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
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
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DOI：
10.1016/j.jtho.2019.05.032
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发表时间：
2019-10-01
影响因子：
20.4
通讯作者：
Rudin, Charles M.
中科院分区：
文献类型：
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作者：
Laird, James;Lok, Benjamin H.;Rudin, Charles M.
前言：聚腺苷二磷酸核糖聚合酶（PARP）抑制剂是治疗小细胞肺癌的有效药物。我们测试了通过氟18-放射性标记的PARPi（[F-18] PARPi）测量的PARP抑制剂（PARPi）靶向接合是否具有预测体内药物功效的潜力。方法：在移植有SCLC患者来源的异种移植物的小鼠中评价每日talazoparib治疗期间的肿瘤生长抑制，以评价多剂量talazoparib的功效。在单次口服talazoparib后的多个时间点，给小鼠静脉注射[F-18] PARPi放射性示踪剂，以定量评估talazoparib可降低肿瘤放射性示踪剂摄取和正电子发射断层扫描（PET）/计算机断层扫描活性的程度。结果：建立了具有不同治疗效果的talazoparib剂量范围，对于用0.3 mg/kg（p = 0.02）而不是0.1 mg/kg talazoparib治疗的肿瘤，达到1000 mm 3的时间显著延迟（p = 0.02）。在使用[F-18] PARPi的PET/计算机断层扫描中，talazoparib给药后[F-18] PARPi摄取的降低与talazoparib清除一致，PET活性降低在24小时内减弱。通过最大肿瘤PET摄取测量的Talazoparib靶向结合以剂量依赖性方式增加（在talazoparib给药后3小时，0.1和0.3 mg/kg组分别为3.9%和2.1%注射剂量/g，p = 0.003），并与通过总肿瘤聚（ADP）核糖测定的单个肿瘤中的PARP酶活性相关结论：使用[F-18] PARPi的PET成像具有通过实时评估PARPi靶标接合而成为治疗监测中的有力工具的潜力。(C)2019年国际肺癌研究协会。爱思唯尔公司出版All rights reserved.
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 ([F-18] 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 [F-18] 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 mm(3) for tumors treated with 0.3 mg/kg (p = 0.02) but not 0.1 mg/kg talazoparib. On PET/computed tomography with [F-18] PARPi, reduction in [F-18] 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 [F-18] PARPi has the potential to be a powerful tool in treatment monitoring by assessing PARPi target engagement in real-time. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.