Young Robert J, Demétrio De Souza França Paula, Pirovano Giacomo, Piotrowski Anna F, Nicklin Philip J, Riedl Christopher C, Schwartz Jazmin, Bale Tejus A, Donabedian Patrick L, Kossatz Susanne, Burnazi Eva M, Roberts Sheryl, Lyashchenko Serge K, Miller Alexandra M, Moss Nelson S, Fiasconaro Megan, Zhang Zhigang, Mauguen Audrey, Reiner Thomas, Dunphy Mark P
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
The Brain Tumor Center, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Neurooncol Adv. 2020 Sep 15;2(1):vdaa119. doi: 10.1093/noajnl/vdaa119. eCollection 2020 Jan-Dec.
We report preclinical and first-in-human-brain-cancer data using a targeted poly (ADP-ribose) polymerase 1 (PARP1) binding PET tracer, [F]PARPi, as a diagnostic tool to differentiate between brain cancers and treatment-related changes.
We applied a glioma model in p53-deficient nestin/tv-a mice, which were injected with [F]PARPi and then sacrificed 1 h post-injection for brain examination. We also prospectively enrolled patients with brain cancers to undergo dynamic [F]PARPi acquisition on a dedicated positron emission tomography/magnetic resonance (PET/MR) scanner. Lesion diagnosis was established by pathology when available or by Response Assessment in Neuro-Oncology (RANO) or RANO-BM response criteria. Resected tissue also underwent PARPi-FL staining and PARP1 immunohistochemistry.
In a preclinical mouse model, we illustrated that [F]PARPi crossed the blood-brain barrier and specifically bound to PARP1 overexpressed in cancer cell nuclei. In humans, we demonstrated high [F]PARPi uptake on PET/MR in active brain cancers and low uptake in treatment-related changes independent of blood-brain barrier disruption. Immunohistochemistry results confirmed higher PARP1 expression in cancerous than in noncancerous tissue. Specificity was also corroborated by blocking fluorescent tracer uptake with an excess unlabeled PARP inhibitor in patient cancer biospecimen.
Although larger studies are necessary to confirm and further explore this tracer, we describe the promising performance of [F]PARPi as a diagnostic tool to evaluate patients with brain cancers and possible treatment-related changes.
我们报告了使用靶向聚（ADP - 核糖）聚合酶1（PARP1）的正电子发射断层显像（PET）示踪剂[F]PARPi作为诊断工具来区分脑癌和治疗相关变化的临床前及首例人脑癌数据。
我们在p53基因缺陷的巢蛋白/tv - a小鼠中应用了胶质瘤模型，给这些小鼠注射[F]PARPi，然后在注射后1小时处死以进行脑部检查。我们还前瞻性地招募了脑癌患者，在专用的正电子发射断层显像/磁共振（PET/MR）扫描仪上进行动态[F]PARPi采集。病变诊断在可行时通过病理确定，或根据神经肿瘤学反应评估（RANO）或RANO - BM反应标准确定。切除的组织也进行了PARPi - FL染色和PARP1免疫组织化学检查。
在临床前小鼠模型中，我们证明[F]PARPi穿过血脑屏障并特异性结合癌细胞核中过表达的PARP1。在人类中，我们证明在活跃的脑癌中PET/MR上[F]PARPi摄取高，而在与治疗相关的变化中摄取低，且与血脑屏障破坏无关。免疫组织化学结果证实癌组织中PARP1表达高于非癌组织。在患者癌症生物样本中用过量未标记的PARP抑制剂阻断荧光示踪剂摄取也证实了其特异性。
尽管需要更大规模的研究来证实并进一步探索这种示踪剂，但我们描述了[F]PARPi作为评估脑癌患者及可能的治疗相关变化的诊断工具的良好性能。
