In Vitro Models From Pediatric Brain Tumors

Tumors of the Central Nervous System (CNS) represent the leading cause of cancer-related deaths in children. Current treatment options are not curative for most malignant histologies, and intense preclinical and clinical research are necessary to develop more effective therapeutic interventions against these tumors, most of which meet the FDA definition for orphan diseases. The majority of malignant CNS tumors in children and adolescents belong to two broad histologic tumor entities: those of glial origin, such as high-grade glioma (HGG)and ependymoma (EPN), and those of neuronal origin, also identified as embryonal tumors, that include medulloblastoma and AT/RT(1). Over the last few years, whole-genome sequencing, gene-expression profiling and genome-wide methylation studies have greatly deepened our understanding of the biology and genetics of these tumors, allowing for robust stratification in clinically relevant molecular subgroups. The advancement of single-cell omics over the last decade have highlighted the enormous heterogeneity of tumors, a complex mixture of co-existing cancer subclones and supportive normal cell populations.

However, current treatments have remained largely static, and 5-year survival rate for children with malignant CNS tumors only achieves a modest 57.5%.

More effective treatment strategies should include novel chemotherapeutic agents that take into account high intrinsic tumor heterogeneity as well as the complex regulations of transcriptional and translational mechanisms that control protein expression. Identification of novel drugs and treatment strategies is further limited by the paucity of appropriate preclinical models, which mirror the molecular characteristics of distinct tumor subgroups.

We propose to establish patient-derived in vitro models to predict chemotherapeutic drug sensitivity/resistance in malignant pediatric CNS tumors. Next, we propose to perform molecular analyses in tissues of pediatric CNS tumors to determine whether in vitro findings have clinical correlates.