Multikinase inhibitors in globlastoma

Standard treatment for GBM, IDH wildtype, consists of surgical resection followed by adjuvant radiotherapy and chemotherapy with temozolomide. Despite intense research activity in the field, with a consistent number of novel treatments proposed, the expectations were substantially disappointed. The studies we present here are focused on two drugs already proposed for GBM: the multikinase inhibitors axitinib and regorafenib. We previously demonstrated that axitinib triggers cellular senescence through a mechanisms involving ROS increase and ATM activation (1). Co-treatment with the antioxidant N-acetyl cysteine (NAC) prevents axitinib-induced senescence in normal cells, i.e. endothelial cells, without reducing axitinib efficacy on GBM tumor cells. Here we investigated the hypothesis that NAC co-treatment might protect normal cells from axitinib adverse effects. Using mouse orthotopic tumor xenografts of glioma stem cells (GSCs), we demonstrated that NAC is effective in preventing axitinib induced senescence in brain tumor xenografts as well as in filter organs. Our preliminary data suggest that endothelial cells benefit from NAC co-treatment, which eventually results in endothelial cells protection. If confirmed, these data support the possibility of repurposing NAC as a co-treatment to i) reduce axitinib off-target effects on non-tumor tissues; ii) promote normalization of tumor vessels, allowing an improved drug delivery to the tumor. The multikinase inhibitor regorafenib was recently approved as a therapy for GBM relapsed patients on the basis of the encouraging results of the phase II clinical study REGOMA (2). Despite its introduction into clinical practice, little is known about the molecular mechanisms that regulate GBM response to regorafenib. We preliminary conducted an in vitro characterization of GSCs exposed to regorafenib. Overall, the drug significantly reduced cell growth of 2D tumor cell cultures and of 3D tumor spheroids. Strikingly, this effect was paralleled by transcriptional regulation of epithelial to mesenchymal transition genes and by an increased ability of surviving tumor cells to invade the surrounding matrix in the 3D model, suggesting that regorafenib might elicit a pro-invasive phenotype, an issue already described upon targeting Vascular Endothelial Growth Factor pathway. Finally, we present preliminary data from our ongoing CRISPR-Cas9 chemogenomic screening on regorafenib-treated GSCs. References Mongiardi et al (2019), Oncogene. doi: 10.1038/s41388-019-0798-2 Lombardi et al (2019), Lancet Oncol. doi: 10.1016/S1470-2045(18)30675-2