PMID- 31766580
OWN - NLM
STAT- MEDLINE
DCOM- 20200817
LR  - 20200817
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 8
IP  - 12
DP  - 2019 Nov 21
TI  - Mechanism-Specific Pharmacodynamics of a Novel Complex-I Inhibitor Quantified by 
      Imaging Reversal of Consumptive Hypoxia with [(18)F]FAZA PET In Vivo.
LID - 10.3390/cells8121487 [doi]
LID - 1487
AB  - Tumors lack a well-regulated vascular supply of O(2) and often fail to balance 
      O(2) supply and demand. Net O(2) tension within many tumors may not only depend 
      on O(2) delivery but also depend strongly on O(2) demand. Thus, tumor O(2) 
      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, (18)F-fluoroazomycin 
      arabinoside ([(18)F]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 [(18)F]FAZA retention. Notably, in an 
      OxPhos-reliant melanoma tumor, a titration curve using [(18)F]FAZA PET retention 
      in vivo yielded an IC(50) for IACS-010759 (1.4 mg/kg) equivalent to analysis ex 
      vivo. Pilot [(18)F]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, [(18)F]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.
FAU - Gammon, Seth T
AU  - Gammon ST
AD  - Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer 
      Center, Houston, TX 77030, USA.
FAU - Pisaneschi, Federica
AU  - Pisaneschi F
AD  - Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer 
      Center, Houston, TX 77030, USA.
FAU - Bandi, Madhavi L
AU  - Bandi ML
AD  - Translational Research to Advance Therapeutics and Innovation in Oncology, The 
      University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
FAU - Smith, Melinda G
AU  - Smith MG
AD  - Translational Research to Advance Therapeutics and Innovation in Oncology, The 
      University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
FAU - Sun, Yuting
AU  - Sun Y
AD  - Translational Research to Advance Therapeutics and Innovation in Oncology, The 
      University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
FAU - Rao, Yi
AU  - Rao Y
AD  - Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer 
      Center, Houston, TX 77030, USA.
FAU - Muller, Florian
AU  - Muller F
AD  - Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer 
      Center, Houston, TX 77030, USA.
FAU - Wong, Franklin
AU  - Wong F
AD  - Department of Nuclear Medicine, The University of Texas MD Anderson Cancer 
      Center, Houston, TX 77030, USA.
FAU - De Groot, John
AU  - De Groot J
AD  - Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 
      Houston, TX,77030, USA.
FAU - Ackroyd, Jeffrey
AU  - Ackroyd J
AD  - Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer 
      Center, Houston, TX 77030, USA.
FAU - Mawlawi, Osama
AU  - Mawlawi O
AD  - Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, 
      Houston, TX 77030, USA.
FAU - Davies, Michael A
AU  - Davies MA
AD  - Department of Melanoma Medical Oncology, The University of Texas MD Anderson 
      Cancer Center, Houston, TX 77030, USA.
FAU - Gopal, Y N Vashisht
AU  - Gopal YNV
AD  - Department of Melanoma Medical Oncology, The University of Texas MD Anderson 
      Cancer Center, Houston, TX 77030, USA.
FAU - Di Francesco, M Emilia
AU  - Di Francesco ME
AD  - Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer 
      Center, Houston, TX 77030, USA.
FAU - Marszalek, Joseph R
AU  - Marszalek JR
AD  - Translational Research to Advance Therapeutics and Innovation in Oncology, The 
      University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
FAU - Dewhirst, Mark
AU  - Dewhirst M
AD  - Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 
      27710, USA.
FAU - Piwnica-Worms, David
AU  - Piwnica-Worms D
AD  - Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer 
      Center, Houston, TX 77030, USA.
LA  - eng
GR  - P30 CA016672/CA/NCI NIH HHS/United States
GR  - P50 CA127001/CA/NCI NIH HHS/United States
GR  - R01 CA231506/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20191121
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Nitroimidazoles)
RN  - 0 (Oxadiazoles)
RN  - 0 (Piperidines)
RN  - 0 (Radiopharmaceuticals)
RN  - 1QR3UU6P48 (fluoroazomycin arabinoside)
RN  - EC 7.1.1.2 (Electron Transport Complex I)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Animals
MH  - Biomarkers, Tumor/metabolism
MH  - Brain Neoplasms/diagnostic imaging/drug therapy/metabolism
MH  - Cell Line, Tumor
MH  - Electron Transport Complex I/*antagonists & inhibitors/metabolism
MH  - Female
MH  - Glioblastoma/diagnostic imaging/drug therapy/metabolism
MH  - Humans
MH  - Inhibitory Concentration 50
MH  - Mice
MH  - Mice, Nude
MH  - Nitroimidazoles
MH  - Oxadiazoles/*pharmacology
MH  - Oxidative Phosphorylation/drug effects
MH  - Oxygen/metabolism
MH  - Piperidines/*pharmacology
MH  - Positron Emission Tomography Computed Tomography/methods
MH  - Radiopharmaceuticals
MH  - Tumor Hypoxia/*drug effects
PMC - PMC6952969
OTO - NOTNLM
OT  - IACS-010759
OT  - PET
OT  - [18F]FAZA
OT  - collateral lethality
OT  - hypoxia
OT  - metabolism
OT  - mitochondrial complex I
OT  - oxidative phosphorylation
OT  - pharmacodynamics
COIS- The IACS-010759 patent is issued and held by UT MD Anderson Cancer Center.
EDAT- 2019/11/27 06:00
MHDA- 2020/08/18 06:00
PMCR- 2019/12/01
CRDT- 2019/11/27 06:00
PHST- 2019/10/30 00:00 [received]
PHST- 2019/11/14 00:00 [revised]
PHST- 2019/11/18 00:00 [accepted]
PHST- 2019/11/27 06:00 [entrez]
PHST- 2019/11/27 06:00 [pubmed]
PHST- 2020/08/18 06:00 [medline]
PHST- 2019/12/01 00:00 [pmc-release]
AID - cells8121487 [pii]
AID - cells-08-01487 [pii]
AID - 10.3390/cells8121487 [doi]
PST - epublish
SO  - Cells. 2019 Nov 21;8(12):1487. doi: 10.3390/cells8121487.