PROJECT SUMMARY Patients diagnosed with glioblastoma (GBM) have a median overall survival of less than two years even after receiving multimodal therapies. Multiple factors account for treatment resistance including: 1) Inability of therapies to cross the blood-brain barrier to reach invading cells; 2) GBM’s molecular heterogeneity and overlapping escape mechanisms that overcome targeted therapies; 3) Evasive mechanisms that render GBMs resistant to immunotherapy. Therefore, there is an unmet need for GBM treatment approaches that address multiple resistance mechanisms. The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily, which was discovered as a transmembrane receptor for the products of nonenzymatic glycation and oxidation of proteins. RAGE is expressed by glioma cells and is activated by ligands present in the GBM tumor microenvironment (TME). Activation of RAGE stimulates multiple signaling pathways that promote GBM progression. Recently, we demonstrated that genetic ablation of intracellular RAGE in gliomas inhibited multiple oncogenic pathways that not only regulate glioma growth and invasion, but also improve the efficacy of immunotherapies by inhibiting galactin-3 production and promoting an immunologically “permissive” TME. Based on these observations, we propose to target RAGE as a multifaceted therapy for GBM. Our central hypothesis is that RAGE inactivation will suppress oncogenic pathways that are important for GBM growth and invasion and enhance responses to immunotherapy. Three aims are proposed to test this hypothesis. Aim 1 will optimize a multifunctional anti-RAGE oligo-based strategy to target GBM. As an alternative approach to blocking RAGE extracellular receptor with small molecules, we propose to inhibit its signaling by optimizing the design of anti-RAGE antisense oligos. The “scavenger” receptor property of RAGE will be exploited to develop multifunctional oligos that are rapidly internali