Abstract 2708: Prediction of radiosensitivity in glioblastoma tumors after standard and low dose rates of ionizing radiation

Glioblastomas (GBM) exhibit high infiltration into the brain parenchyma, impairing surgical resection and leading to recurrence. After standard of care, including tumor resection, radiation therapy (RT) and chemotherapy, most tumors recur at the tumor margins. These tumors show an increased aggressiveness and therapeutic resistance. The underlying mechanisms for these cellular transitions are unclear. Research suggests that RT paradoxically alters the GBM microenvironment promoting cancer cell survival upon recurrence. Some of these alterations in the irradiated tumor microenvironment include increased oxidative stress, hypoxia, cellular senescence, vasculogenesis and ECM compositional and structural changes.We use an ex vivo platform that combines the hallmarks of GBM tumors: high cellularity, the neural circuitry that surrounds tumors, a hydrogel-based ECM that mimics the biophysical and biochemical properties of GBM and the intermittent hypoxic environment present in native tumors, to characterize and evaluate the therapeutic benefits of RT and the underlying mechanisms of neurotoxicity to more effectively treat the tumor while minimizing the deleterious side effects.Our results show that radiation treatment increases glycolysis in tumor cells and that immediate response to radiation produces a more significant ATP production decrease in hypoxia environments. We have also investigated the long-term energy production and mitochondrial dysfunction in the tumor cells at different radiation rates and under low oxygen environments. Interestingly, the maximal respiration capacity in GBM cells increases with the presence of conditioned media from neuronal cultures in normoxic conditions but has the opposite effect in hypoxic environments.Proliferation ability of cells on stiffer matrices is greater than that on softer matrices. In the presence of an altered biomechanical microenvironment, a stiffer tumor tissue is more prone to immunosuppression and epithelial-mesenchymal transition. After cells are irradiated, the cell migration is different with different matrix stiffness. Moreover, softer matrices are more likely to promote cellular radiosensitivity, while stiffer matrices can inhibit cellular radiosensitivity.The use of preclinical tools that can model key features of the GBM and normal brain tissue can give a better understanding of the spatial-temporal characteristics of tumor microenvironment alterations during progression and response to therapy. Citation Format: Isabella Rivera, Ryan Yao, Kim Selting, Catherine Best-Popescu, Brendan Harley, Sara Pedron-Haba. Prediction of radiosensitivity in glioblastoma tumors after standard and low dose rates of ionizing radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2708.