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Imaging IDH1 Mutations in Glioma and Other Malignancies

胶质瘤和其他恶性肿瘤中 IDH1 突变的成像

基本信息

批准号：
8788512
负责人：
Satish K. Chitneni
金额：
$ 23.9万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8788512
关键词：
Address Animals Binding Biodistribution Biologic Characteristic Biological Biological Assay Biological Markers Brain Neoplasms Cancer Patient Cell Line Cell physiology Cells Characteristics Clinical Detection Development Diagnostic Dioxygenases Drug Targeting Drug or chemical Tissue Distribution Enzymes Evaluation Fluorine Frequencies Genes Genomics Glioblastoma Glioma Goals Health Image In Vitro Inhibitory Concentration 50 Investigation Isocitrate Dehydrogenase Isocitrates Malignant Neoplasms Metabolic Methods Modeling Monitor Mus Mutate Mutation Mutation Detection NADP Normal tissue morphology Nude Mice Outcome Pathogenesis Patients Play Positron-Emission Tomography Procedures Prognostic Marker Property Quality of life Radioactive Iodine Radiolabeled Research Role Somatic Mutation Specificity Structure Testing Translations alpha ketoglutarate analog base cancer type clinically relevant enzyme activity glioma cell line imaging biomarker imaging modality improved in vivo inhibitor/antagonist isocitrate mutant neoplastic cell non-invasive imaging novel radiotracer research study small molecule subcutaneous targeted treatment tool tumor tumor initiation tumor xenograft uptake

项目摘要

DESCRIPTION (provided by applicant): Isocitrate dehydrogenase IDH1 and IDH2 are metabolic enzymes that catalyze the conversion of isocitrate to ¿-ketoglutarate (¿-KG) in cells. Genes encoding for IDH1 and IDH2 are mutated in >70% of grade II and III gliomas and secondary glioblastomas. They are also present in a variety of non-CNS tumors with varying frequencies. Mutant IDH1/2 lose their normal catalytic activity but gain the ability to convert ¿-KG to 2-hydroxyglutarate (2-HG). 2-HG has a structure similar to ¿-KG and competitively inhibits several of the ¿-KG-dependent dioxygenases in cells, thereby, playing a role in tumor initiation. IDH mutations are the earliest genetic changes in the formation of low-grade gliomas. On the other hand, glioma patients with IDH1/2 mutations are found to have significantly longer survival compared to those with normal IDH1 tumors, suggesting the use of these mutations as prognostic biomarkers. IDH mutations are analyzed by ex vivo procedures and currently, there is no clinically applicable method available for noninvasive detection of these mutations in cancers. We aim to develop a positron emission tomography (PET) imaging method using radiolabeled probes to image IDH1 mutations, with the goal of addressing the critical need for an imaging biomarker to study these cancer-associated mutations. Our preliminary studies demonstrate the feasibility of developing radiotracers for the most commonly occurring IDH1 mutation, IDH1-R132H, using small-molecule inhibitors of the mutant enzyme. In this project, we will synthesize nonradioactive analogs for several candidate radiotracers and examine their inhibitory potency against the purified mutant enzyme IDH1-R132H in vitro. These experiments will establish the potential of these analogs to bind to the mutant IDH1 and will enable selection of compounds for radiolabeling experiments in Specific Aim 2. In Specific Aim 2, we will synthesize radiolabeled compounds starting from appropriate precursors and fluorine-18 and/or radioiodine. The uptake and retention of radiotracers in mutant IDH1-expressing cells will be examined using glioma cell lines having native IDH1-R132H mutations or stably-expressing the mutant enzyme (R132H). The specificity will be verified in parallel experiments using isogenic cell lines carrying wild-type IDH1. Specific Aim 3 will expand into in vivo evaluation and will investigate the biological characteristics and tumor localization properties of promising radiotracers. Biodistribution studies will be conducted initially in normal mice to study normal tissue distribution characteristics. This will be followed by studies in athymic mice carrying mutant IDH1 tumor xenografts to investigate the in vivo binding and retention of radiotracers in tumors. Finally, small-animal PET studies will be conducted using clinically relevant orthotopic tumor models (R132H) to demonstrate the feasibility of imaging IDH1 mutations in vivo. The information obtained from these studies will help in developing a method for PET imaging of IDH1 mutations with potential for clinical translation.

描述（由申请人提供）：异柠檬酸脱氢酶IDH 1和IDH 2是在细胞中催化异柠檬酸转化为<$-酮戊二酸（<$-KG）的代谢酶。编码IDH 1和IDH 2的基因在>70%的II级和III级胶质瘤和继发性胶质母细胞瘤中突变。它们也以不同的频率存在于各种非CNS肿瘤中。突变体IDH 1/2失去了它们正常的催化活性，但获得了将<$-KG转化为2-羟基戊二酸（2-HG）的能力。2-HG具有与<$-KG相似的结构，并且竞争性地抑制细胞中的几种<$-KG依赖性双加氧酶，从而在肿瘤起始中发挥作用。IDH突变是低级别胶质瘤形成中最早的遗传变化。另一方面，发现具有IDH 1/2突变的胶质瘤患者与具有正常IDH 1肿瘤的患者相比具有显著更长的生存期，这表明使用这些突变作为预后生物标志物。 IDH突变通过离体程序进行分析，目前，没有临床适用的方法可用于癌症中这些突变的非侵入性检测。我们的目标是开发一种使用放射性标记探针对IDH 1突变进行成像的正电子发射断层扫描（PET）成像方法，目的是解决对成像生物标志物的迫切需求，以研究这些癌症相关突变。我们的初步研究证明了使用突变酶的小分子抑制剂开发最常见的IDH 1突变IDH 1-R132 H的放射性示踪剂的可行性。在这个项目中，我们将合成几种候选放射性示踪剂的非放射性类似物，并在体外检测它们对纯化的突变酶IDH 1-R132 H的抑制效力。这些实验将确定这些类似物与突变体IDH 1结合的潜力，并将能够选择化合物用于特定目标2中的放射性标记实验。在具体目标2中，我们将从适当的前体和氟-18和/或放射性碘开始合成放射性标记的化合物。将使用具有天然IDH 1-R132 H突变或稳定表达突变体酶（R132 H）的神经胶质瘤细胞系来检查放射性示踪剂在突变体IDH 1表达细胞中的摄取和保留。将在使用携带野生型IDH 1的等基因细胞系的平行实验中验证特异性。Specific Aim 3将扩展到体内评价，并将研究生物学特性和肿瘤定位特性。很有前途的放射性示踪剂生物分布研究最初将在正常小鼠中进行，以研究正常组织分布特色随后将在携带突变IDH 1肿瘤异种移植物的无胸腺小鼠中进行研究，以研究放射性示踪剂在肿瘤中的体内结合和保留。最后，将使用临床相关的原位肿瘤模型（R132 H）进行小动物PET研究，以证明IDH 1突变体内成像的可行性。从这些研究中获得的信息将有助于开发具有临床转化潜力的IDH 1突变PET成像方法。