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.

SUBMITTER: Laird J 

PROVIDER: S-EPMC6764879 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature