Abstract 1334: FLASH proton radiotherapy mitigates corneal damage and stimulates wound healing in mice

Eye cancers are rare but highly aggressive, with significant risk to vision and quality of life. Worldwide, thousands are affected by ocular cancers, which are challenging to treat due to their proximity to sensitive structures. Proton radiotherapy (PRT) is the current gold standard for intraocular tumors due to its precision in limiting RT exposure to surrounding healthy tissue. However, the delicate location restricts the PRT dose that can be safely administered without risking damage to essential orbital structures. FLASH (FR), a novel approach delivering PRT at ultrahigh dose rates (>40 Gy/s) compared to standard dose rate PRT (SR, <0.003 Gy/s), has shown reduced toxicity in normal tissues like the brain and skin without compromising tumor control. However, its protective effects on eye structures remain unexplored. This study aims to investigate the potential of FR in preserving ocular tissues in a mouse model. Female C57BL/6J mice received 24 Gy of either FR or SR or remained untreated (control) using a "shoot-through" approach, in which both eyes received the same dose. Retinal and corneal damage were monitored using optical coherence tomography and confocal scanning laser ophthalmoscopy, with retinal vascular permeability evaluated by fluorescein angiography and retinal function by electroretinography (ERG). Corneal wound healing was assessed using corneal micro puncture. Evaluations occurred at one week, one, three, and five months post-PRT. Mice treated with SR showed significant corneal thickening and ulceration, leading to visual impairment, while those treated with FR did not. SR mice also showed declining ERG responses, suggesting diminished response to light stimuli, while FR mice demonstrated significantly less ERG abnormalities. Additionally, mice treated with SR showed over 55% reduction in eye surface area compared to both FR and control mice. Both SR and FR reduced retinal thickness, with no significant difference between the PRT treatment groups. Fluoresceine angiography showed no leakage in the retinal microvasculature. To further characterize corneal repair following PRT, we performed a corneal wound healing assay. Notably, FR demonstrated an enhanced wound healing response, with faster recovery of corneal incisions compared to both SR and control mice. This study presents a novel model for evaluating PRT-induced ocular damage, highlighting FR’s potential to protect healthy tissues. FR was particularly effective in preserving corneal integrity and promoting wound healing, which are crucial for maintaining both visual function and cosmetic outcomes. Ongoing studies aim to quantify the preservation of stem cells in the corneoscleral junction as a potential mechanism for the observed tissue-sparing effects. Citation Format: Elias El Hoyek, Uri Amit, Brent A. Bell, Vivian Lee, Joshua L. Dunaief, Costantinos Koumenis. FLASH proton radiotherapy mitigates corneal damage and stimulates wound healing in mice [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 1334.