P17.29IDENTIFICATION OF NOVEL MOLECULAR TARGETS FOR TEMOZOLOMIDE-BASED THERAPIES AGAINST GLIOBLASTOMA: A COMPREHENSIVE SHRNA-BASED SCREEN OF DNA REPAIR FACTORS

• Published in: Neuro-oncology (Charlottesville, Va.) Vol. 16; no. Suppl 2; p. ii93
• Main Authors: Erasimus, H., Fritah, S., Haan, S., Niclou, S.P., Van Dyck, E.
• Format: Journal Article
• Language: English
• Published: Oxford University Press 01-09-2014
• Subjects: Poster Presentations
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/nou174.358

Glioblastoma multiforme (GBM) is an aggressive brain tumor with poor prognosis (the median survival of GBM patients is 14.6 months). Current GBM treatment, which consists of surgical resection followed by radiation therapy and temozolomide (TMZ) chemotherapy, is faced with the development of resistance. The DNA-alkylating agent TMZ exerts its cytotoxic function by damaging DNA and inducing tumor cell death. However, efficient repair and/or tolerance of TMZ-induced DNA lesions can mediate resistance to chemotherapy. One such important factor is the O-6-methylguanine-DNA methyltransferase (MGMT). In addition to mediating the cellular response to anti-cancer therapeutics, DNA repair pathways also help cancer cells to cope with the extra load of endogenous DNA damage that occurs as a consequence of the tumorigenic process. Which DNA repair molecules are important for GBM survival in the absence of chemotherapeutic treatment and/or in response to anti-cancer genotoxics remains, however, vastly unknown. In this project, we have addressed this question by developing a large-scale differential shRNA screen specifically targeting components of the DNA-damage response (DDR). This includes not only DNA repair genes, but also genes involved in cell cycle checkpoints, DNA damage tolerance pathways and chromatin factors that facilitate DNA repair. Pooled shRNAs will be introduced in selected GBM-derived, cancer stem like cells (GSCs), as well as control non-cancer cells. Genes that appear essential to the survival of GSCs, but dispensable to non-cancer cells, either in the absence of treatment, or following exposure to TMZ, will be selected. Subsequently, promising candidates will be validated individually in vitro, and the best candidates will be further validated in vivo, using patient derived xenograft animal models developed in the laboratory. This will allow us to monitor, in a pre-clinical setting, the impact of depleting selected DDR factors, on tumor formation and response to TMZ. Long-term perspectives include determining the potential of the selected DDR components as druggable, therapeutic targets in the treatment against GBM.