DDDR-43. Oncogenic miRNA-155 modulates copper homeostasis to attenuate oncolytic virus efficacy in Glioblastoma

Abstract Glioblastoma (GBM) is an aggressive and lethal form of primary brain tumor that rapidly progresses and infiltrates into adjacent normal brain areas. Despite extensive research and aggressive treatments with surgical resection, radiation, chemotherapy with temozolomide (TMZ), and tumor-treating fields (TTFields) devices, the median survival rate of GBM patients has remained at less than two years for decades. Thus, there is an urgent need for a paradigm shift in treating this disease. Engineered herpes simplex virus-1-derived oncolytic viruses (oHSVs) are a clinically approved biological therapy to kill cancer cells without harming the adjacent normal cells and are capable of inducing anti-tumor immunity. While oHSV has been FDA-approved for metastatic melanoma and has shown safety and therapeutic advantages, its clinical benefit has been limited to a small subset of GBM patients due to unknown resistance mechanisms. We newly identified miR-155, an endogenous small non-coding oncogenic microRNA, as responsible for the failure of these viro-immunotherapies to deliver on their promise in most patients with GBM. We found that miR-155 significantly modulates intracellular copper homeostasis to increase anti-viral responses, impairing oHSV efficacy. We demonstrated that inhibition of intratumoral miR-155 with miR-155-targeting Locked Nucleic Acid (LNA) restores oHSV replication and oncolysis in preclinical GBM models. These findings position miR-155 as a promising target to improve the therapeutic efficacy of oHSV in GBM patients.