Next Generation Targeting of OncomiRs for Pediatric Glioma Therapy

Key Words: Brain and Other Central Nervous System Tumors, Neuroblastoma, Treatment

Glioblastoma multiforme (GBM) is a common pediatric cancer in the US, causing tens of thousands of deaths each year and its incidence is on the rise. MicroRNAs (miRNAs or miRs) are small non-coding RNAs that are often misregulated in cancers (also called oncomiRs) including pediatrics GBM. In particular, miR-21 and miR-10b are upregulated in GBM, and direct evidence exists to show that its over-expression causes GBM in pediatric patients. Interestingly, the tumors induced by over-expression of miRs depend on the continued expression of the miRNA for survival since, if the miRNAs are withdrawn, the tumors rapidly regress via apoptosis. Here, we propose to exploit this striking nature of oncogene addiction to develop therapeutics tailored to antagonize crucial oncomiRs for pediatrics GBM therapy. However, targeting single oncomiRs could dampen the long terms therapeutic effect. Therefore, inhibiting multiple oncomiRs simultaneously and selectively using novel delivery systems may offer a novel avenue for pediatrics GBM therapeutics. In a collaborative effort, we published an approach to target antimiR-21 peptide nucleic acids (PNAs) to the brain by hyperbranched polyglycerol (PLA-HPG) based nanoparticles (NPs) with spectacular effects in vivo. PNAs are a synthetic DNA mimics in which the phosphodiester backbone is substituted with a neutral N-(2-aminoethyl) glycine backbone. PNAs can bind single-strand targets with high specificity and affinity and are not susceptible to nucleases, making PNAs ideal molecules for targeting miRNAs. We propose a multi-disciplinary project focused on a common aim of translating next-generation technology to advance delivery, targeting and efficacy of this promising pediatrics GBM therapy. The overall goal is effective delivery of stable PNAs targeting oncogenic miR-21 and miR-10b in miRs addicted GBM by PLA-HPG NPs. As proof of principle, we propose to test our strategy in GBM rat models with the ultimate goal of preparing a personalized drug suitable for clinical trials.