Preclinical and First-in-human-brain-cancer Applications of [F]poly (ADP-ribose) Polymerase Inhibitor PET/MR

Overview

Journal Neurooncol Adv

Publisher Oxford University Press

Date 2021 Jan 4

PMID 33392502

Citations 14

Authors

Robert J Young

Paula Demetrio de Souza Franca

Giacomo Pirovano

Anna F Piotrowski

Philip J Nicklin

Christopher C Riedl

Jazmin Schwartz

Tejus A Bale

Patrick L Donabedian

Susanne Kossatz

Eva M Burnazi

Sheryl Roberts

Serge K Lyashchenko

Alexandra M Miller

Nelson S Moss

Megan Fiasconaro

Zhigang Zhang

Audrey Mauguen

Thomas Reiner

Mark P Dunphy

Affiliations

Soon will be listed here.

Abstract

Background: We report preclinical and first-in-human-brain-cancer data using a targeted poly (ADP-ribose) polymerase 1 (PARP1) binding PET tracer, [F]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 [F]PARPi and then sacrificed 1 h post-injection for brain examination. We also prospectively enrolled patients with brain cancers to undergo dynamic [F]PARPi acquisition on a dedicated positron emission tomography/magnetic resonance (PET/MR) scanner. Lesion diagnosis was established by pathology when available or by Response Assessment in Neuro-Oncology (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 [F]PARPi crossed the blood-brain barrier and specifically bound to PARP1 overexpressed in cancer cell nuclei. In humans, we demonstrated high [F]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 noncancerous tissue. Specificity was also corroborated by blocking fluorescent tracer uptake with an 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 [F]PARPi as a diagnostic tool to evaluate patients with brain cancers and possible treatment-related changes.

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