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.

Public Health Relevance

The proposed project aims to rapid clinical translation of recent discovery of onco-metabolite, R(-)-2-hydroxyglutarate (2-HG), that is found in low grade gliomas and secondary glioblastoma (GBM) harboring mutations in isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2). Our investigation will enable us to establish 2-HG as an imaging biomarker of IDH mutations and to develop a clinically feasible combined MRI and MRS approach for detecting and quantifying 2-HG for characterization of genetic and metabolic alterations in brain tumor patients. Non-invasive detection and quantification 2-HG may improve diagnosis, predict prognosis and assist subtype specific therapeutic intervention in brain tumor treatment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Clinical Molecular Imaging and Probe Development (CMIP)
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Menkens, Anne E
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Emory University
Schools of Medicine
United States
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