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

描述（由申请人提供）：我们提议开发一种新型、非侵入性和临床可行的磁共振光谱（MRS）方法，用于研究可能参与神经胶质瘤（最常见的原发性脑肿瘤类型）进展的致癌代谢物R（-）-2-羟基戊二酸（2-HG）。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，在诊断和治疗方面提出了巨大的挑战。最近发现的“癌代谢物”2-HG是由低级别胶质瘤和继发性GBM中异柠檬酸脱氢酶（IDH）1和IDH 2活性位点的杂合突变引起的，将遗传改变与肿瘤代谢联系起来。这种突变导致抑制野生型IDH 1/2将异柠檬酸转化为α-酮戊二酸（α-KG）的活性，并通过催化NADP依赖性还原α-酮戊二酸（α-KG）赋予酶新功能。 α-KG到2-HG。因此，在具有IDH 1/2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IDH 1/2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提供了机会，以检测和定量2-HG作为生物标志物，用于早期诊断，预测预后和对患者进行亚组特异性个性化治疗和监测治疗反应。我们假设癌代谢物2-HG可以通过离体和体内的磁共振光谱（NMR和MRS）方法检测到，因此建立2-HG作为弥漫性低级别胶质瘤中IDH 1/2突变的成像标记物。我们基于分析肿瘤组织样品的初步研究和最近的出版物已经鉴定了2-HG的独特MRS特征，并且表明升高的2-HG的浓度在用于非侵入性体内检测的MRS的检测范围内。随后，我们开发并实现了一个本地化的2维J耦合相关光谱方法（2D L-COSY）的临床MRI系统上检测和定量2-HG患者的方法。本研究的主要目的是：1）建立2-HG作为IDH 1/2突变的MRS可检测的肿瘤代谢物标志物，并利用脑肿瘤组织样本和基于代谢组学的离体高分辨率魔角自旋（HRMAS）NMR研究2-HG与肿瘤发生和肿瘤代谢的关系; 2）开发和优化新的2D J-耦合L-COSY和回波平面光谱成像（EPSI）方法，这将使得能够检测脑肿瘤患者中的2-HG;（3）应用改进的二维L-COSY方法研究MRS检测的癌代谢产物2-HG作为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IDH突变的非侵入性和及时成像的成像标记物，监测和定量脑肿瘤患者的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.