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

描述(由申请人提供)：非侵入性方法成像肿瘤代谢具有突出的潜力，原则上可以允许临床医生预测肿瘤遗传学、分期、治疗反应的可能性和其他与患者护理直接相关的关键参数。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，并不提供任何关于肿瘤的特定分子信息。在这里，我们建议开发一种基于体内“肿瘤代谢物”2-羟基戊二酸(2HG)的成像来预测胶质瘤基因分型的方法。这种代谢物仅在编码异柠檬酸脱氢酶-1和异柠檬酸脱氢酶-2(IDH)基因发生特定突变的胶质瘤中积累，而这些突变在胶质瘤中的存在与低级别病变和良好预后密切相关。我们将开发一种3T质子磁共振光谱成像(1H-MRSI)技术来检测人脑中的2HG，并在体内无创性地确定IDH突变是否发生在胶质瘤患者中。具体地说，研究小组将研究光谱编辑技术，包括标量差编辑和多量子过滤。MRSI序列将首先使用计算机模拟来设计，并将在幻影和体内健康的大脑中进行验证。下一步，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。将对切除的肿瘤进行免疫组织化学(IHC)分析以评估IDH1的状态，患者将接受1H-MRSI以评估2-HG的状态。结果将与IDH1突变状态相关。我们将研究30名患者，我们预计其中约20人会有这种突变。另外15名胶质母细胞瘤患者将作为阴性对照对象进行研究，因为在这组患者中没有发现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磁共振临床系统中，并且不需要放射性探测器，因此我们预计将其转化为一般实践没有什么障碍。虽然这项研究将促进建议的技术在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其他与2HG水平变化有关的疾病。

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.