Imaging PARP with [18F]rucaparib in pancreatic cancer models.
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Embargo End Date
ICR Authors
Authors
Chan, CY
Chen, Z
Destro, G
Veal, M
Lau, D
O'Neill, E
Dias, G
Mosley, M
Kersemans, V
Guibbal, F
Gouverneur, V
Cornelissen, B
Chen, Z
Destro, G
Veal, M
Lau, D
O'Neill, E
Dias, G
Mosley, M
Kersemans, V
Guibbal, F
Gouverneur, V
Cornelissen, B
Document Type
Journal Article
Date
2022-09-01
Date Accepted
2022-05-08
Abstract
PURPOSE: Rucaparib, an FDA-approved PARP inhibitor, is used as a single agent in maintenance therapy to provide promising treatment efficacy with an acceptable safety profile in various types of BRCA-mutated cancers. However, not all patients receive the same benefit from rucaparib-maintenance therapy. A predictive biomarker to help with patient selection for rucaparib treatment and predict clinical benefit is therefore warranted. With this aim, we developed [18F]rucaparib, an 18F-labelled isotopologue of rucaparib, and employed it as a PARP-targeting agent for cancer imaging with PET. Here, we report the in vitro and in vivo evaluation of [18F]rucaparib in human pancreatic cancer models. METHOD: We incorporated the positron-emitting 18F isotope into rucaparib, enabling its use as a PET imaging agent. [18F]rucaparib binds to the DNA damage repair enzyme, PARP, allowing direct visualisation and measurement of PARP in cancerous models before and after PARP inhibition or other genotoxic cancer therapies, providing critical information for cancer diagnosis and therapy. Proof-of-concept evaluations were determined in pancreatic cancer models. RESULTS: Uptake of [18F]rucaparib was found to be mainly dependent on PARP1 expression. Induction of DNA damage increased PARP expression, thereby increasing uptake of [18F]rucaparib. In vivo studies revealed relatively fast blood clearance of [18F]rucaparib in PSN1 tumour-bearing mice, with a tumour uptake of 5.5 ± 0.5%ID/g (1 h after i.v. administration). In vitro and in vivo studies showed significant reduction of [18F]rucaparib uptake by addition of different PARP inhibitors, indicating PARP-selective binding. CONCLUSION: Taken together, we demonstrate the potential of [18F]rucaparib as a non-invasive PARP-targeting imaging agent for pancreatic cancers.
Citation
European Journal of Nuclear Medicine and Molecular Imaging, 2022, 49 (11), pp. 3668 - 3678
Source Title
European Journal of Nuclear Medicine and Molecular Imaging
Publisher
SPRINGER
ISSN
1619-7070
eISSN
1619-7089
Collections
Research Team
Pre-Clinical MRI