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A new study has identified miR-181d, a naturally occurring microRNA that regulates gene expression, as a potential mediator of glioblastoma (GBM) treatment sensitivity. The study team found that higher miR-181d levels were associated with GBM “exceptional responders,” the rare patients who experience unusually durable responses to therapy.
The data suggest miR-181d improves treatment response by suppressing multiple resistance pathways. Prior work showed miR-181d suppresses MGMT, a key mediator of temozolomide resistance. In this study, the authors show that miR-181d also suppresses RAD51, a critical DNA repair protein, thereby increasing tumor sensitivity to radiation and other DNA-damage therapy. Lower RAD51 expression in patient tumors was associated with longer survival, consistent with prior reports.
In preclinical models, intracranial delivery of miR-181d prior to radiation improved tumor control and survival. In an immunocompetent recurrent GBM mouse model, median survival increased from 41 days with radiation alone to 58 days with the addition of miR-181d, with roughly half of treated animals surviving beyond three months. Re-implantation of GBM cells into long-term survivors resulted in lower tumor burden by bioluminescence imaging, consistent with durable anti-tumor immune recognition.
These findings support the concept that miR-181d may both enhance tumor sensitivity to standard therapy and help sustain anti-tumor immunity. The authors are now working toward a clinical trial evaluating local delivery of miR-181d during surgery.