[¹⁸F]rucaparib to Image PARP in Pancreatic Cancer Models

Take-Away Points

• ■ Major Focus: To develop a poly (adenosine diphosphate-ribose) polymerase (PARP)–targeting PET imaging agent to visualize PARP expression in pancreatic cancer.

• ■ Key Result: Fluorine 18–labeled rucaparib ([¹⁸F]rucaparib) uptake correlated with PARP expression levels in both human pancreatic cancer cell lines and tumor xenografts.

• ■ Impact: [¹⁸F]rucaparib PET may be used to noninvasively predict response to PARP inhibition therapy in patients with cancer.

PARP inhibition is an effective treatment strategy to primarily target cancer cells with defects in the homologous recombination (HRD) repair pathway. However, clinical studies show that HRD status alone does not accurately predict PARP inhibitor (PARPi) response. Imaging of PARP expression may serve as a noninvasive method to improve patient stratification and predict treatment response to PARPi therapy.

In this proof-of-concept study, Chan et al used human pancreatic cancer cells to demonstrate the PARP-1–dependent uptake of [¹⁸F]rucaparib, a PET-labeled isotopologue of rucaparib. Uptake was reduced by several different clinically used PARPi. Direct comparison between [¹⁸F]rucaparib and [¹⁸F]olaparib, a different PARPi, revealed 100-fold higher uptake and retention for [¹⁸F]rucaparib, which correlated with PARP-1 expression. This finding was also observed in cells exposed to DNA damage. PET imaging in tumor-bearing pancreatic cancer xenografts revealed hepatobiliary and renal clearance with fast tumor uptake and blood clearance of [¹⁸F]rucaparib. Good tumor-to-background signal could be achieved 1 hour after injection with uptake significantly reduced by coadministration of excess olaparib or rucaparib, indicating excellent binding specificity in vivo. Autoradiography and immunohistochemical analyses revealed heterogeneity of [¹⁸F]rucaparib uptake, correlating with heterogeneity of PARP-1 expression in tumors.

This study suggests the potential of [¹⁸F]rucaparib as a PET imaging agent for noninvasive visualization of PARP expression levels in preclinical models and paves the way for first-in-human studies to facilitate clinical translation of this radiotracer and improve PARPi treatment outcome in patients with cancer.

Highlighted Article

• Chan CY, Chen Z, Destro G, et al. Imaging PARP with [¹⁸F]rucaparib in pancreatic cancer models. Eur J Nucl Med Mol Imaging 2022;(49):3668–3678. doi: https://doi.org/10.1007/s00259-022-05835-4