Abnormal metabolism is a hallmark of cancer and results in altered immune function. Notably, glycolysis is of- ten enhanced in cancers, even in the presence of abundant oxygen (i.e. the Warburg effect). This form of ?aer- obic glycolysis? results in a dramatic decrease in tumor acidity due to increased concentration of lactic acid, which comes with dramatic consequences, as this is directly linked to increased tumor aggressiveness, in- creased invasion, increased genetic mutations, increased resistance to therapy, increased angiogenesis, and decreased immune function. Extensive scientific evidence supports the hypothesis that aerobic glycolysis plays an important role in gliomagenesis and altered tumor-infiltrating CD8+ T lymphocytes (TIL)-cell function; how- ever, there remains a critical gap in our understanding of the role of extracellular acidosis and oxygen metabo- lism in altering immune function in human gliomas due to the lack of a robust non-invasive tool for measuring low pH and oxygen consumption. Thus, the purpose of the current project is to validate a new imaging tech- nique that can provide high-resolution images of regions of aerobic glycolysis, or high lactic acid production but low oxygen consumption, and explore the association between this new measurement and measures of both tumor and TIL metabolic function. The current study will investigate the central hypotheses that 1) tumor tissue undergoing high aerobic glycolysis defined by low pH and low O2 consumption can be reliably detected using multi-echo amine CEST imaging; 2) regions with high ?aerobic glycolytic index? (AGI) on MRI will have elevat- ed hypoxic and glycolytic expression levels independent of the concentration of immune cells; 3) tumors with high in vivo AGI using MRI will have high ex vivo measurements of AGI in tumor, but not immune cells; and 4) TILs extracted from tumors with high in vivo AGI measurements will have lower glucose consumption and cy- tokine production, suggestive of functional impairment. To accomplish this we will first verify the specificity of to areas of the tumor undergoing abnormal metabolism using tissue from image-guided biopsies. We hypothesize the AGI will provide high specificity for tumor and high levels of AGI will correlate with a high expression of fea- tures involved in aerobic glycolysis, including hypoxia inducible factor (HIF)-1?, GLUT3, and HK2. Next, we will explore the association between in vivo AGI and ex vivo AGI in both tumor and TILs using a functional assay and extracellular flux analysis estimates of the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) during metabolic manipulations of tissue extracted using image-guided biopsy. We theorize the MRI-derived AGI will show a strong positive association with the ex vivo AGI estimate of glycolytic potential in tumor but no association in TILs. Lastly, we will test whether tumors with an elevated in vivo AGI measured with MRI have dampened glucose utilization and cytokine production through ex vivo metabolic manipulation.
Abnormal metabolism is a hallmark of cancer and triggers a variety of catastrophic biologic events including increased tumor aggressiveness, resistance to treatments, altered gene expression, formation of new blood vessels, and immunosuppression. We have recently developed a fast, non-invasive, high-resolution imaging method to create maps of an ?aerobic glycolytic index?, or AGI, based on simultaneously estimating regions of increased acidity from lactic acid build-up (via glycolysis) and oxygen consumption throughout the entire human brain using clinical MRI systems. In the current study we will push the state-of-the-art by performing image-guided biopsy in regions with high AGI, examine tissue markers of abnormal metabolism and an in vitro ?functional assay? of resected tumor tissue that is analogous to our in vivo imaging measures, and explore the relationship between MRI-measured AGI measurements and immune cell functional impairment.
|Harris, Robert J; Yao, Jingwen; Chakhoyan, Ararat et al. (2018) Simultaneous pH-sensitive and oxygen-sensitive MRI of human gliomas at 3 T using multi-echo amine proton chemical exchange saturation transfer spin-and-gradient echo echo-planar imaging (CEST-SAGE-EPI). Magn Reson Med 80:1962-1978|
|Chakhoyan, Ararat; Woodworth, Davis C; Harris, Robert J et al. (2018) Mono-exponential, diffusion kurtosis and stretched exponential diffusion MR imaging response to chemoradiation in newly diagnosed glioblastoma. J Neurooncol 139:651-659|
|Yao, Jingwen; Ruan, Dan; Raymond, Catalina et al. (2018) Improving B0 Correction for pH-Weighted Amine Proton Chemical Exchange Saturation Transfer (CEST) Imaging by Use of k-Means Clustering and Lorentzian Estimation. Tomography 4:123-137|
|Patel, Chirag B; Fazzari, Elisa; Chakhoyan, Ararat et al. (2018) 18F-FDOPA PET and MRI characteristics correlate with degree of malignancy and predict survival in treatment-naïve gliomas: a cross-sectional study. J Neurooncol 139:399-409|