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

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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.