Dnar-13. targeting the dna damage response in glioblastoma propagating cells: from molecular mechanisms to precision medicine

Abstract Glioblastoma (GBM) is the most aggressive and lethal primary tumor of the central nervous system (CNS). Despite surgical resection and a combination of radiotherapy and alkylation chemotherapy, the median survival for patients with newly diagnosed GBM is only ~ 14 months. Among the many challenges confronting clinicians are subpopulations of tumor-propagating cells named GBM Stem-like Cells (GSCs), which have been proposed to drive treatment resistance and foster tumor relapse. At the mechanistic level, GSCs have been shown to display constitutive activation of the DNA damage response (DDR) due to chronic replication stress (RS), which enhances their ability to repair the DNA lesions induced by chemoradiation. Thus, developing new therapeutic strategies against glioblastoma is of paramount importance. Cell cycle regulation and DNA damage response are two crucial molecular networks altered in most cancer types. In this context, we have previously identified a DNA repair and cell cycle gene expression signature that results in the classification of GBM tumors in two major groups, G1 and G3, which differ in the expression of survival and proliferation pathways. Using bioinformatics analysis of the GLASS consortium database, we have created an exhaustive oncopanel of the molecular alterations defining the G1 and G3 groups. Furthermore, using G1- and G3-patient-derived GSC cell lines as experimental models, we have identified crucial differences in the mechanisms orchestrating the cell cycle, DDR, and treatment resistance between G1 and G3 cells. Finally, we have also identified group-specific therapeutic strategies combining repositioned FDA-approved drugs with the inhibition of crucial DDR factors. Our long-term goals are i) to understand the molecular basis behind the differential response to DNA damage and replication stress developed by G1 and G3 cells and ii) to propose group-specific, DDR-based combination therapies that prevent treatment resistance and promote long-lasting treatment.