Imaging PARP with [18F]rucaparib in pancreatic cancer models.

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.

• Authors: Chung Ying Chan, Zijun Chen, Gianluca Destro, Mathew Veal, Doreen Lau, Edward O'Neill, Gemma Dias, Michael Mosley, Veerle Kersemans, Florian Guibbal, Véronique Gouverneur, Bart Cornelissen
• Journal: European journal of nuclear medicine and molecular imaging (Eur J Nucl Med Mol Imaging) Vol. 49 Issue 11 Pg. 3668-3678 (09 2022) ISSN: 1619-7089 [Electronic] Germany
• PMID: 35614267 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).

Chemical References

• Antineoplastic Agents
• Indoles
• Poly(ADP-ribose) Polymerase Inhibitors
• rucaparib

Topics

• Animals
• Antineoplastic Agents
• Humans
• Indoles
• Mice
• Pancreatic Neoplasms (diagnostic imaging)
• Poly(ADP-ribose) Polymerase Inhibitors (pharmacology, therapeutic use)