Abstract 4541: Reduced severity of radiation esophagitis in mice following 2 weeks of ONC212 treatment

Abstract Radiotherapy administered with curative intent or palliation in lung cancer, esophageal cancer, breast cancer or head and neck cancer is often associated with inflammation, debilitating esophageal injury, pain, difficulty swallowing, and dehydration. We previously showed that deletion of innate immune TRAIL death receptor DR5 in mice is associated with acute inflammation and chronic fibrosis in the lungs following sublethal irradiation. More recently we found that TRAIL receptor agonists including TLY012 and TRAIL-Inducing Compound TIC10/ONC201/Dordaviprone can rescue mice from severe pneumonitis and lethality of thoracic radiation. In the present studies we investigated the potential for rescue of radiation injury to the esophagus in wild-type C57Bl/6 mice by oral administration of the potent TIC10/ONC201 analogue ONC212. Female C57Bl/6 mice received a single 20 Gy thoracic x-ray radiation dose with shielding of other organs and were treated with 25 mg/kg of ONC212 or control twice a week via oral gavage, with the first dose being administered 1 hour before radiation (n = 8/treatment/group). Thirteen days post-irradiation mice were euthanized, peripheral blood was collected, and the esophagus was harvested. Upon histological analysis, the esophagus appeared to be more inflamed in the control group. After quantifying the radial thickness inner esophageal layer (IEL), lamina propria (LP), muscularis externae (ME), muscularis mucosa (MM), and submucosa (SM), it was found that there was a decrease in thickness in the mice that were treated with ONC212 compared to the control mice. There was a statistically significant decrease seen in the MM and ME layers (p-value = 0.0099, 0.0366) respectively. While this study was not intended to be a survival study, it should be noted that ONC212 may have provided a rescue from lethality as three of the control mice succumbed to injuries meanwhile only one of the ONC212 treated mice died. Cytokine analysis showed ONC212 rescue was associated with serum downregulation of EGF, IL-16, CCL3, CCL7, and prolactin suggesting a decreased inflammatory response while upregulation of CCL5, CXCL12, CCL22, and IGF-1 is consistent with healing from radiation damage. Our results provide a strategy with an orally bioavailable drug for treatment of severe esophagitis that is caused by therapeutic radiotherapy involving the esophagus. Additional directions for future research include studies of other TRAIL pathway agonists such as TRAIL itself, TLY012, or other imipridones including ONC201 or ONC206 effects on severity of radiation esophagitis. Citation Format: Jillian Strandberg, Thomas DiPetrillo, Thomas J. Miner, Christopher G. Azzoli, Stephanie L. Graff, Leiqing Zhang, Abbas E. Abbas, Evgeny Yakirevich, Howard P. Safran, Wafik S. El-Deiry. Reduced severity of radiation esophagitis in mice following 2 weeks of ONC212 treatment [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 4541.