Mechanism-Specific Pharmacodynamics of a Novel Complex-I Inhibitor Quantified by Imaging Reversal of Consumptive Hypoxia with [<sup>18</sup>F]FAZA PET <i>In Vivo</i>
Seth T. Gammon,
Federica Pisaneschi,
Madhavi L. Bandi,
Melinda G. Smith,
Yuting Sun,
Yi Rao,
Florian Muller,
Franklin Wong,
John De Groot,
Jeffrey Ackroyd,
Osama Mawlawi,
Michael A. Davies,
Y.N. Vashisht Gopal,
M. Emilia Di Francesco,
Joseph R. Marszalek,
Mark Dewhirst,
David Piwnica-Worms
Affiliations
Seth T. Gammon
Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Federica Pisaneschi
Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Madhavi L. Bandi
Translational Research to Advance Therapeutics and Innovation in Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Melinda G. Smith
Translational Research to Advance Therapeutics and Innovation in Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Yuting Sun
Translational Research to Advance Therapeutics and Innovation in Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Yi Rao
Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Florian Muller
Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Franklin Wong
Department of Nuclear Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
John De Groot
Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX,77030, USA
Jeffrey Ackroyd
Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Osama Mawlawi
Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Michael A. Davies
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Y.N. Vashisht Gopal
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
M. Emilia Di Francesco
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Joseph R. Marszalek
Translational Research to Advance Therapeutics and Innovation in Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Mark Dewhirst
Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27710, USA
David Piwnica-Worms
Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Tumors lack a well-regulated vascular supply of O2 and often fail to balance O2 supply and demand. Net O2 tension within many tumors may not only depend on O2 delivery but also depend strongly on O2 demand. Thus, tumor O2 consumption rates may influence tumor hypoxia up to true anoxia. Recent reports have shown that many human tumors in vivo depend primarily on oxidative phosphorylation (OxPhos), not glycolysis, for energy generation, providing a driver for consumptive hypoxia and an exploitable vulnerability. In this regard, IACS-010759 is a novel high affinity inhibitor of OxPhos targeting mitochondrial complex-I that has recently completed a Phase-I clinical trial in leukemia. However, in solid tumors, the effective translation of OxPhos inhibitors requires methods to monitor pharmacodynamics in vivo. Herein, 18F-fluoroazomycin arabinoside ([18F]FAZA), a 2-nitroimidazole-based hypoxia PET imaging agent, was combined with a rigorous test-retest imaging method for non-invasive quantification of the reversal of consumptive hypoxia in vivo as a mechanism-specific pharmacodynamic (PD) biomarker of target engagement for IACS-010759. Neither cell death nor loss of perfusion could account for the IACS-010759-induced decrease in [18F]FAZA retention. Notably, in an OxPhos-reliant melanoma tumor, a titration curve using [18F]FAZA PET retention in vivo yielded an IC50 for IACS-010759 (1.4 mg/kg) equivalent to analysis ex vivo. Pilot [18F]FAZA PET scans of a patient with grade IV glioblastoma yielded highly reproducible, high‐contrast images of hypoxia in vivo as validated by CA-IX and GLUT-1 IHC ex vivo. Thus, [18F]FAZA PET imaging provided direct evidence for the presence of consumptive hypoxia in vivo, the capacity for targeted reversal of consumptive hypoxia through the inhibition of OxPhos, and a highly-coupled mechanism-specific PD biomarker ready for translation.
