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INVESTIGATING NEUROTOXICTY OF BRAIN AND GLIOBLASTOMA TUMOUR CONTROL WITH FLASH RADIATION AND PARP INHIBITORS
Abstract
Background and Aims
Radiotherapy is part of the standard of care in treating glioblastoma. However, to completely encompass infiltrative disease, irradiation of normal brain tissue is unavoidable and results in both acute and long-term neurotoxicity. Recent studies show that whole brain irradiation using FLASH radiotherapy can reduce neurotoxicity compared to conventional radiotherapy. PARP inhibitors have also been shown to enhance the radiosensitivity of multiple cancers and reduce neuroinflammation in many brain diseases. Here we investigate if combining PARP inhibitors with hemi-brain FLASH radiotherapy could further reduce radiation-induced neurotoxicity while maintaining tumour-killing efficacy.
Methods
For normal tissue toxicity, C57BL/6 mice were irradiated once with 20 Gy to the right hemisphere, and changes in the brain were studied by preclinical imaging and histology. For tumour response, athymic nude mice with subcutaneous U87MG tumours were used. Mice were randomly allocated to the following groups: control, conventional irradiation (Conv-IR, 0.1 Gy/s), FLASH irradiation (FLASH-IR, 2000 Gy/s), PARP inhibitor (PARPi, pamiparib, oral gavage, 12.5 kg/mg, twice daily for 7 days), PARPi+Conv-IR, and PARPi+FLASH-IR.
Results
Combining PARPi with Conv-IR or FLASH-IR showed a ~2-fold reduction in the tumour growth rate compared to the control and PARPi groups. While a significant reduction in tumour growth rate was observed in mice treated with PARPi+Conv-IR compared to Conv-IR, a smaller difference was observed between mice treated with PARPi+FLASH-IR and FLASH-IR. One week after PARPi+Conv-IR, a significant reduction in body weight was observed, with no significant weight change in any of the other groups. An increase in brain perfusion in the irradiated hemisphere was observed in mice treated with Conv-IR, while no differences between hemispheres were seen in the other groups. A reduction in vascular density for mice treated with Conv-IR compared to FLASH-IR was also found one-month post-irradiation.
Conclusions
Overall, this research demonstrates the potential of using FLASH radiotherapy and PARP inhibitors to treat glioblastoma.