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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA169937-05
Application #
9247144
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Menkens, Anne E
Project Start
2013-04-15
Project End
2018-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
5
Fiscal Year
2017
Total Cost
$337,909
Indirect Cost
$121,301
Name
Emory University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Fleischer, Candace C; Zhong, Xiaodong; Mao, Hui (2018) Effects of proximity and noise level of phased array coil elements on overall signal-to-noise in parallel MR spectroscopy. Magn Reson Imaging 47:125-130
Langley, Jason; Huddleston, Daniel E; Sedlacik, Jan et al. (2017) Parkinson's disease-related increase of T2*-weighted hypointensity in substantia nigra pars compacta. Mov Disord 32:441-449
Langley, Jason; Huddleston, Daniel E; Merritt, Michael et al. (2016) Diffusion tensor imaging of the substantia nigra in Parkinson's disease revisited. Hum Brain Mapp 37:2547-56
Kalinina, Juliya; Ahn, Jun; Devi, Narra S et al. (2016) Selective Detection of the D-enantiomer of 2-Hydroxyglutarate in the CSF of Glioma Patients with Mutated Isocitrate Dehydrogenase. Clin Cancer Res 22:6256-6265
Orza, Anamaria; Yang, Yi; Feng, Ting et al. (2016) A nanocomposite of Au-AgI core/shell dimer as a dual-modality contrast agent for x-ray computed tomography and photoacoustic imaging. Med Phys 43:589
Fan, Jun; Lin, Ruiting; Xia, Siyuan et al. (2016) Tetrameric Acetyl-CoA Acetyltransferase 1 Is Important for Tumor Growth. Mol Cell 64:859-874
Chen, Hongbo; Wang, Liya; King, Tricia Z et al. (2016) Increased frontal functional networks in adult survivors of childhood brain tumors. Neuroimage Clin 11:339-346
Langley, Jason; Huddleston, Daniel E; Chen, Xiangchuan et al. (2015) A multicontrast approach for comprehensive imaging of substantia nigra. Neuroimage 112:7-13