Imaging and Targeted Auger Radiotherapy of High-Grade Glioma

总结/摘要 胶质母细胞瘤（GBM）是一种高度侵袭性的恶性原发性脑肿瘤。神经外科最大肿瘤 切除术，然后是高度适形放疗和同步化疗，仍然是标准的护理， GBM患者。这些肿瘤不可避免地会复发。鉴于前景黯淡，改进的技术 迫切需要更好地治疗复发性GBM。另一个复杂的因素是 非侵入性区分复发性GBM与放射性坏死（RN）的诊断挑战。PARP-1， 参与DNA修复的酶，在神经胶质瘤细胞的细胞核中选择性过表达。近年来， 已经研究了放射性标记的PARP-1抑制剂用于PARP-1表达的非侵入性成像， 神经胶质瘤以及其他肿瘤。放射性标记的PARP-1抑制剂也已被提议用于靶向治疗。 然而，迄今为止，只有两份已发表的报告。在本申请中，我们建议 检查现有的放射性标记的PARP-1抑制剂，并合成和评价新的放射性标记的PARP-1 抑制剂，作为胶质母细胞瘤的治疗诊断剂。碘和溴的放射性核素被提议用于成像 和治疗研究。在此，我们将重点介绍用于PET成像和俄歇电子扫描的正电子发射放射性核素。 放射放射性核素用于治疗。这些研究将得到先进的MRI实验的支持， 表征肿瘤和RN的生理学，并用于评估治疗反应。的目标 建议是：i）合成各种已建立的和新的放射性标记的PARP-1抑制剂，并评估它们的活性。 ii）评价放射性标记的PARP-1抑制剂在以下小鼠模型中的摄取： 胶质母细胞瘤和实验性放射性坏死，和iii）确定PARP-1的治疗功效 在胶质母细胞瘤的鼠模型中的抑制剂。这项拨款申请将由一个高质量的专家团队领导， 专门研究实验性放射性坏死模型和MR成像（Joel Garbow博士）;靶向放射 治疗和PET成像（Buck Rogers博士）;放射性配体开发和标记（Dong Zhou博士）;体外 结合试验和放射自显影（Jinbin Xu博士）;放射性标记的PARP-1抑制剂和胶质瘤动物 模型（托马斯雷纳博士）。如果成功，我们的方法将提供一个新的技术驱动的范例， 治疗复发性胶质母细胞瘤患者。

SUMMARY/ABSTRACT Glioblastoma (GBM) is a highly aggressive, malignant, primary brain tumor. Maximal neurosurgical tumor resection, followed by highly conformal radiation and concurrent chemotherapy, remains the standard of care for GBM patients. These tumors inevitably recur. Given the dismal prognosis, improved technologies are desperately needed to enable better treatment of recurrent GBM. An additional complicating factor is the diagnostic challenge of non-invasively discriminating recurrent GBM from radiation necrosis (RN). PARP-1, an enzyme involved in DNA repair, is selectively overexpressed in the nuclei of glioma cells. In recent years, radiolabeled PARP-1 inhibitors have been investigated for the non-invasive imaging of PARP-1 expression in glioma, as well as other tumors. Radiolabeled PARP-1 inhibitors have also been proposed for targeted radiotherapy, though, to date, there have only been two published reports. In this application, we propose to examine existing radiolabeled PARP-1 inhibitors and to synthesize and evaluate novel radiolabeled PARP-1 inhibitors, as theranostic agents for glioblastoma. Radionuclides of iodine and bromine are proposed for imaging and therapeutic studies. Herein, we will focus on positron-emitting radionuclides for PET imaging and Auger- emitting radionuclides for therapy. These studies will be supported by advanced MRI experiments aimed at characterizing the physiology of tumors and RN, and for assessing therapeutic response. The aims of the proposal are to: i) synthesize various established and novel radiolabeled PARP-1 inhibitors, and evaluate their uptake and efficacy in vitro, ii) evaluate radiolabeled PARP-1 inhibitors for uptake in murine models of glioblastoma and experimental radiation necrosis, and iii) determine the therapeutic efficacy of the PARP-1 inhibitors in murine models of glioblastoma. This grant application will be led by a quality team of experts, specializing in models of experimental radiation necrosis and MR imaging (Dr. Joel Garbow); targeted radiation therapy and PET imaging (Dr. Buck Rogers); radioligand development and labeling (Dr. Dong Zhou); in vitro binding assays and autoradiography (Dr. Jinbin Xu); and radiolabeled PARP-1 inhibitors and glioma animal models (Dr. Thomas Reiner). If successful, our approach will provide a new technology driven paradigm for treating patients with recurrent glioblastoma.