Kinetic and Static Analysis of Poly-(Adenosine Diphosphate-Ribose) Polymerase-1-Targeted 18F-Fluorthanatrace PET Images of Ovarian Cancer

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 F-18-fluorthanatrace uptake has been shown to correspond to PARP-1 expression in tissue. This study characterized the pharmacokinetics of F-18-fluorthanatrace and tested kinetic and static models to guide metric selection in future studies assessing F-18-fluorthanatrace as a biomarker of response to PARPi therapy. Methods: Fourteen prospectively enrolled ovarian cancer patients were injected with F-18-fluorthanatrace and imaged dynamically for 60 min after injection followed by up to 2 whole-body scans, with venous blood activity and metabolite measurements. SUVmax and SUVpeak were extracted from dynamic images and whole-body scans. Kinetic parameter estimates and SUVs were assessed for correlations with tissue PARP-1 immunofluorescence (n = 7). Simulations of population kinetic parameters enabled estimation of measurement bias and precision in parameter estimates. Results: F-18-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 (r = 0.76 and 0.83, respectively; P < 0.05). DVR bias and precision estimates were 6.4% and 29.1%, respectively. SUVmax and SUVpeak acquired from images with midpointsof 57.5,110 +/- 3, and 199 +/- 4 min highly correlated with PARP-1 expression (mean +/- SD, r >= 0.79; P < 0.05). Conclusion: Tumor SUVmax and SUVpeak 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. F-18-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.

Automated summary

The PARP family of proteins is involved in various functions, including the DNA damage response. PARP inhibitors have shown therapeutic efficacy in cancer treatment, and F-18-fluorthanatrace uptake can serve as a biomarker for response to PARP inhibitor therapy. SUVmax and SUVpeak are robust measures of PARP-1 binding.