Positron-emission tomographic imaging of a fluorine 18-radiolabeled Poly(ADP-ribose) polymerase 1 inhibitor monitors the therapeutic efficacy of talazoparib in SCLC patient-derived xenografts Journal Article

   

Authors:	Laird, J.; Lok, B. H.; Carney, B.; Kossatz, S.; de Stanchina, E.; Reiner, T.; Poirier, J. T.; Rudin, C. M.
Article Title:	Positron-emission tomographic imaging of a fluorine 18-radiolabeled Poly(ADP-ribose) polymerase 1 inhibitor monitors the therapeutic efficacy of talazoparib in SCLC patient-derived xenografts
Abstract:	Introduction: Inhibitors of poly-(ADP)-ribose polymerase (PARP) are promising therapeutics for SCLC. We tested whether PARP inhibitor (PARPi) target engagement as measured by a fluorine 18–radiolabeled PARPi ([18F]PARPi) has the potential to predict drug efficacy in vivo. Methods: Tumor growth inhibition during daily talazoparib treatment was evaluated in mice engrafted with SCLC patient-derived xenografts to evaluate talazoparib efficacy at multiple doses. Mice were intravenously injected with [18F]PARPi radiotracer at multiple timepoints after single doses of oral talazoparib to quantitatively assess the extent to which talazoparib could reduce tumor radiotracer uptake and positron-emission tomographic (PET)/computer tomographic activity. Tumors were harvested and tumor poly-(ADP) ribose level was measured by enzyme-linked immunosorbent assay. Results: A dose range of talazoparib with differential therapeutic efficacy was established, with significant delay in time to reach 1000 mm3 for tumors treated with 0.3 mg/kg (p = 0.02) but not 0.1 mg/kg talazoparib. On PET/computed tomography with [18F]PARPi, reduction in [18F]PARPi uptake after talazoparib dosing was consistent with talazoparib clearance, with reduction in PET activity attenuating over 24 hours. Talazoparib target engagement, measured by maximum tumor PET uptake, increased in a dose-dependent manner (3.9% versus 2.1% injected dose/g for 0.1 and 0.3 mg/kg at 3 hours post-talazoparib, p = 0.003) and correlated with PARP enzymatic activity among individual tumors as measured by total tumor poly-(ADP) ribose (p = 0.04, R = 0.62 at 1 hour post-talazoparib). Conclusions: PET imaging using [18F]PARPi has the potential to be a powerful tool in treatment monitoring by assessing PARPi target engagement in real-time. © 2019 International Association for the Study of Lung Cancer
Keywords:	positron-emission tomography; sclc; talazoparib; drug target engagement; poly(adp-ribose) polymerase 1 inhibitors
Journal Title:	Journal of Thoracic Oncology
Volume:	14
Issue:	10
ISSN:	1556-0864
Publisher:	Elsevier Inc.
Date Published:	2019-10-01
Start Page:	1743
End Page:	1752
Language:	English
DOI:	10.1016/j.jtho.2019.05.032
PUBMED:	31195178
PROVIDER:	scopus
PMCID:	PMC6764879
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85069448082&doi=10.1016%2fj.jtho.2019.05.032&partnerID=40&md5=023e182dbc1b26a22476a8202d6ad2f5
Notes:	Source: Scopus

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