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Differentiation therapy for GBM through synergic action of 11 miRNAs/drugs delivered via polymeric nanoparticles

Background: Glioblastoma (GBM) is one of the most fatal type of Gliomas. 70% of patients experience recurrence related to drug resistant cancer stem-like cells (CSCs). CSCs-targeted therapies might overcome GBM drug resistance and recurrence. "Differentiation therapies" could be a possible way to achieve this goal, but several challenges remain unresolved: CSCs are difficult to reach; can "evolve" over time, thus leading to amplification of differentiation-resistant clones. Synergic therapies capable to simultaneously treat increased survival, apoptosis resistance and trigger irreversible differentiation of CSCs might be more effective. MicroRNAs (miRNAs) are small noncoding RNAs, which exert gene regulatory functions on the majority of mRNA (targets), and have been shown to control a number of pathways involved in differentiation, survival and proliferation of NSCs. Thus, there is a vast prospective for the development of miRNA-based therapies. Despite miRNAs need to synergize to achieve greater effects, they were mostly administered singularly in tumours. Rationale and Goal: We identified a pool of 11 miRNAs (therefrom the "miRNA-pool") required and sufficient to sustain neuronal differentiation of adult murine NSCs. All the miRNA of this pool are conserved in humans and deregulated in GBM. We will exploit the synergic action of the miRNA-pool in a nanomedicine approach to achieve a "differentitiation therapy" for GBM The project will provide: -Mechanism of the miRNA-pool action in cell subpopulations of patient derived GBM (CSCs Vs. non-CSCs), novel biomarkers/druggable targets. -Evidence of the therapeutic efficacy of the synergic action of the miRNA pool on GBM growth and recurrence in vitro. -Efficacy of the miRNA-pool delivery in a relevant preclinical model of human GBM enhanced by a nanomedicine approach.

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Davide De Pietri Tonelli
Davide De Pietri Tonelli
Neurobiology of miRNA
Total budget: 596.000,00€
Total contribution: 596.000,00€