Imaging and Targeted Auger Radiotherapy of High-Grade Glioma

摘要/摘要 胶质母细胞瘤(GBM)是一种高度侵袭性、恶性的原发脑肿瘤。最大神经外科肿瘤 切除，然后进行高度适形放疗和同步化疗，仍然是治疗的标准。 GBM患者。这些肿瘤不可避免地会复发。考虑到糟糕的预后，改进的技术是 迫切需要对复发的基底膜进行更好的治疗。另一个复杂的因素是 非侵入性鉴别复发性基底膜和放射性坏死的诊断挑战。PARP-1、AN 参与DNA修复的酶，选择性地在胶质瘤细胞的细胞核中过表达。近年来， 放射性标记的PARP-1抑制剂已被研究用于非侵入性成像PARP-1表达 胶质瘤，以及其他肿瘤。放射性标记的PARP-1抑制剂也被提出用于靶向 然而，到目前为止，放射治疗只有两篇发表的报告。在本申请中，我们建议 检查现有的放射性标记PARP-1抑制剂并合成和评价新型放射性标记PARP-1 抑制物，作为治疗胶质母细胞瘤的药物。碘和溴的放射性核素被建议用于成像 和治疗研究。在这里，我们将集中在正电子发射的正电子放射性核素的PET成像和俄歇- 为了治疗而发射放射性核素。这些研究将得到高级核磁共振实验的支持，旨在 确定肿瘤和RN的生理学特征，并用于评估治疗反应。该计划的目标是 建议：i)合成各种已建立的和新的放射性标记的PARP-1抑制剂，并评价它们的 体外摄取和疗效，II)评价放射性标记PARP-1抑制剂在小鼠体内的摄取 胶质母细胞瘤和实验性放射性坏死，以及III)确定PARP-1的治疗效果 小鼠胶质母细胞瘤模型中的抑制剂。这项拨款申请将由一支高素质的专家团队领导， 专门研究实验性辐射坏死和核磁共振成像模型(乔尔加博博士)；定向辐射 治疗和正电子发射计算机断层扫描(Buck Rogers博士)；放射配基发展和标记(周栋博士)；体外 结合分析和放射自显影(徐进斌博士)；放射性标记的PARP-1抑制剂和胶质瘤动物 模特(托马斯·莱纳博士)。如果成功，我们的方法将提供一个新的技术驱动的范例 治疗复发的胶质母细胞瘤患者。

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.