Inhibition of Glucose-6-Phosphate Dehydrogenase Activity Attenuates Right Ventricle Pressure and Hypertrophy Elicited by VEGFR Inhibitor + Hypoxia

Abstract

The poly-(adenosine diphosphate-ribose) polymerase (PARP) family of proteins participates in numerous functions, most notably the DNA damage response. Cancer vulnerability to DNA damage has led to development of several PARP inhibitors (PARPi). This class of drugs has demonstrated therapeutic efficacy in ovarian, breast, and prostate cancers, but with variable response. Consequently, clinics need to select patients likely to benefit from these targeted therapies. In vivo imaging of ¹⁸F-fluorthanatrace uptake has been shown to correspond to PARP-1 expression in tissue. This study characterized the pharmacokinetics of ¹⁸F-fluorthanatrace and tested kinetic and static models to guide metric selection in future studies assessing ¹⁸F-fluorthanatrace as a biomarker of response to PARPi therapy. <b>Methods:</b> Fourteen prospectively enrolled ovarian cancer patients were injected with ¹⁸F-fluorthanatrace and imaged dynamically for 60 min after injection followed by up to 2 whole-body scans, with venous blood activity and metabolite measurements. SUV_max and SUV_peak were extracted from dynamic images and whole-body scans. Kinetic parameter estimates and SUVs were assessed for correlations with tissue PARP-1 immunofluorescence (<i>n</i> = 7). Simulations of population kinetic parameters enabled estimation of measurement bias and precision in parameter estimates. <b>Results:</b>¹⁸F-fluorthanatrace blood clearance was variable, but labeled metabolite profiles were similar across patients, supporting use of a population parent fraction curve. The total distribution volume from a reversible 2-tissue-compartment model and Logan reference tissue distribution volume ratio (DVR) from the first hour of PET acquisition correlated with tumor PARP-1 expression by immunofluorescence (<i>r</i> = 0.76 and 0.83, respectively; <i>P</i> &lt; 0.05). DVR bias and precision estimates were 6.4% and 29.1%, respectively. SUV_max and SUV_peak acquired from images with midpoints of 57.5, 110 ± 3, and 199 ± 4 min highly correlated with PARP-1 expression (mean ± SD, <i>r</i> ≥ 0.79; <i>P</i> &lt; 0.05). <b>Conclusion:</b> Tumor SUV_max and SUV_peak at 55–60 min after injection and later and DVR from at least 60 min appear to be robust noninvasive measures of PARP-1 binding. ¹⁸F-fluorthanatrace uptake in ovarian cancer was best described by models of reversible binding. However, pharmacokinetic patterns of tracer uptake were somewhat variable, especially at later time points.