This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Glioblastoma, the most common primary brain tumor in adults, is considered to be among the deadliest of human cancers. With a median survival time of 14.6 months and approximately 25% of patients alive at 2 years after the most aggressive treatment regimens, there is clearly a desperate need to improve the understanding of basic biological processes in glioblastoma. The molecular aberrations underlying this disease have been extensively characterized and an important framework of critical cancer pathways involved in glioblastoma growth and survival has emerged, centered prominently on activation of the RAS/MAPK pathway and dysregulation of the PI3Kinase pathway. However, targeted inhibition of these and other molecular pathways in glioblastoma patients has been largely ineffective and, as a result, there is increasing interest in understanding mechanisms of altered metabolism since it represents a 'functional readout'of the constellation of genetic mutations that interact to influence cell growth and survival. The characteristic and well established metabolic features of glioblastoma - intense glucose uptake on FDG-PET, abundant lactate production, and a defect in NADP+ - dependent isocitrate dehydrogenase - may be interconnected events due to a specific genetic mutation. Alternatively, these features may be a common endpoint reflecting redundancy in the cancer cell's genetic program. To address basic questions related to the genotype-metabolic phenotype connection in glioblastoma we have engaged a multidisciplinary team of physicians and scientists in a clinical and translational study designed to identify the critical metabolic pathways that drive unregulated tumor cell proliferation in the brain microenvironment in vivo.
In Aim 1 we will define the metabolic phenotype of glioblastoma in a novel human orthotopic mouse model by 13C NMR spectral analysis of genetically characterized tumors following infusion of [U-13C]glucose or [1,2-13C]glucose to assess, respectively, the pathways intersecting in the citric acid cycle and relative flux through the pentose phosphate pathway. Specifically, we will determine whether the FDG signature of glioblastoma - increased glucose uptake - is feeding one or some combination of three pathways: excess anaerobic glycolysis to lactate, excess aerobic glycolysis to pyruvate followed by oxidation in the citric acid cycle, or excess flux through the pentose phosphate pathway to support proliferation or to compensate for loss of NADPH production due to mutation of IDH-1.
In Aim 2 we will define the metabolic phenotype in glioblastoma patients undergoing surgical resection for presumed high grade glioma. In each patient, 13C NMR spectral analysis of tumor extracts will be obtained after intra-operative infusion of [U-13C]glucose or [1,2-13C]glucose. Results will be correlated with preoperative imaging by FDG-PET, ultra high resolution MR imaging on a 7T magnet, diffusion tensor imaging and 1H-spectroscopy to generate a comprehensive non-invasive view of the tumor with the goal of identifying infiltrative, metabolically active tumor cells within the brain.

Public Health Relevance

Glioblastoma is the most common primary brain tumor and is considered to be among the deadliest of human cancers. The metabolism of the cells is much higher than normal cells and, like many cancers, represents a possible target for new drugs in cancer therapy. Our proposed research will dissect the metabolic pathways that are abnormal in glioblastoma in a concerted effort to develop new therapies quickly.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Biotechnology Resource Grants (P41)
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Special Emphasis Panel (ZRG1-SBIB-Q (40))
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University of Texas Sw Medical Center Dallas
Schools of Medicine
United States
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Chiu, Tsuicheng D; Arai, Tatsuya J; Campbell Iii, James et al. (2018) MR-CBCT image-guided system for radiotherapy of orthotopic rat prostate tumors. PLoS One 13:e0198065
Funk, Alexander M; Anderson, Brian L; Wen, Xiaodong et al. (2017) The rate of lactate production from glucose in hearts is not altered by per-deuteration of glucose. J Magn Reson 284:86-93
Mishkovsky, Mor; Anderson, Brian; Karlsson, Magnus et al. (2017) Measuring glucose cerebral metabolism in the healthy mouse using hyperpolarized 13C magnetic resonance. Sci Rep 7:11719
Moreno, Karlos X; Harrison, Crystal E; Merritt, Matthew E et al. (2017) Hyperpolarized ?-[1-13 C]gluconolactone as a probe of the pentose phosphate pathway. NMR Biomed 30:
Zhang, Liang; Habib, Amyn A; Zhao, Dawen (2016) Phosphatidylserine-targeted liposome for enhanced glioma-selective imaging. Oncotarget 7:38693-38706
Walker, Christopher M; Merritt, Matthew; Wang, Jian-Xiong et al. (2016) Use of a Multi-compartment Dynamic Single Enzyme Phantom for Studies of Hyperpolarized Magnetic Resonance Agents. J Vis Exp :e53607
Wu, Yunkou; Zhang, Shanrong; Soesbe, Todd C et al. (2016) pH imaging of mouse kidneys in vivo using a frequency-dependent paraCEST agent. Magn Reson Med 75:2432-41
Malloy, Craig R; Sherry, A Dean (2016) Biochemical Specificity in Human Cardiac Imaging by 13C Magnetic Resonance Imaging. Circ Res 119:1146-1148
Moss, Lacy R; Mulik, Rohit S; Van Treuren, Tim et al. (2016) Investigation into the distinct subcellular effects of docosahexaenoic acid loaded low-density lipoprotein nanoparticles in normal and malignant murine liver cells. Biochim Biophys Acta 1860:2363-2376
Bastiaansen, Jessica A M; Merritt, Matthew E; Comment, Arnaud (2016) Measuring changes in substrate utilization in the myocardium in response to fasting using hyperpolarized [1-(13)C]butyrate and [1-(13)C]pyruvate. Sci Rep 6:25573

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