MODL-22. DEVELOPMENT OF A PATIENT-DERIVED MODEL BIOBANK TO PROVIDE AN ACCURATE TOOL DECIPHERING BRAIN TUMOR INITIATION, PROGRESSION, AND THERAPEUTIC RESISTANCE

Abstract

Abstract Brain cancers are the most incident and deadliest tumor types in pediatric and young adult populations. Among them, several histotypes are characterized by their molecular drivers and co-alterations currently guiding our therapeutic strategies. Due to inter- and intra-tumoral heterogeneity, those tumors are becoming rapidly chemo- and radioresistant. To encompass all their intrinsic and extrinsic mechanisms of therapeutic resistances, there is an urgent need to generate accurate brain tumors’ modeling to predict therapeutic responses. Patient-derived cell lines (PDCL) remain for now the most reliable model to estimate and mimic evolutive situation. Main difficulties rely on the derivation methods themselves (2D vs. 3D, in vitro vs. in vivo), but also on the methods to validate their molecular similarities comparatively to the primary tumors. Here we collected, through the PEDIAMODECAN program, 104 fresh brain tumors (e.g., 23 pilocytic astrocytomas (PA), 3 low-grade gliomas (LGG), 13 supra-tentorial high-grade gliomas and 10 DIPG/DMGs, 19 ependymomas, 19 medulloblastomas, 17 other rare entities) to generate PDCL and patient-derived xenografts (PDX). Using Next-Generation Sequencing (NGS), methylome assay and RNA sequencing, we were in capacity to underline similarities with initiated samples. Looking to derivation itself, we successfully maintained 80% samples in 2D cultures and 54% were derived in PDX. As expected, the PA/LGG group shows the higher percentage of failure of PDX generation (90%) and all established PA/LGG PDCLs were limited to a low number of passages. Nevertheless, for high-grade subtypes, PDX generation rate increased to 85,7%. No correlation was observed between derivation success and time between surgical removal and dissociation process. Whereas PDX histology was reproducing the same microscopic features than the primary tumors, methylome assay proves to be a good method to confirm original histotype group. Furthermore, those primary models afford a large biobank reproducing the diversity of pediatric brain tumors and were easily drug screened.