Abstract 218: Novel SOD mimetics GC4419 & GC4711 induce synergistic tumoricidal effects combined with radiotherapy in lung cancer models
Authors: Langen Britta , Pop Laurentiu , Shang Zengfu , Iijima Moito , Nicholson James , Yang Mingming , Story Michael D. 
Published: June 2022

Abstract
Introduction: Superoxide dismutase mimetics (SODm) synergize with radiation (IR) by converting radiolytically produced superoxide to hydrogen peroxide. Cancer cells lacking catalase function fail to clear H2O2 resulting in increased tumoricidal load. In addition, complex interactions through redox signaling and immune interplay are suggested mechanisms of action. Our pre-clinical studies with the SODm GC4419 (AVA) indicated that increased inflammatory, TNFα, and apoptosis signaling contribute to treatment synergy that was most effective at hypofractionation (Sci Transl Med. 13:593). The analogue GC4711 (GC) is currently in clinical trials for SBRT against NSCLC and pancreatic cancer. However, optimal combination schedules and molecular mechanisms are largely unknown. Here, we present optimized combination schedules using human lung tumor xenografts regarding drug administration timing and dosage, as well as local and abscopal tumor control in a syngeneic lung tumor model. Further, we tested various cell stress and immune pathways to identify targets of synergistic IR-drug interaction.
Methods: Female athymic nude and C57BL/6 mice were inoculated with H1299 and LLC, respectively. H1299 tumors were irradiated with 10-15 Gy and GC was given once or twice daily (24 or 2x20 mg/kg, respectively) over 5 days, including untreated controls. LLC tumors were set up as an abscopal model and mice received combination treatment with GC and 15 Gy, 15 Gy only, or GC only, including untreated controls. In vitro, lung cancer cell lines were pre-treated with AVA or GC 30 min prior to IR and assayed for various immune or DNA damage-related endpoints.
Results: The anti-tumor efficacy of single or double GC administration showed nonlinear dose-dependence indicating complex drug-IR interplay. Optimal drug administration appears to be around 3 hours prior to irradiation while time-of-day of treatment has no observable effect in this model. In the LLC double tumor model, GC in combination with IR induced significant and pronounced abscopal tumor control. In vitro, analysis revealed GC action related to e.g. 53BP1, yH2AX, Akt, R-loop formation and replication stress, and interaction with various immune pathways.
Discussion and Conclusions: The radiotherapeutic effect can be vastly increased with superoxide dismutase mimetics, both within and outside the treatment field. Combination therapy requires screening of schedules regarding timing, drug dosage, and IR dose and fractionation to achieve optimal tumoricidal effects. SODm synergize with IR acting on various molecular targets that can be harnessed to overcome treatment resistance. Secondary tumor control is a promising new venue for IR-SODm combination therapy. Moreover, redox-immune interaction opens new therapeutic applications with combined immune checkpoint inhibitors for unprecedented tumor control and cure rate.
Citation Format: Britta Langen, Laurentiu Pop, Zengfu Shang, Moito Iijima, James Nicholson, Mingming Yang, Michael D. Story. Novel SOD mimetics GC4419 & GC4711 induce synergistic tumoricidal effects combined with radiotherapy in lung cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 218.