Stratified Glioblastoma Management: Leveraging pre- and intraoperative molecular subclassification and longitudinal surveillance for tailored surgical planning through liquid biopsies.

• Applicants: Professor Dr. Franz Ricklefs; Professor Dr. Ulrich Schüller
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology ; Molecular and Cellular Neurology and Neuropathology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 550889519

This project is aiming at establishing a diagnostic pipeline that allows pre- and intraoperative molecular brain tumor sub-/classification and longitudinal molecular follow-up. Based on this classification, surgical intervention and adjuvant therapy shall be planned and adapted based on our previous work showing that GBM belonging to the mesenchymal (MES) subtype do not necessarily benefit from a gross total resection and may even be harmed if a supramarginal resection is performed. We hypothesize, based on our previous work and preliminary data, that pre- and intraoperative molecular tumor classification is feasible on CSF and tumor tissue, respectively. Respective results shall reliably predict what the post-operative work up of FFPE tumor tissue will confirm using well established global DNA methylation profiling by array methylation technology. If our feasibility study will obtain the expected results, we plan to translate our findings into a prospective clinical trial with the aim to significantly increase the quality of life of a distinct subset of glioblastoma patients.To allow a precise longitudinal surveillance of our patients to detect treatment success and failure we will obtain DNA from CSF and fresh tissue during recurrence and will perform additional methylation profiling. Objective 1: “Preoperative CSF sequencing”. Through a preoperative subclassifation of GBMs using Nanopore sequencing of ctDNA from the CSF we will obtain important information for the personalized planning of the surgical approach in precision medicine. Objective 2: “Intraoperative tumor classification”. This objective aims to enable the fast subclassification of GBM methylation subtypes during surgery using Nanopore sequencing of fresh tumor tissue. Objective 3: “Comparison of pre-, intra- and postoperative analyses”. This aim will prove that subclassification through Nanopore sequencing correlates to the routinely used DNA methylation analyses of FFPE material by Methylation EPICv2 arrays. Objective 4: “Enabling epigenetic surveillance of glioblastoma subgroups during treatment for the discrimination of treatment success and failure.” This aim will provide an epigenetic framework to distinguish methylation subclass transition and or pseudoprogression during treatment.

• DFG Programme: Research Grants