Imaging and Targeted Auger Radiotherapy of High-Grade Glioma

高级别胶质瘤的成像和靶向俄歇放射治疗

基本信息

批准号：
10375467
负责人：
Joel Richard Garbow
金额：
$ 67.29万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10375467
关键词：
Affinity Amino Acids Animal Model Applications Grants Area Autoradiography Binding Biological Assay Brain Brain Neoplasms Bromine Cell Nucleus Cells Conformal Radiotherapy DNA Repair DNA Repair Enzymes Development Diagnostic Diffusion Dose Enzymes Excision Exhibits Experimental Models Future Glioblastoma Glioma Goals Image Implant In Vitro Iodine Irradiated tumor Label Lead Magnetic Resonance Imaging Malignant - descriptor Maximum Tolerated Dose Measures Modeling Mus Necrosis Neurosphere Pathology Patients Performance Perfusion Physiology Positron Positron-Emission Tomography Primary Brain Neoplasms Prognosis Protocols documentation Publications Publishing Radiation Radiation necrosis Radiation therapy Radioisotopes Radiolabeled Radionuclide therapy Recurrence Recurrent tumor Reporting Research Project Grants Surgically-Created Resection Cavity Targeted Radiotherapy Technology Therapeutic Therapeutic Agents Therapeutic Studies Time Tissues Toxic effect Treatment Efficacy Tumor Volume U251 analog cell killing chemotherapy cytotoxicity design experimental study image guided imaging study improved in vivo inhibitor mouse model new technology non-invasive imaging novel overexpression radioligand research clinical testing response biomarker small molecule inhibitor standard of care theranostics therapeutic biomarker tissue oxygenation treatment effect treatment response tumor uptake

项目摘要

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.

摘要/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。最大的神经外科肿瘤切除，随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。鉴于预后不佳，需要改进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 和放射性坏死 (RN) 的诊断挑战。 PARP-1，一个参与 DNA 修复的酶在神经胶质瘤细胞的细胞核中选择性过度表达。最近几年，放射性标记的 PARP-1 抑制剂已被研究用于 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 抑制剂也被提议用于靶向治疗然而，迄今为止，放射治疗只发表了两篇报告。在本申请中，我们建议检查现有的放射性标记 PARP-1 抑制剂并合成和评估新型放射性标记 PARP-1 抑制剂，作为胶质母细胞瘤的治疗诊断剂。建议使用碘和溴的放射性核素进行成像和治疗研究。在此，我们将重点关注用于 PET 成像和俄歇发射的正电子发射放射性核素发射放射性核素进行治疗。这些研究将得到先进的 MRI 实验的支持，旨在描述肿瘤和 RN 的生理学特征，并评估治疗反应。该组织的目标建议是： i) 合成各种已建立的和新型的放射性标记 PARP-1 抑制剂，并评估它们的体外摄取和功效，ii) 评估放射性标记的 PARP-1 抑制剂在小鼠模型中的摄取情况胶质母细胞瘤和实验性放射性坏死，以及 iii) 确定 PARP-1 的治疗效果胶质母细胞瘤小鼠模型中的抑制剂。该拨款申请将由优质专家团队领导，专长于实验性放射性坏死模型和磁共振成像（Joel Garbow 博士）；定向辐射治疗和 PET 成像（Buck Rogers 博士）；放射性配体开发和标记（周东博士）；体外结合测定和放射自显影（徐金斌博士）；和放射性标记的 PARP-1 抑制剂和神经胶质瘤动物模型（Thomas Reiner 博士）。如果成功，我们的方法将为治疗复发性胶质母细胞瘤患者。