Glioma Longitudinal AnalySiS in Luxembourg (GLASS-LUX): ex vivo and in vivo Functional Profiling of Recurrent Gliomas

Diffuse gliomas are the most frequent and most dismal primary brain tumours in adults. These neoplasms represent a fatal disease with high disease burden. Patients with the most aggressive glioma, i.e. glioblastoma,normally die within 1-1.5 years after diagnosis. Patients with a lower grade diffuse glioma, are generally younger patients and have a variably longer survival, yet recurrence is inevitable. Recent studies have shown that gliomas undergo cellular and molecular evolution during disease progression, which is only partially explained by treatment-induced mutational signatures, suggesting that transcriptional and epigenetic changes may be the basis of cellular adaptation processes. Furthermore there is insufficient understanding of the underlying mechanisms of these changes and the therapeutic impact. Several multi-institutional efforts, including the international GLASS (Glioma Longitudinal AnalySiS) initiative, aim to systematically catalogue the temporal changes in gliomas at the genetic and epigenetic level. In this context, GLASS-LUX will expand on the overall GLASS objectives by focusing on the differential functional drug response of primary versus recurrent glioma. By applying a high content drug screen on patient-derived ex vivo 3D tumour organoids from paired longitudinal specimens, we will determine differences in drug sensitivity and predict personalized treatment options for recurrent glioma patients. A specific focus will be on drugs targeting epigenetic reprogramming and the elucidation of the underlying mechanisms. We will validate the ex vivo drug screen in unique patient-derived orthotopic xenografts (PDOX) generated from paired primary and recurrent glioma samples. This project adds a functional and translational dimension to the GLASS activities and will lead to the design of an innovative personalized clinical trial, which hopefully will spearhead a better outcome for patients with diffuse gliomas.