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GBM evades toxicity from therapies by activating genetic programs, which induce damage repair, escape from the immune system, and regress to a more undifferentiated state. This response is mediated at the epigenetic level by the activation of a multitude of oncogenes which are often redundant, making their targeting extremely challenging, and current therapies largely ineffective. MicroRNAs, short non-coding genes which regulate protein expression, are a promising solution to this problem, as we recently found that in normal cells a specific group of them is the natural gatekeeper of a large component of this epigenetic survival response. We have also observed that microRNA genes produce previously unrecognized accessory RNA sequences, which are leftovers from a process of sequence “pruning”, and which persist within the cell, providing a tool for expanded gene therapy applications.