Preclinical and first-in-human-brain-cancer applications of [18F]poly (ADP-ribose) polymerase inhibitor PET/MR
| Autor: | Alexandra Miller, Patrick L. Donabedian, Audrey Mauguen, Giacomo Pirovano, Serge K. Lyashchenko, Sheryl Roberts, Nelson S Moss, Jazmin Schwartz, Thomas Reiner, Zhigang Zhang, Susanne Kossatz, Robert J. Young, Anna F. Piotrowski, Philip J. Nicklin, Christopher C. Riedl, Megan Fiasconaro, Eva Burnazi, Mark Dunphy, Tejus Bale, Paula Demétrio De Souza França |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Clinical Investigations PARP1 Poly (ADP-Ribose) Polymerase Inhibitor 03 medical and health sciences 0302 clinical medicine Glioma medicine AcademicSubjects/MED00300 brain cancer medicine.diagnostic_test business.industry Cancer medicine.disease PET/MR PET 030104 developmental biology [18F]PARPi Positron emission tomography 030220 oncology & carcinogenesis Cancer cell PARP inhibitor Cancer research Immunohistochemistry AcademicSubjects/MED00310 business |
| Zdroj: | Neuro-oncology Advances |
| ISSN: | 2632-2498 |
| Popis: | Background We report preclinical and first-in-human-brain-cancer data using a targeted poly (ADP-ribose) polymerase 1 (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 h post-injection for brain examination. We also prospectively enrolled patients with brain cancers to undergo dynamic [18F]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 [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 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 [18F]PARPi as a diagnostic tool to evaluate patients with brain cancers and possible treatment-related changes. |
| Databáze: | OpenAIRE |
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