Targeted Epigenetic Therapy for Relapsed Glioblastoma

Glioblastoma (GBM) is the most frequent and most aggressive glioma subtype with currently no curative treatment available. Despite standard therapy including surgical resection, radiation and concomitant chemotherapy, patients show a very rapid disease progression with only a mean life expectancy of 12-15 months. In particular, GBMs are characterised by a high degree of heterogeneity at the histological, cellular and molecular level, a major driving force, eventually contributing to treatment resistance and tumor relapse. The main objective of this project is to identify key drivers contributing to disease progression and therapy-related resistance in GBM taking into account inter-patient heterogeneity. To address this question, we have investigated exemplary longitudinal GBM specimen of initial tumors and tumors that relapsed after standard therapy. Preliminary data from targeted genomic sequencing of paired longitudinal samples indicate that tumor recurrences accumulate somatic mutations in epigenetic effectors. Therefore, we plan to profile our existing cohort of paired longitudinal GBM patients, both at the genomic and epigenetic level using targeted sequencing, methylation profiling and chromatin-immunoprecipitation (ChIP) methodologies. In parallel, we will recapitulate clinical evasion strategies based on patient-derived organotypic 3D-cultures and orthotopic xenografts (PDOXs) from initial and relapsed GBM samples of the same patients. By collating an appropriate selected epigenetic drug library, based on the target genes identified in step one, we will functionally validate the target genes and selected compounds: (1) in vitro: 3D-cultures of patient-derived spheroids, (2) ex vivo: 3D-cultures of patient-derived spheroids on brain explants, (3) in vivo: patient-derived xenografts. Thus, PDXs will enable pre-clinical personalised epigenetic-centered treatment approaches overcoming resistance associated with heterogeneity and clonal evolution. In conclusion, the current project will contribute to our understanding on how distorted epigenetic mechanisms contribute to tumor recurrence in GBM and propose novel personalized treatment approaches for relapsed GBM patients.