LAUSR

Thoracic therapeutic ionizing radiation is limited by toxicities such as pneumonitis and fibrosis of the lungs. Such limitation restricts therapeutic doses and adversely affects patient quality of life while undergoing and following treatment. ONC201/TIC10 is a small-molecule anti-cancer drug that activates the integrated stress response (ISR) and drives the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway. Pegylated recombinant long-acting TRAIL (TLY012) has been shown in preclinical models to induce the reversal of fibrosis and currently has orphan drug status for systemic sclerosis and chronic pancreatitis. We show a similar effect of both TLY012 and ONC201 in vivo in protecting from radiation pneumonitis and fibrosis of the lungs. WT and TRAIL-/- C57Bl/6 mice receiving a single 20 Gy thoracic radiation dose with shielding of other organs and treated with 10 mg/kg of TLY012 twice a week showed a significantly reduced alveolar wall thickness and lessened inflammation compared to controls and DR5-/- mice receiving the same treatment upon histological analysis of the lungs conducted 13 days post-irradiation. WT and TRAIL-/- C57Bl/6 mice treated with 100 mg/kg of ONC201 once a week showed similar effect to a lesser extent. Further analysis in C57Bl/6 WT mice bearing orthotopic mammary fat pad e0771 TNBC tumors similarly receiving a single 20 Gy thoracic radiation dose revealed the same pattern of protection from radiation pneumonitis upon TRAIL-pathway agonism through treatment with TLY012 and ONC201 both in combination and alone, while also showing a significant reduction in tumor burden at the experimental endpoint (day 9 post-irradiation) in the combination treated mice. Further, pulse oximetry readings of the hind paw revealed a notable reduction in oxygen saturation in all mice except those treated with TLY012. Cytokinomic profiling of mouse serum upon sacrifice revealed a significant reduction in CCL22/MDC levels in the TLY012 cohort. Additional post-hoc analysis including immunophenotyping, immunostaining, and bulk RNA analysis through Nanostring nCounter technologies is underway. Altogether, these findings suggest a role for TLY012, ONC201, or broader modulation of the TRAIL/DR5 pathway in mitigating adverse effects and outcomes of therapeutic radiation, and may serve as a foundation for safer use of radiation in the clinic. Citation Format: Jillian R. Strandberg, Anna Louie, Marina Hahn, Praveen Srinivasan, Andrew George, Arielle De La Cruz, Leiqing Zhang, Liz Hernandez Borrero, Kelsey Huntington, Christopher Azzoli, Abbas E. Abbas, Lanlan Zhou, Seulki Lee, Wafik S. El-Deiry. Post exposure suppression of radiation pneumonitis by TRAIL pathway agonists TLY012 and ONC201. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4457.