Glioblastoma (GBM) is the most common and invasive adult brain cancer. The rapid invasion of cancer cells into the normal brain is a major cause of treatment failure, yet the mechanisms that regulate this process are poorly understood. We have identified a novel mechanism of brain cancer invasion. We show that downregulated in renal cell carcinoma (DRR), which is newly expressed in invasive gliomas, recruits AKT to focal adhesions. This DRR- induced pathological relocalization of AKT bypasses commonly altered upstream signaling events and leads to AKT activation and invasion. We also developed an oligonucleotide therapeutic that reduces DRR expression and prevents glioma invasion in an in vivo preclinical model of the disease. Our findings identify DRR as a novel GBM target and show that oligonucleotides targeting DRR is a novel therapeutic approach for the treatment of DRR-positive GBMs.