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的、无创的、临床可行的磁共振波谱（MRS）方法来研究肿瘤代谢物R(-)-2-羟戊二酸酯（2-HG），它可能与胶质瘤（最常见的原发性脑肿瘤）的进展有关。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引起的继发性胶质母细胞瘤是最致命的癌症之一，在诊断和治疗方面存在巨大挑战。最近在低级别胶质瘤和继发性GBM中发现由异柠檬酸脱氢酶（IDH）1和IDH2活性位点杂合突变引起的“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？酮戊二酸(?- kg)，并通过催化NADP依赖性还原？-KG到2hg。因此，2-HG水平在IDH1/2突变的恶性胶质瘤中显著升高。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提供了机会，以检测和量化2-HG作为早期诊断、预测预后、分层患者进行亚群特异性个性化治疗和监测治疗反应的生物标志物。我们假设肿瘤代谢物2-HG可以通过磁共振波谱（NMR和MRS）方法在体内和体外检测到，因此建立2-HG作为弥漫性低级别胶质瘤中IDH1/2突变的成像标记物。我们的初步研究和最近发表的基于对肿瘤组织样本的分析，已经确定了2-HG独特的MRS特征，并建议升高的2-HG浓度在MRS的检测范围内，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耦合相关光谱方法（2D L-COSY），用于检测和量化患者的2-HG。该项目将专注于以下具体目标：1)建立2-HG作为IDH1/2突变的MRS检测肿瘤代谢物标记物，并利用具有良好特征的脑肿瘤组织样本和体外高分辨率魔角旋转（HRMAS）核磁共振代谢组学研究2-HG与肿瘤发生和肿瘤代谢的关系；2)开发和优化新的二维j耦合L-COSY和回波平面光谱成像（EPSI）方法，使脑肿瘤患者的2- hg检测成为可能；3)利用开发的2D L-COSY方法，探讨MRS检测肿瘤代谢物2-HG作为胶质瘤预后和治疗反应评估的生物标志物。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。本研究将建立2-HG作为无创、及时成像IDH突变的影像学标志物，监测和量化脑肿瘤患者的2-HG，从而提高脑肿瘤的分类，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 ?-ketoglutarate (?-KG) and confers the enzyme with a neofunction by catalyzing the NADP- dependent reduction of ?-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.