In vivo detection of 2-hydroxyglutarate in gliomas by spectroscopic MRI

光谱 MRI 体内检测神经胶质瘤中的 2-羟基戊二酸

• 批准号: 8338812
• 负责人: Changho Choi
• 金额: $ 20.75万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8338812
• 关键词: 17p; Active Sites; Adult; Biological Markers; Biology; Brain; Brain Neoplasms; Cataloging; Catalogs; Cells; Clinical; Clinical Protocols; Clinical Research; Computer Simulation; Data; Detection; Diagnosis; Diffuse; Disease; Enrollment; Evaluation; Event; General Practices; Genes; Genetic; Genotype; Glioblastoma; Glioma; Gliomagenesis; Health; Human; Image; Imaging Device; Impairment; Infiltration; Institutional Review Boards; Investigation; Isocitrate Dehydrogenase; Lead; Lesion; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malignant Glioma; Malignant Neoplasms; Measurable; Measures; Metabolic; Metabolism; Methods; Mitochondria; Molecular; Monitor; Mutate; Mutation; Neurocognitive; Oligodendroglioma-Astrocytoma; Oncologist; PDGFRB gene; Pathogenesis; Patient Care; Patients; Pilocytic Astrocytoma; Positron-Emission Tomography; Primary Brain Neoplasms; Property; Protocols documentation; Radioactive; Recurrence; Reporting; Reproducibility; Research; Resected; Sampling; Scanning; Sequence Analysis; Spatial Distribution; Spectrum Analysis; Staging; Stress; System; TP53 gene; Techniques; Technology; Testing; Therapeutic; Time; Translations; Unresectable; Ursidae Family; Validation; Work; angiogenesis; base; clinical application; comparative genomic hybridization; design; follow-up; genome-wide; healthy volunteer; in vivo; magnetic resonance spectroscopic imaging; neuro-oncology; novel; outcome forecast; overexpression; quantum; response; surveillance study; tool; tumor

DESCRIPTION (provided by applicant): Non-invasive methods to image tumor metabolism have outstanding potential and could in principle allow the clinician to predict tumor genetics, stage, likelihood of therapeutic response and other crucial parameters that have direct bearing on patient care. However, the forms of metabolic imaging currently in use - particularly FDG-PET and low-field magnetic resonance spectroscopy - focus on general hallmarks of malignancy and do not provide any specific molecular information about the tumor. Here we propose to develop a method to predict the genotype of gliomas based on in vivo imaging of the "oncometabolite" 2-hydroxyglutarate (2HG). This metabolite accumulates only in gliomas that bear specific mutations in the genes encoding isocitrate dehydrogenase-1 and -2 (IDH), and the presence of these mutations in gliomas is strongly associated with low- grade lesions and a favorable prognosis. We will develop a proton magnetic resonance spectroscopic imaging (1H-MRSI) technique at 3T for detection of 2HG in the human brain and to determine noninvasively in vivo if the IDH mutations occur in patients with gliomas. Specifically, the research team will investigate spectral editing techniques, including scalar difference editing and multiple-quantum filtering. MRSI sequences will be first designed using computer simulations and will be validated in phantoms and healthy brain in vivo. Next, a clinical study in brain tumor patients will be carried out in patients with low grade gliomas or secondary glioblastomas enrolled in our clinical protocol. Evaluation of the IDH1 status by immunohistochemical (IHC) analysis of resected tumor will be performed and the patients will undergo 1H-MRSI to assess 2-HG status. The results will be correlated with IDH1 mutational status. We will study 30 patients of which we anticipate ~20 will have the mutation. An additional 15 patients with glioblastoma will be studied as negative control subjects since IDH1/2 mutations have not been found in this patient group. This work will lead to the first method to detect a tumor-specific metabolite in vivo. Furthermore, because our approach is easily integrated into existing 3T MR clinical systems and does not require radioactive probes, we anticipate few barriers to its translation into general practice. While this research will facilitate the utility of the proposed technology in the study of gliomas, it should be stressed that the technique will be widely applicable to other diseases in which alterations of 2HG levels are implicated.

描述（由申请人提供）：对肿瘤代谢进行成像的非侵入性方法具有突出的潜力，原则上可以让临床医生预测肿瘤遗传学、阶段、治疗反应的可能性以及对患者护理有直接影响的其他关键参数。然而，目前使用的代谢成像形式 - 特别是 FDG-PET 和低场磁共振波谱 - 侧重于恶性肿瘤的一般特征，并且不提供有关肿瘤的任何特定分子信息。在这里，我们建议开发一种基于“致癌代谢物”2-羟基戊二酸（2HG）的体内成像来预测神经胶质瘤基因型的方法。这种代谢物仅在编码异柠檬酸脱氢酶-1和-2 (IDH)的基因具有特定突变的神经胶质瘤中积累，并且神经胶质瘤中这些突变的存在与低度病变和良好的预后密切相关。我们将开发一种 3T 质子磁共振波谱成像 (1H-MRSI) 技术，用于检测人脑中的 2HG，并在体内无创地确定神经胶质瘤患者是否发生 IDH 突变。具体来说，研究团队将研究光谱编辑技术，包括标量差异编辑和多量子滤波。 MRSI 序列将首先使用计算机模拟进行设计，并将在人体模型和健康大脑中进行验证。接下来，将在我们的临床方案中登记的低级别胶质瘤或继发性胶质母细胞瘤患者中进行脑肿瘤患者的临床研究。将通过切除肿瘤的免疫组织化学 (IHC) 分析来评估 IDH1 状态，并且患者将接受 1H-MRSI 以评估 2-HG 状态。结果将与 IDH1 突变状态相关。我们将研究 30 名患者，预计其中约 20 名患者将出现突变。另外 15 名胶质母细胞瘤患者将作为阴性对照受试者进行研究，因为在该患者组中尚未发现 IDH1/2 突变。这项工作将导致第一种在体内检测肿瘤特异性代谢物的方法。此外，由于我们的方法很容易集成到现有的 3T MR 临床系统中，并且不需要放射性探针，因此我们预计其转化为一般实践的障碍很少。虽然这项研究将促进所提出的技术在神经胶质瘤研究中的应用，但应该强调的是，该技术将广泛适用于与 2HG 水平改变有关的其他疾病。

项目成果

Proton T2 measurement and quantification of lactate in brain tumors by MRS at 3 Tesla in vivo.

• DOI: 10.1002/mrm.25352
• 发表时间: 2015-06
• 期刊: MAGNETIC RESONANCE IN MEDICINE
• 影响因子: 3.3
• 作者: Madan, Akshay;Ganji, Sandeep K.;An, Zhongxu;Choe, Kevin S.;Pinho, Marco C.;Bachoo, Robert M.;Maher, Elizabeth M.;Choi, Changho
• 通讯作者: Choi, Changho