MR Investigation of IDH Mutation and Its Marker 2-HG in Brain Tumor Patients

描述(申请人提供)：我们建议开发一种新的、非侵入性的和临床可行的磁共振波谱(MRS)方法来研究肿瘤代谢物R(-)-2-羟基戊二酸(2-HG)，它可能参与胶质瘤的进展，胶质瘤是最常见的脑肿瘤类型。起源于弥漫性低级别胶质瘤的高级别星形细胞瘤(WHO IV)和原发性多形性胶质母细胞瘤(GBM)或继发性多形性胶质母细胞瘤(GBM)是致死率最高的肿瘤之一，给诊断和治疗带来了巨大的挑战。最近在低级别胶质瘤和继发性脑胶质瘤中发现了异柠檬酸脱氢酶(IDH)1和IDH2活性部位杂合性突变所致的肿瘤代谢物2-HG，并将遗传改变与肿瘤代谢联系起来。这种突变导致野生型IDH1/2将异柠檬酸转化为α-酮戊二酸(α-KG)的活性受到抑制，并通过催化依赖于NADP的还原来赋予该酶新的功能 α-KG到2-HG。因此，在IDH1/2突变的恶性胶质瘤中，2-HG水平显著升高。这些重要的发现将IDH1/2突变和2-HG与脑肿瘤生物学联系起来，并为开发新的非侵入性方法来检测和量化2-HG作为生物标志物提供了机会，用于进行早期诊断、预测预后、对患者进行特定亚组的个性化治疗和监测治疗反应。我们假设核磁共振和磁共振波谱方法可以在体内外检测到肿瘤代谢物2-HG，从而建立了2-HG作为弥漫性低级别胶质瘤IDH1/2突变的影像标志物。我们的初步研究和最近发表的基于对肿瘤组织样本分析的研究已经确定了2-HG独特的MRS特征，并提示升高的2-HG浓度在MRS的检测范围内，用于体内的非侵入性检测。随后，我们开发并实现了一种局部化的二维J-耦合相关光谱方法(2D L-COSY)在临床磁共振系统上用于检测和定量患者的2-HG。该项目将集中于以下具体目标：1)建立2-HG作为IDh1/2突变的MRS可检测的肿瘤代谢标记物，并利用表征良好的脑肿瘤组织样本和基于体外高分辨率魔角旋转核磁共振的代谢组学研究2-HG与肿瘤发生和肿瘤代谢的关系；2)开发和优化新型的二维J-耦合L-COSY和回声平面光谱成像方法，使2-HG能够在脑肿瘤患者中检测到；3)应用改进的二维L-COSY方法研究MRS可检测的肿瘤代谢物2-HG作为评估脑胶质瘤预后和治疗疗效的生物标志物。我们的研究旨在将新的生物标记物发现和新的成像技术快速转化为临床应用。本研究将建立2-HG作为无创性、及时的IDH突变的影像标志物，监测和定量脑肿瘤患者的2-HG，从而改进脑肿瘤的分类，预测预后，辅助亚型特异性治疗干预治疗脑癌。

DESCRIPTION (provided by applicant): We propose to develop a novel, non-invasive and clinically feasible magnetic resonance spectroscopic (MRS) method for investigating onco-metabolite, R(-)-2-hydroxyglutarate (2-HG), that may be involved in the progression of gliomas, the most common type of primary brain tumors. The high grade astrocytoma (WHO IV) and primary glioblastoma multiforme (GBM) or secondary GBM rising from diffuse low grade gliomas are among the most lethal cancers and present great challenges in diagnosis and treatment. The recent discovery of "onco-metabolite" 2-HG resulting from the heterozygous mutations in the active site of isocitrate dehydrogenase (IDH)1 and IDH2 in low-grade gliomas and secondary GBM links genetic alterations to the tumor metabolism. Such mutation leads to inhibition of the wild-type IDH1/2 activity of converting isocitrate to α-ketoglutarate (α-KG) and confers the enzyme with a neofunction by catalyzing the NADP- dependent reduction of α-KG to 2-HG. As a consequence, 2-HG level is substantially elevated in malignant gliomas with IDH1/2 mutations. These important findings link IDH1/2 mutations and 2-HG with brain tumor biology and presented opportunities to develop novel non-invasive approaches to detect and quantify 2-HG as a biomarker for making early diagnosis, predicting prognosis and stratifying patients for subset-specific personalized treatments and monitoring therapeutic responses. We hypothesize that oncometabolite 2-HG can be detected by magnetic resonance spectroscopic (NMR and MRS) methods ex vivo and in vivo, therefore establishing 2-HG as an imaging marker of IDH1/2 mutations in diffuse low grade gliomas. Our preliminary study and recent publication based on analyzing tumor tissue samples has identified the unique MRS features of 2-HG and suggested that the concentration of elevated 2-HG is in the detection range of MRS for non- invasive in vivo detection. Subsequently, we have developed and implemented a localized 2-dimensional J-coupled correlation spectroscopic method (2D L-COSY) method on the clinical MRI systems for detecting and quantifying 2-HG in patients. The proposed project will focus on following Specific Aims: 1) to establish 2-HG as an MRS detectable oncometabolite marker of IDH1/2 mutations and investigate the associations of 2-HG with oncogenesis and tumor metabolism using well-characterized brain tumor tissue samples and ex vivo high- resolution magic angle spinning (HRMAS) NMR based metabolomics; 2) to develop and optimize novel 2D J-coupled L-COSY and echo planar spectroscopic imaging (EPSI) methods that will enable the detection of 2-HG in brain tumor patients; 3) to investigate the MRS detectable onco-metabolite 2-HG as a biomarker for assessment of glioma prognosis and treatment response using developed 2D L-COSY method. Our investigation is aimed to rapid translation of new biomarker discoveries and new imaging technologies to clinical applications. The study will establish 2-HG as an imaging marker for non-invasive and timely imaging of IDH mutations, monitoring and quantifying 2-HG in brain tumor patients, therefore, to improve brain tumor classification, predict prognosis and assist subtype specific therapeutic intervention to treat brain cancer.