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Radiotherapy is part of the standard of care in treating glioblastoma. However, irradiation of normal brain tissue is required to encompass this infiltrative disease. Radiation-induced neurotoxicity is mediated by neuroinflammation and blood-brain barrier disruption and causes irreversible cognitive impairment. Therefore, reducing neurotoxicity without costing tumor response would be beneficial. Recent preclinical studies have shown that whole-brain irradiation using FLASH radiotherapy can reduce radiation-induced neurotoxicity compared to conventional radiotherapy. PARP inhibitors have also been shown to enhance the radiosensitivity of multiple cancers and also reduce neuroinflammation in many brain diseases. Here we investigate if combining PARP inhibitors with hemibrain FLASH radiotherapy could further reduce radiation-induced neurotoxicity while maintaining tumor-killing efficacy.

Mice were randomly allocated to the following groups: 1) control; 2) FLASH irradiation (FLASH IR, mean dose rate= 2000 Gy/s); 3) Conventional dose rate irradiation (CONV IR, 0.1 Gy/s); 4) PARP inhibitor (PARPi, pamiparib, oral gavage, 12.5 mg/kg, twice daily for 7 days); 5) PARPi+CONV IR; and 6) PARPi+FLASH IR. Mice were irradiated once with 20 Gy from a 6 MeV electron beam to the right hemisphere. For combinatory therapy, the first dose of PARPi was administered 1 hour before irradiation. For normal tissue toxicity studies, normal C57BL6 mice were used. MRI, PET/CT, IHC and lightsheet microscopy were used to study structural and vascular changes in the brain. Systemic toxicity was assessed by weight change post-treatment. For tumor response, athymic nude mice with subcutaneous U87MG tumours were irradiated. 

Both PARPi+FLASH IR and PARPi+CONV IR showed around a 2-fold reduction in the tumor growth rate compared to control and PARPi groups. While a significant reduction in tumor growth rate was observed in mice treated with PARPi+CONV IR compared to CONV IR, a smaller, non-significant difference was observed between mice treated with PARPi+FLASH IR and FLASH IR alone. One week after irradiation, only mice treated with PARPi+CONV IR showed a significant weight reduction. A significant increase in brain perfusion in the irradiated hemisphere was observed in mice treated with CONV IR, while no significant differences in perfusion between hemispheres were seen in the other groups. Analysis of brain vasculature 1-month post-irradiation showed a reduction in vascular density for mice treated with CONV IR compared to FLASH IR.

The combinatory treatment of PARP inhibitor with radiotherapy prolonged tumor growth delay and reduced radiation-induced neurotoxicity. The synergistic tumor effect was more pronounced with CONV IR than FLASH IR. However, the combination of PARPi+CONV IR was also associated with increased acute systemic toxicity. Overall, this research demonstrates the potential of using FLASH radiotherapy together with PARP inhibitors for the treatment of glioblastoma.