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Mechanism-Specific Pharmacodynamics of a Novel Complex-I Inhibitor Quantified by Imaging Reversal of Consumptive Hypoxia with [18F]FAZA PET In Vivo.
Gammon, Seth T; Pisaneschi, Federica; Bandi, Madhavi L; Smith, Melinda G; Sun, Yuting; Rao, Yi; Muller, Florian; Wong, Franklin; De Groot, John; Ackroyd, Jeffrey; Mawlawi, Osama; Davies, Michael A; Gopal, Y N Vashisht; Di Francesco, M Emilia; Marszalek, Joseph R; Dewhirst, Mark; Piwnica-Worms, David.
Affiliation
  • Gammon ST; Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Pisaneschi F; Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Bandi ML; Translational Research to Advance Therapeutics and Innovation in Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Smith MG; Translational Research to Advance Therapeutics and Innovation in Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Sun Y; Translational Research to Advance Therapeutics and Innovation in Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Rao Y; Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Muller F; Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Wong F; Department of Nuclear Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • De Groot J; Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX,77030, USA.
  • Ackroyd J; Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Mawlawi O; Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Davies MA; Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Gopal YNV; Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Di Francesco ME; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Marszalek JR; Translational Research to Advance Therapeutics and Innovation in Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Dewhirst M; Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27710, USA.
  • Piwnica-Worms D; Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cells ; 8(12)2019 11 21.
Article in En | MEDLINE | ID: mdl-31766580
ABSTRACT
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Oxadiazoles / Piperidines / Electron Transport Complex I / Tumor Hypoxia Limits: Animals / Female / Humans Language: En Journal: Cells Year: 2019 Document type: Article Affiliation country: Estados Unidos

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Oxadiazoles / Piperidines / Electron Transport Complex I / Tumor Hypoxia Limits: Animals / Female / Humans Language: En Journal: Cells Year: 2019 Document type: Article Affiliation country: Estados Unidos
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