In vivo visualization of PARP inhibitor pharmacodynamics

Abstract

BACKGROUND[18F]FluorThanatrace ([18F]FTT) is a radiolabeled poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi) that enables noninvasive quantification of PARP with potential to serve as a biomarker for patient selection for PARPi therapy. Here we report for the first time to our knowledge noninvasive in vivo visualization of drug-target engagement during PARPi treatment.METHODSTwo single-arm, prospective, nonrandomized clinical trials were conducted at the University of Pennsylvania from May 2017 to March 2020. PARP expression in breast cancer was assessed in vivo via [18F]FTT PET before and after initiation of PARPi treatment and in vitro via [125I]KX1 (an analog of [18F]FTT) binding to surgically removed breast cancer.RESULTSThirteen patients had baseline [18F]FTT PET. Nine of these then had resection and in vitro evaluation of [18F]FTT uptake with an analog and uptake was blocked with PARPi. Of the other 4 patients, 3 had [18F]FTT PET uptake, and all had uptake blocked with treatment with a therapeutic PARPi. Initial in vivo [18F]FTT tumor uptake ranged from undetectable to robust. Following initiation of PARPi therapy, [18F]FTT uptake was not detectable above background in all cases. In vitro tumor treatment with a PARPi resulted in 82% reduction in [125I]KX1 binding.CONCLUSION[18F]FTT noninvasively quantifies PARP-1 expression. Early results indicate ability to visualize PARPi drug-target engagement in vivo and suggest the utility of further study to test [18F]FTT PET as a predictive and pharmacodynamic biomarker.TRIAL REGISTRATIONClinicalTrials.gov identifiers NCT03083288 and NCT03846167.FUNDINGMetavivor Translational Research Award, Susan G. Komen for the Cure (CCR 16376362), Department of Defense BC190315, and Abramson Cancer Center Breakthrough Bike Challenge.

Keywords: Diagnostic imaging; Oncology.

Conflict of interest statement

Conflict of interest: The spouse of RKD has received fees for consulting from Trevarx Biomedical, Inc., which holds a license for [18F]FluorThanatrace. DAP reports grants and personal fees from Siemens, grants and personal fees from 511 Pharma, personal fees from Bayer, grants and personal fees from Fusion Pharmaceuticals, grants and personal fees from Progenics Pharmaceuticals, personal fees from Actinium Pharmaceuticals, grants from Nordic Nanovector, and personal fees from Ipsen.

Figures

Figure 1. Baseline expression and subsequent suppression of PARP-1 after PARPi treatment in breast cancer.

(A) Representative whole-tumor section demonstrates suppression of PARP radiotracer uptake with olaparib. Quantitative radioligand binding analysis (autoradiography) was followed by hematoxylin and eosin (H&E) staining. Contiguous cryosections were used to perform chromogenic PARP-1 immunofluorescence (red) with DAPI counterstain (blue). AE1/AE3 staining was performed to discriminate epithelial tumor cells (red), and CD3 staining was used to identify tumor-infiltrating T cells (green). Autoradiography demonstrates heterogeneity of PARP-1 expression at the microscopic level with spatial concordance between the intensity of [125I]KX1 uptake and expression of PARP-1 measured by immunofluorescence. [125I]KX1 plus 20 µM olaparib on a sequential section demonstrates tracer reduction to background levels. Scale bar on whole specimen H&E-stained slide is 1 mm. (B) [18F]FTT PET/CT image taken before and approximately 1 week after PARPi treatment for 2 women with advanced triple-negative breast cancer. Subject 1 had moderate [18F]FTT uptake pretherapy (SUVmax breast 4.7 g/mL) and blockade of uptake posttherapy (SUVmax breast 2.4 g/mL) and went on to have response to PARPi. Subject 2 had minimal uptake pretherapy (SUVmax breast 2.3 g/mL) and similar uptake posttherapy (SUVmax breast 2.4 g/mL) and had progression on PARPi.