MR Imaging of IDH Mutational Status in Brain Tumors

脑肿瘤 IDH 突变状态的 MR 成像

• 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
• 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

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（由申请人提出）：该项目的目的是通过检测oncometabolite 2-羟基甲酸盐酸盐（2-羟基甲酸盐酸盐（2-羟基）的合成，开发了超极化的13c磁共振光谱（MRS）H，以对突变状态和异急塞脱氢酶（IDH）的无创评估进行开发。 -hg），这是通过杂交IDH产生的。 。 -Ketoglutarate（Alpha-KG），突变体催化α-KG的相反，通过抑制突变体IDH作为一种新的治疗方法来积累。实施这种疗法可观的疗法，GBM中2-HG的存在与一组患者的结局更好，因此IDH较少的攻击性治疗将使患者分层分子亚替代。 HG累积仅通过涉及提取和使用高分辨率的魔术角旋转1H MRS的高度入侵方法检测到，最近检测到2-H的活检。 Chellenge，由于2-HG的复杂频谱模式及其与相邻的代谢物重叠。使用超极化的13c MRS探测α-KG到2-Hg的转化，我们将通过以下AMS进行测试：AIM 1。验证使用13C MRS的超极化[1-13C] Cular Imaging剂，以监测unteatiant的IDH活性。我们将使用13C MRS和超极化[1-13c] -alpha-kg监测野生型和突变体IDH细胞中α2-HG的转化，作为确定体内正常动物脑肿瘤状态的方法。我们将型和突变的IDH原位脑肿瘤确认为体内研究开发的AIM 1。