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.
Highlights
The concentration of intracellular oxygen in tumor cells is the net result of the rate at which oxygen (O2 ) diffuses into cells and the rate at which oxygen is consumed [1], and tumor hypoxia results from a mismatch in the diffusion of O2 relative to the consumption rate [1,2]
oxygen consumption rate (OCR) and consumptive hypoxia, we demonstrated that in living animals [18 F]FAZA positron emission tomography (PET) can serve as a quantitative PD biomarker in vivo of IACS-010759
D423-Fluc glioblastoma tumor cells are deficient in glycolysis through deletion of enolase-1, which is on the 1p36 tumor suppressor locus, sensitizing them to mitochondrial metabolic blockers [30,37,38]
Summary
The concentration of intracellular oxygen in tumor cells is the net result of the rate at which oxygen (O2 ) diffuses into cells and the rate at which oxygen is consumed [1], and tumor hypoxia results from a mismatch in the diffusion of O2 relative to the consumption rate [1,2]. Diffusional hypoxia in tumors is generally attributed to O2 supply, such as low blood O2 tension (hypoxemic hypoxia); reduced capacity of blood to carry O2 (anemia, methemoglobin, or carbon monoxide; anemic hypoxia); and reduced tissue perfusion through disorganized tumor blood vessels and deterioration of diffusion geometries, e.g., heterogeneous diffusion distances, and concurrent versus countercurrent blood flow within microvessels [3,4,5]. Because of finely tuned regulatory processes in normal tissues, increases in the tissue O2 consumption rate (OCR) are generally matched by an increase in blood flow and, do not usually lead to hypoxia. In the context of neuronal activation and injury, the systems regulating blood flow can fail to meet the increased O2 demand of the tissue in question, leading Scholz et al to coin the phrase “consumptive hypoxia” [6]. The biochemical details of how metabolic reprogramming and O2 consumption rates impact tumor hypoxia in vivo remain under intense study [14,15]
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