vienna General Hospital/IMBA), stem cells were modified so that they have the same mutations as those in the rare DHG brain tumor. This showed that typical molecular changes in this brain tumor trigger a mechanism for lengthening the telomeres (the protective caps of the chromosomes). This leads to a kind of “immortality” in the tumor cells, 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 targets for therapy,” says study leader Walter Berger. With international partners, it has been shown that tumor cells respond to combination therapy with PARP inhibitors. “These drugs block the repair of DNA damage – a mechanism that tumors rely on. In addition, a so-called topoisomerase inhibitor was used, an active ingredient 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,” explains lead author Anna Lämmerer, explaining the essential part of the therapy.
The therapeutic strategy developed here has already been successfully used in a patient with 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 achieved in collaboration between several different disciplines at the Comprehensive Cancer Center of MedUni Vienna and Vienna General Hospital as well as national and international collaboration partners.
Publikation: 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*.
two: 10.1093/neuonc/noae228
https://academic.oup.com/neuro-oncology/advance-article/doi/10.1093/neuonc/noae228/7903167