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

描述（由申请人提供）：我们建议开发一种新型、非侵入性且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），该方法可能参与神经胶质瘤（最常见的原发性脑肿瘤类型）的进展。高级别星形细胞瘤（WHO IV）和原发性多形性胶质母细胞瘤（GBM）或由弥漫性低级别胶质瘤产生的继发性GBM是最致命的癌症之一，对诊断和治疗提出了巨大的挑战。最近发现低级别胶质瘤和继发性 GBM 中异柠檬酸脱氢酶 (IDH)1 和 IDH2 活性位点杂合突变产生的“肿瘤代谢物”2-HG，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 NADP 依赖性还原，赋予该酶新功能。 α-KG 至 2-HG。因此，具有 IDH1/2 突变的恶性神经胶质瘤中 2-HG 水平显着升高。这些重要发现将 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，用于早期诊断、预测预后、对患者进行分层以进行子集特异性个性化治疗和监测治疗反应。我们假设肿瘤代谢物 2-HG 可以通过磁共振波谱（NMR 和 MRS）方法在体外和体内检测到，因此将 2-HG 确立为弥漫性低级别胶质瘤中 IDH1/2 突变的成像标记物。我们基于分析肿瘤组织样本的初步研究和最近发表的文章已经确定了 2-HG 独特的 MRS 特征，并表明升高的 2-HG 浓度在 MRS 的检测范围内，可用于无创体内检测。随后，我们在临床 MRI 系统上开发并实施了一种局部二维 J 耦合相关光谱法 (2D L-COSY) 方法，用于检测和量化患者中的 2-HG。拟议项目将重点关注以下具体目标：1）建立2-HG作为IDH1/2突变的MRS可检测肿瘤代谢物标记物，并使用充分表征的脑肿瘤组织样本和基于体外高分辨率魔角旋转（HRMAS）NMR的代谢组学研究2-HG与肿瘤发生和肿瘤代谢的关联； 2) 开发和优化新型 2D J 耦合 L-COSY 和回波平面光谱成像 (EPSI) 方法，以实现脑肿瘤患者中 2-HG 的检测； 3) 使用开发的 2D L-COSY 方法研究 MRS 可检测的肿瘤代谢物 2-HG 作为评估神经胶质瘤预后和治疗反应的生物标志物。我们的研究旨在将新的生物标志物发现和新的成像技术快速转化为临床应用。该研究将建立2-HG作为影像学标志物，用于IDH突变的无创及时成像，监测和量化脑肿瘤患者的2-HG，从而改善脑肿瘤分类、预测预后并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.