Abstract 6036: Flash proton radiotherapy mitigates radiation-induced salivary gland dysfunction and oral mucositis in mice

Abstract Background- Recent studies have reported that ultra-high dose rate “FLASH” Proton radiation therapy (F-PRT) decreases normal tissue toxicity while maintaining tumor-controlling efficacy compared to Standard Proton RT (S-PRT), that are used for patient treatments. However, although highly efficacious in eliminating tumors, damage to the otherwise healthy salivary glands and oral mucosa is often unavoidable in patients with head and neck cancer, leaving patients with lifelong xerostomia and other comorbidities. Aim- In this study, we aimed to investigate the effect of F-PRT on radiation-induced oral mucositis and salivary gland dysfunction and in controlling orthotopic tumor growth. Methods- The head and neck area of C57Bl/6 mice was irradiated with a single dose of 16 Gy or a fractionated dose of 8 Gy x 3 of F-PRT (128Gy/s) or S-PRT (0.95 Gy/s). Oral mucositis was analyzed by histopathological examination. Radiation-induced xerostomia was studied by measuring the saliva flow rate of mice. To examine the ability of F-PRT to control orthotopic head and neck tumors, tongue tumors were generated in mice and then irradiated with F-PRT/S-PRT. Results- Following irradiation with a single dose or a fractionated dose, saliva flow was reduced by both treatments. However, the F-PRT-treated mice showed a significant improvement in salivary flow at 14 days (p<0.05) and 28 days (p<0.005) post irradiation. Expression of AQP5 was found to be significantly down-regulated at 2, 5, 10, and 14 days post irradiation with S-PRT. However, mice irradiated with F-PRT showed a significant restoration of the AQP5 expression post-RT. Oral mucositis started to appear on day 14, which showed more severity on day 28 post-irradiation with S-PRT. Histopathological analysis showed the presence of lingual gland atrophy only in the tongue of mice treated with S-PRT 28 and 60 days post-irradiation. F-PRT ameliorates radiation-induced jawbone loss compared to S-PRT as observed in mice irradiated either with a single dose or in a fractionated regime. The surviving fraction of F-PRT-treated mice with orthotopic tongue tumors was significantly ameliorated compared to S-PRT-treated mice. Conclusion- This study demonstrates that F-PRT minimizes radiation-induced normal tissue toxicity after irradiation in mice’s head and neck region. Moreover, the ability of F-PRT to control orthotopic head and neck tumors further determines the efficacy of this modality for clinical applications. Citation Format: Priyanka Chowdhury, Anastasia Velalopoulou, Ioannis Verginadis, George Morcos, Michele Kim, James Metz, Lei Dong, Alexander Lin, Constantinos Koumenis. Flash proton radiotherapy mitigates radiation-induced salivary gland dysfunction and oral mucositis in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6036.