RBIO-08. INVESTIGATING THE EFFICACY AND MECHANISMS OF TUMOR TREATING FIELDS IN RADIATION-RESISTANT GLIOBLASTOMA MODELS

Abstract Glioblastoma (GBM) is an aggressive malignant brain tumor with poor prognosis despite current treatment regimens involving surgical resection, radiation, temozolomide, and the newly approved use of Tumor Treating Fields (TTFields; a noninvasive, transdermal, administration of alternating low-intensity, intermediate-frequency electrical fields). Acquired radiation resistance, thought to be partially driven by brain tumor-initiating cells (BTICs), underscores therapeutic challenges in GBM. While clinical evidence supports the therapeutic benefit of TTFields, its precise mechanisms of action are poorly understood, and TTFields impact on radiation-resistant GBM is unknown. To better understand the effect and mechanism of TTFields in radiation-resistant GBM, we utilized patient-derived xenolines (PDX) and their acquired radio-resistant pairs to assess changes in viability and molecular signaling. PDX were previously developed by subcutaneous implantation of patient GBM cells into immunodeficient (nu/nu) mice. Acquired radiation-resistant PDX were generated through serial in vivo radiation. TTFields were administered with the Novocure inovitroTM device in a cooling incubator to maintain 37oC sample temperature in the ceramic well plates of the device. PDX were cultured on geltrex-coated coverslips under serum-free conditions. Cytotoxicity was quantified 72h post TTFields with crystal violet. Molecular signaling was captured with PamChip peptide-based kinase activity arrays and RayBiotech proteomic arrays. We found that TTFields inhibit cell growth in both parental and acquired radiation-resistant PDX. Differences in molecular signatures between the PDX lines suggest molecular mechanisms of TTFields sensitivity signatures and interactions with acquired radio-resistant PDX. We are currently trying to generate TTFields-resistant PDX lines through serial treatment with plans to examine BTIC populations relative to TTFields efficacy. We also plan to explore targetable TTFields-induced alterations in the future.