DNAR-09. GB13 IS A POTENT NEOADJUVANT TREATMENT OPTION FOR IL13RA2-EXPRESSING GBM AND IMPROVES STANDARD-OF-CARE THERAPY

Abstract Glioblastoma (GBM) is the most common primary adult brain cancer and is uniformly fatal. Despite maximum safe surgical resection followed by radiation and temozolomide chemotherapy, current median survival is 14-18 months. GB13 is a novel therapy for treatment of GBM and received Orphan Drug Designation by the Food and Drug Administration (FDA) for treatment of malignant gliomas. GB13 specifically targets the tumor-restricted IL13Ra2 receptor that is highly expressed in GBM, among other cancers, but not on non-cancerous cells. IL13Ra2 represents a clinically viable target for directed therapies and is being explored by numerous approaches. Previous data demonstrate that GB13 potently kills GBM and diffuse midline glioma (DMG) cells and tumors, IL13Ra2 correlates to GB13 sensitivity and, GB13 can significantly improve the cytotoxic effects of ionizing radiation (IR) when tested in models of pediatric diffuse midline glioma. In the current studies, the ability of GB13 to enhance the effects of IR were explored using IL13Ra2-positive and negative GBM models. Major findings demonstrate that neoadjuvant GB13 treatment increases cytotoxic effects of IR, enhances cell apoptosis and decreases cell viability. These results were not observed in IL13Ra2-negative settings, demonstrating the necessity for this clinical target. Mechanistically, increased cell death was caused by sustained apoptotic signaling through caspase-mediated pathways. Preclinical models support the use of GB13 prior to radiation for decreased tumor proliferation. Using multiple models, our results identify a temporal benefit for treating GBM tumors prior to IR and this should be tested in future clinical studies.