[F-18]FAZA PET imaging reveals precise pharmacodynamics in vivo of the novel chemotherapeutic IACS-010759

Abstract Genetic deletions and mutations resulting in defects in glycolysis, force these tumors to depend on oxidative phosphorylation (OxPhos) for growth. IACS-010759 is a nanomolar inhibitor of Complex I, and in phase I clinical trials at MD Anderson for both AML and solid tumors. While ex vivo monitoring of inhibition of oxygen consumption in leukocytes was sufficient for AML, non-invasive methods of monitoring target engagement in solid tumors was desired. Tumors, particularly those that rely on oxidative phosphorylation, yield hypoxic and reducing environments. These conditions are ideal for trapping 2-nitroimidazole based imaging agents, such as F18-labeled fluoroazomycin arabinoside ([18F]FAZA). IACS-010759 inhibited oxygen consumption in vitro with IC50 values ranging from 1.3 nM to 6 nM across a variety of cell lines with a diversity of glycolysis defects. In H460 NSLC, SKMEL5 melanoma, A375R melanoma, and D423-Fluc orthotopic GBM in vivo, at the MTD 10 mg/kg, a robust, up to 6 fold, (2 way ANOVA, p<0.0001) decrease in FAZA T/B ratio was observed. A slight, 1.5-fold, but detectable increase in [18F]FDG was also observed at 10mg/kg in A375 and A375R cells (p=0.002), but smaller than the decrease [18F]FAZA retention. Thus neither cell death nor loss of perfusion could explain the reduction in [18F]FAZA retention. To further test the robustness of the mechanism of inhibition, the converse experiment was conducted. Both 2,4-dinitrophenol and pyruvate were utilized to stimulate oxygen consumption in vivo, and as predicted [18F]FAZA retention increases (p<0.05 in both cases). Finally, [18F]FAZA retention by PET yielded the same IC50 for IACS-010759 as by IHC in a dose-dependent manner, with an apparent IC50 of 1.4 mg/kg (95%CI 0.48 to 4.1 mg/kg, n=12 mice) for A375R melanoma tumors. The PET measurement was more precise than an independently scored IHC metric based upon staining for pimonidazole from the same mice. [18F]FAZA can be a powerful PD marker for the complex-I inhibitor IACS-010759 in preclinical models, and is translatable to upcoming clinical trials in patients. Citation Format: Seth T. Gammon, Federica Pisaneschi, Madhavi Bandi, Melinda Smith, Yi Rao, Vashisht G. Yennu Nanda, Yuting Sun, Michael Davies, Emilia Di Francesco, Joseph Marszalek, David Piwnica-Worms. [18F]FAZA PET imaging reveals precise pharmacodynamics in vivo of the novel chemotherapeutic IACS-010759 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-367.