Abstract
Glioblastoma (GBM) is a lethal brain tumor with limited therapeutic options. Therapeutic resistance arises from the collaboration among heterogeneous and highly plastic cellular entities and states conserved across GBM patients and the tumor microenvironment.Tumor cells adapt in response to the current standard of care and infiltration of innate immune cells, recurrently acquiring a mesenchymal state that drives therapeutic resistance.Moreover, the blood-brain barrier (BBB) poses challenges to the effectiveness and bioavailability of approved therapeutics, as well as the discovery of new ones.Our lab has developed synthetic locus control regions (sLCRs) as transcriptional reporters for glioblastoma subtypes, enabling the study of cell identity and state transitions in vitro and in vivo. We have combined this tool with validated cellular models for glioblastoma mesenchymal transition and therapeutic resistance to establish an in vitro phenotypic screening platform. Currently, we are utilizing this platform to identify treatment combinations and dosing schemes that aim to overcome innate immunity-driven resistance and synergize with the standard of care. As a proof-of-concept for a new generation of brain tumor target discovery platforms, we will present the setup of our platform and preliminary results for a class of BBB-penetrant drugs.