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

描述（由申请人提供）：无创成像肿瘤代谢的方法具有突出的潜力，原则上可以让临床医生预测肿瘤的遗传学、分期、治疗反应的可能性以及其他直接影响患者护理的关键参数。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，而不能提供任何关于肿瘤的特定分子信息。在这里，我们提出了一种基于“肿瘤代谢物”2-羟基戊二酸（2HG）的体内成像来预测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）基因发生特异性突变的胶质瘤中积累，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。我们将开发一种质子磁共振光谱成像（1H-MRSI）技术，用于检测人脑中的2HG，并在体内非侵入性地确定脑胶质瘤患者是否发生IDH突变。具体来说，研究小组将研究光谱编辑技术，包括标量差分编辑和多量子滤波。核磁共振成像序列将首先使用计算机模拟设计，并将在体内的幻影和健康大脑中进行验证。下一步，将在我们临床方案中纳入的低级别胶质瘤或继发性胶质母细胞瘤患者中开展脑肿瘤患者的临床研究。将对切除肿瘤进行免疫组化（IHC）分析，评估IDH1状态，并对患者进行1H-MRSI以评估2-HG状态。结果将与IDH1突变状态相关。我们将对30名患者进行研究，我们预计其中约20人会有这种突变。另外15例胶质母细胞瘤患者将作为阴性对照组进行研究，因为在该患者组中未发现IDH1/2突变。这项工作将导致第一个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，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涉及2HG水平改变的其他疾病。

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.