2D MR Correlational Spectroscopy Platform for Molecular and Genetic Characterizations of Glioma

随着对分子和遗传基础研究的日益重视和临床需求的增加，项目总结 诊断和治疗监测，学术项目和扫描仪制造商都在制作 改进和创新磁共振成像(MRI)和波谱(MRS)的重大努力 询问患者代谢功能和异常的方法。弥漫性浸润性低品位 胶质瘤(Lgg)是最致命的癌症之一，在诊断和治疗方面面临着巨大的挑战。 它们在形态、位置、基因改变和对治疗的反应方面有很大的不同。一大专业 LGG患者的临床治疗面临的挑战是缺乏准确和非侵入性的方法 根据肿瘤亚型对患者进行分层，以帮助早期诊断、个体化治疗和纵向临床 管理层。异柠檬酸脱氢酶(IDH1和IDH2)杂合性突变的发现 高达70%的LGG和继发性多形性胶质母细胞瘤(GBM)中的基因将基因改变与肿瘤联系起来 代谢、预后和治疗反应。IDH突变导致一种新的催化功能 α-酮戊二酸依赖NADP还原为肿瘤代谢物R(-)-2-羟基戊二酸，(2-HG)。这些 重要的发现正在改变胶质瘤的临床治疗模式，如果给予检测和治疗的能力 检测2-HG以识别携带IDH突变的肿瘤，预测预后，定义亚群特异性 治疗和监测治疗反应。我们早期的研究发现了独一无二的磁共振光谱特征 2-HG，这使得我们能够建立2-HG作为IDH突变的生物标记物，有可能定量2-HG在 脑肿瘤患者的空间定位二维相关波谱(COSY)MRS研究 方法。这种检测2-HG的新策略可以克服传统的一维J耦合的局限性 编辑MRS方法以拆分2-HG和其他感兴趣的代谢物。埃默里大学的研究人员 在与西门子工程师的合作下，研发人员计划开发和实施2D COSY 临床扫描仪上的平台，用于非侵入性基因分类和胶质瘤特征以及 使用2-HG作为监测IGG患者再治疗反应和肿瘤进展的潜在指标 生物标志物。该项目结合了埃默里和西门子的互补优势、专业知识和资源 其翻译目标是整合最新的癌症生物学和生物标记物研究以及先进的成像技术 技术为脑肿瘤的临床治疗提供了一种范式转换的成像工具。具体的 目标是：1)开发一种使用最新的通道线圈阵列和新型线圈的灵敏度增强策略 用于2D COSY的邻近加权并行磁共振波谱数据采集和合并；2)为了测试， 对所开发的方法进行了优化和实施，并开发了在线数据处理工具箱 并在临床扫描仪上对2D COSY数据进行分析；3)对所开发的2D COSY进行验证 使用2-HG作为标记物并检测患者中其他代谢物的神经胶质瘤遗传学分析平台。

PROJECT SUMMARY With the growing emphases and clinical needs for molecular and genetic based diagnosis and treatment monitoring, both academic programs and scanner manufactures are making significant effort to improve and innovate magnetic resonance imaging (MRI) and spectroscopy (MRS) methods for interrogating metabolic functions and abnormalities in patients. Diffuse infiltrating low grade gliomas (LGG) are among the most lethal cancers and present great challenges in diagnosis and treatment, as they vary considerably in morphology, location, genetic alterations and response to therapy. One major challenge in the clinical management of LGG patients is the lack of accurate and non-invasive methods to stratify patients by tumor subtype to help with early diagnosis, individualized treatment and longitudinal clinical management. The discovery of heterozygous mutations in the isocitrate dehydrogenase (IDH1 and IDH2) genes in up to 70 % of LGG and secondary glioblastoma multiforme (GBM) links genetic alterations to tumor metabolism, prognosis and responses to treatment. IDH mutations lead to a neofunction of catalyzing the NADP-dependent reduction of α-ketoglutarate to oncometabolite R(-)-2-hydroxyglutarate, (2-HG). These important findings are changing the clinical paradigm of managing gliomas, if given the ability of detecting and measuring 2-HG to identify IDH mutation-bearing tumors, predict the prognosis, define subset-specific treatments and monitor therapeutic response. Our early study found the unique MR spectroscopic signature of 2-HG, which allowed us to establish 2-HG as a biomarker of IDH mutations with potential to quantify 2-HG in brain tumor patients using a spatially localized two-dimensional (2D) correlation spectroscopy (COSY) MRS method. This new strategy for detecting 2-HG can overcome the limitation of conventional 1D J-coupling editing MRS approaches in resolving 2-HG and other metabolites of interest. Investigators at Emory University in partnership with engineers from Siemens MR R&D are proposing to develop and implement a 2D COSY platform on the clinical scanner for non-invasive genetically classifying and characterizing gliomas as well as potentially monitoring retreatment responses and tumor progression in LGG patients using 2-HG as a biomarker. This project combines complementary strengths, expertise and resources of Emory and Siemens with a translational goal to integrate the latest cancer biology and biomarker research and advanced imaging technology to provide a paradigm shifting imaging tool for clinical management of brain tumors. The specific aims are: 1) to develop a sensitivity enhancing strategy with the latest 64-channel coil array and a novel coil proximity weighted parallel MR spectroscopy data acquisition and combination for 2D COSY; 2) to test, optimize and implement the developed method and to develop in-line data processing toolbox for processing and analyzing 2D COSY data on the clinical scanner; and 3) to test and validate the developed 2D COSY platform for genetically profiling gliomas using 2-HG as a marker and detecting other metabolites in patients.