MR Imaging of IDH Mutational Status in Brain Tumors

脑肿瘤 IDH 突变状态的 MR 成像

基本信息

批准号：
8452079
负责人：
Sabrina Miriam Ronen
金额：
$ 15.79万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-02 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8452079
关键词：
Acute Myelocytic Leukemia Address Biological Markers Biopsy Biopsy Specimen Brain Neoplasms Caring Cells Citric Acid Cycle Clinical Colon Carcinoma Complex Decarboxylation Detection Development Disease Enzymes Event Genotype Glioblastoma Glioma Goals Image Isocitrate Dehydrogenase Isocitrates Knowledge Magic Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of prostate Mediating Metabolic Diseases Methods Mitochondria Molecular Monitor Motivation Mutation Outcome Patient Care Patients Pattern Phenotype Quality of life Regimen Reporting Research Resolution Risk Stratification Testing Therapeutic alpha ketoglutarate base cancer type imaging modality in vivo innovation isocitrate molecular imaging mutant novel novel therapeutic intervention outcome forecast prevent tool tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The goal of this project is to develop a hyperpolarized 13C magnetic resonance spectroscopy (MRS)- based approach for noninvasive assessment of the mutational status and activity of isocitrate dehydrogenase (IDH) by detecting synthesis of the oncometabolite 2-hydroxyglutarate (2-HG), which is produced by mutant IDH. Motivation: Mutations in IDH enzymes were recently reported in over 70% of low grade gliomas and secondary glioblastomas (GBM) as well as in 23% of acute myeloid leukemia patients and some cases of colon and prostate cancer. Whereas wild type IDH catalyzes the oxidative decarboxylation of isocitrate to ¿- ketoglutarate (alpha-KG), mutant IDH catalyzes the conversion of alpha-KG into 2-HG. Because 2-HG is likely involved in mediating oncogenesis, preventing its accumulation by inhibiting mutant IDH was proposed as a novel therapeutic approach. Noninvasive imaging of IDH mutational status and activity is critical for development and clinical implementation of such a therapy. Furthermore, when considering currently available therapies, the presence of 2-HG in GBM is associated with a group of patients that has better outcomes and benefits from less aggressive treatment. Imaging IDH status would thus serve to stratify GBM patients into molecular subtypes and optimize their treatment. To date, IDH mutations and 2-HG accumulation have only been detected by highly invasive methods involving extraction and analysis of biopsy samples. Using high-resolution magic angle spinning 1H MRS, 2-HG was recently detected in glioma patient biopsies. However, detection of 2-HG by 1H MRS in vivo remains a challenge, due to the complex spectral pattern of 2-HG and its overlap with neighboring metabolites. Noninvasive imaging biomarkers that inform on the mutational status of IDH are therefore needed for patient stratification and implementation of disease-appropriate treatments. Hypothesis: We hypothesize that the mutational status of IDH can be monitored by probing the conversion of alpha-KG into 2-HG using hyperpolarized 13C MRS. We will test this hypothesis through the following aims: Aim 1. To validate hyperpolarized [1-13C]-alpha-KG as a molecular imaging agent for monitoring mutant IDH activity using 13C MRS in cells. We will use 13C MRS and hyperpolarized [1-13C]-alpha-KG to monitor conversion of alpha-KG into 2-HG in wild type and mutant IDH cells. Aim 2. To validate the approach developed in Aim 1 as a method for determining IDH status in orthotopic brain tumors in vivo. We will investigate wild type and mutant IDH orthotopic brain tumors to confirm the value of the approach developed in Aim 1 for in vivo studies.

描述（由申请人提供）：该项目的目标是开发一种基于超极化 13C 磁共振波谱 (MRS) 的方法，通过检测致癌代谢物 2- 的合成来无创评估异柠檬酸脱氢酶 (IDH) 的突变状态和活性。羟基戊二酸 (2-HG)，由突变 IDH 产生动机：IDH 酶突变最近已被报道。 70% 的低度恶性胶质瘤和继发性胶质母细胞瘤 (GBM) 以及 23% 的急性髓系白血病患者以及某些结肠癌和前列腺癌病例中，而野生型 IDH 会催化异柠檬酸的氧化脱羧反应。 - 酮戊二酸 (α-KG)，突变 IDH 催化 α-KG 转化为 2-HG 由于 2-HG 可能参与介导肿瘤发生，因此提出通过抑制突变 IDH 来防止其积累作为一种新型非侵入性成像方法。 IDH 突变状态和活性的研究对于此类疗法的开发和临床实施至关重要。此外，在考虑当前可用的疗法时，GBM 中 2-HG 的存在与一组具有更好疗效的患者相关。因此，对 IDH 状态进行成像可以将 GBM 患者分为分子亚型并优化其治疗，迄今为止，IDH 突变和 2-HG 积累只能通过涉及活检样本的侵入性方法来检测。最近使用高分辨率魔角旋转 1H MRS 在神经胶质瘤患者活检中检测到 2-HG 然而，由于其复杂性，在体内通过 1H MRS 检测 2-HG 仍然是一个挑战。因此，需要了解 2-HG 的光谱模式及其与邻近代谢物的重叠，以了解 IDH 的突变状态，以便对患者进行分层并实施适合疾病的治疗。假设：我们可以确定 IDH 的突变状态。通过使用超极化 13C MRS 探测 α-KG 转化为 2-HG 进行监测我们将通过以下目标检验这一假设：目标 1. 验证超极化。 [1-13C]-α-KG 作为分子成像剂，使用 13C MRS 监测细胞中的突变 IDH 活性我们将使用 13C MRS 和超极化 [1-13C]-α-KG 监测 α-KG 转化为 2。目标 2. 验证目标 1 中开发的方法作为体内确定原位脑肿瘤中 IDH 状态的方法。研究野生型和突变型 IDH 原位脑肿瘤，以确认目标 1 中开发的方法对于体内研究的价值。