Preclinical and first-in-human-brain-cancer applications of [18F]poly-(ADP-ribose) polymerase inhibitor PET/MR

Robert J Young, MD*, Paula Demétrio De Souza França, MD, Giacomo Pirovano, DPhil, Anna F Piotrowski, MD, Philip J Nicklin, Christopher C Riedl, MD PhD, Jazmin Schwartz, PhD, Tejus A Bale, MD PhD, Patrick L Donabedian, Susanne Kossatz, Eva M Burnazi, Sheryl Roberts, PhD, Serge K Lyashchenko, PharmD, Alexandra M Miller, MD PhD, Nelson S Moss, MD, Megan Fiasconaro, Zhigang Zhang, PhD, Audrey Mauguen, PhD, Thomas Reiner, PhD, Mark P Dunphy, MD*

Background: We report preclinical and first-in-human-brain-cancer data using a targeted poly(ADP-ribose)polymerase1 (PARP1) binding PET tracer, [ 18F]PARPi, as a diagnostic tool to differentiate between brain cancers and treatment-related changes.

Methods: We applied a glioma model in p53-deficient nestin/tv-a mice, which were injected with [ 18F]PARPi and then sacrificed 1 hr post-injection for brain examination. We also prospectively enrolled patients with brain cancers to undergo dynamic [ 18F]PARPi acquisition on a dedicated PET/MR scanner. Lesion diagnosis was established by pathology when available or by RANO or RANO-BM response criteria. Resected tissue also underwent PARPi-FL staining and PARP1 immunohistochemistry.

Results: In a preclinical mouse model, we illustrated that [ 18F]PARPi crossed the blood-brain barrier and specifically bound to PARP1 overexpressed in cancer cell nuclei. In humans, we demonstrated high [ 18F]PARPi uptake on PET/MR in active brain cancers and low uptake in treatment-related changes independent of blood-brain barrier disruption. Immunohistochemistry results confirmed higher PARP1 expression in cancerous than in non-cancerous tissue. Specificity was also corroborated by blocking fluorescent tracer uptake with excess unlabeled PARP inhibitor in patient cancer biospecimen.

Conclusions: Although larger studies are necessary to confirm and further explore this tracer, we describe the promising performance of [ 18F]PARPi as a diagnostic tool to evaluate patients with brain cancers and possible treatment-related changes.

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