Investigating tumour suppressor mutations in GBM which impact on tumour angiogenesis

• Applicant: Professor Dr. Rainer Glass
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2013 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 234086640

GBM are invasive and highly angiogenic tumours that origin from neoplastic neural precursor cells (NPCs). The vast majority of primary GBM is driven by genetic mutation in key tumour suppressor genes concomitant with accelerated activity of different proto‐oncogenes. With these key signal transduction pathways driving gliomagenesis separate tumour‐subtypes, which differ in prognosis and treatment characteristics, could be identified and are now termed proneural, classical or mesenchymal. Previously, we identified VEGF‐A as a tumour‐derived chemoattractant and proliferative factor for mouse and human NPCs. Our current preliminary results indicate that neoplastic transformation of (VEGFresponsive) NPCs converts these physiological stem cells into angiogenic (VEGF‐secreting) GBM cells.Our pilot studies suggest that consistent GBM‐subtype specific angiogenic patterns exist in mouse‐ and human‐GBM cells. In proneural GBM the p53‐status appears to be an important factor determining the expression levels of proangiogenic signalling molecules like VEGF‐A, while VEGF‐C/VEGFR3 signalling can constitute a therapeutic target for the remaining GBM‐subtypes. Consequently, we will investigate if distinct genetic markers in GBM have predictive power for individualised anti‐angiogenic treatment. Towards this end we have established subtype‐specific cell‐cultures from GBM‐biopsies and also from transgenic mice, orthotopic implantation models and transgenic mouse lines for the generation of GBM. Phenotypic and genetic analysis of these models will indicate the relation of GBM‐subtypes and p53‐status with the extent of GBM‐angiogenesis and with specific angiogenic signalling pathways. The therapeutic impact of VEGFR2 or VEGFR3‐blockade in different GBM subtypes will be explored in vitro and in vivo. After the clinical failure of anti‐angiogenic treatment using the VEGF‐A blocker bevacizumab it was suggested to restrict the application of the VEGF‐A blocker bevacizumab to patients suffering from proneural GBM. It will be interesting to determine if the p53‐status in proneural GBM provides a refined marker for patients potentially profiting from bevacizumab application. In addition our experiments are also suited to identify new therapeutic strategies for GBM‐patients suffering from the classical or mesenchymal GBM‐subtype.

• DFG Programme: Research Grants
• Co-Investigator: Dr. Roland Kälin