scholarly journals CBMT-08. IN VIVO EVALUATION OF PENTOSE PHOSPHATE PATHWAY ACTIVITY IN ORTHOTOPIC GLIOMA USING HYPERPOLARIZED δ-[1-13C]GLUCONOLACTONE

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi34-vi34
Author(s):  
Georgios Batsios ◽  
Pavithra Viswanath ◽  
Peng Cao ◽  
Celine Taglang ◽  
Elavarasan Subramani ◽  
...  
Keyword(s):  
Pentose Phosphate Pathway ◽  
Tumor Development ◽  
Pentose Phosphate ◽  
Response To Therapy ◽  
Metabolic Imaging ◽  
Normal Brain ◽  
In Vivo Evaluation ◽  
First Time ◽  
Orthotopic Glioma

Abstract The pentose phosphate pathway (PPP) generates NADPH and ribose 5-phosphate, which are involved in the scavenging of reactive oxygen species and the synthesis of nucleotides. As such, the PPP is typically upregulated in cancer cells to address the metabolic needs of rapid cell proliferation. Imaging PPP upregulation could therefore be useful in tumor assessment. One intermediate of the pathway is 6-phospho-δ-gluconolactone (6P-δ-GL), which is produced by phosphorylation of δ-gluconolactone. 6P-δ-GL is further metabolized to 6-phospho-gluconate (6PG). The goal of our study was to evaluate, for the first time, whether hyperpolarized (HP) δ-[1-13C]gluconolactone can be used to assess PPP flux and detect the presence of tumor in an orthotopic glioma rat model. Athymic nude rats bearing orthotropic U87 tumors or age-matched tumor-free controls were investigated. HP studies were performed following intravenous injection of HP δ-[1-13C]gluconolactone and metabolic images using a flyback spectral-spatial echo-planar spectroscopic imaging pulse were acquired. The data were processed using in-house Matlab code. 6P-δ-GL and 6-phospho-γ-[1-13C]gluconolactone were observed in all rats ~10 seconds after HP δ-[1-13C]gluconolactone injection, followed ~5 seconds later by production of 6PG observed at 179.3ppm. These data indicate that HP δ-[1-13C]gluconolactone likely crosses the blood-brain barrier, consistent with its transport via glucose transporters, and is rapidly metabolized. Importantly, 6PG was significantly higher in tumor voxels. The ratio of 6PG-to-6P-δ-GL was comparable in normal brain and in normal-appearing contralateral brain of tumor-bearing rats at 0.43±0.09 and 0.45±0.06 respectively (p=0.85), but significant higher in the tumor regions at 0.70±0.11 (p=0.04 and p=0.02 respectively), consistent with the elevated PPP flux that typically occurs in tumor cells. Our results indicate, to our knowledge for the first time, that metabolism of HP δ-[1-13C]gluconolactone can be assessed in the brain and that elevated 6PG production in glioma provides a potential metabolic imaging approach to probe tumor development, recurrence and response to therapy.

scholarly journals TBMT-01. HYPERPOLARIZED δ-[1-13C]GLUCONOLACTONE MONITORS TERT-INDUCED ELEVATION IN PENTOSE PHOSPHATE PATHWAY FLUX IN BRAIN TUMORS IN VIVO

2021 ◽  
Vol 3 (Supplement_1) ◽  
pp. i20-i20
Author(s):  
Georgios Batsios ◽  
Pavithra Viswanath ◽  
Celine Taglang ◽  
Robert Flavell ◽  
Joseph Costello ◽  
...  
Keyword(s):  
Pentose Phosphate Pathway ◽  
Therapeutic Target ◽  
Pentose Phosphate ◽  
Response To Therapy ◽  
Homogeneous Distribution ◽  
Low Grade ◽  
Tumor Proliferation ◽  
Low Grade Gliomas ◽  
Tert Expression

Abstract Telomerase reverse transcriptase (TERT) expression is essential for tumor proliferation and is an attractive therapeutic target for gliomas. TERT expression has previously been shown to enhance glucose flux via the pentose phosphate pathway (PPP) in low grade gliomas expressing TERT. Hyperpolarized δ-[1-13C]gluconolactone has been used to detect flux via the PPP by monitoring its conversion to 6-phospho-[1-13C]gluconate (6PG) in isolated perfused liver. The goal of our study was to evaluate whether hyperpolarized δ-[1-13C]gluconolactone can be used to monitor elevated PPP flux induced by TERT expression in low grade gliomas, thereby providing a non-invasive method of assessing TERT expression in vivo. Immortalized normal human astrocytes without (NHApre) and with TERT expression (NHApost) were used in cell bioreactor experiments. In vivo experiment with rats bearing orthotopic NHApost or patient-derived low-grade oligodendroglioma (SF10417) tumors were contacted. Dynamic 13C MR spectra were acquired at 14T (cells) or 3T (rats) following injection of hyperpolarized δ-[1-13C]gluconolactone. NHApost cells showed significantly higher flux through the PPP compared to NHApre. This finding was in agreement with previous results indicating that TERT expression elevates PPP flux. In all rats δ-[1-13C]gluconolactone and 6PG were observed indicating that δ-[1-13C]gluconolactone crosses the blood-brain barrier and is rapidly metabolized. Furthermore, both models presented homogeneous distribution of δ-[1-13C]gluconolactone in the brain and higher ratio of 6PG-to-δ-[1-13C]gluconolactone in the tumor area. In summary we show in vivo that hyperpolarized δ-[1-13C]gluconolactone metabolism to 6-phospho-[1-13C]gluconate is significantly higher in tumor compared to contralateral normal brain in TERT-expressing genetically-engineered and patient-derived low-grade oligodendrogliomas. Due to its fundamental role in tumor proliferation, TERT is both a tumor biomarker and a therapeutic target. Monitoring HP δ-[1-13C]gluconolactone metabolism, therefore, has the potential to inform on tumor burden and response to therapy in the clinic.

scholarly journals Imaging 6-Phosphogluconolactonase Activity in Brain Tumors In Vivo Using Hyperpolarized δ-[1-13C]gluconolactone

2021 ◽  
Vol 11 ◽  
Author(s):  
Georgios Batsios ◽  
Céline Taglang ◽  
Peng Cao ◽  
Anne Marie Gillespie ◽  
Chloé Najac ◽  
...  
Keyword(s):  
Redox Homeostasis ◽  
Pentose Phosphate ◽  
Response To Therapy ◽  
Live Cells ◽  
Normal Brain ◽  
Glioblastoma Cells ◽  
Non Invasive ◽  
Contralateral Normal Brain ◽  
Magnetic Resonance Imaging Mri

IntroductionThe pentose phosphate pathway (PPP) is essential for NADPH generation and redox homeostasis in cancer, including glioblastomas. However, the precise contribution to redox and tumor proliferation of the second PPP enzyme 6-phosphogluconolactonase (PGLS), which converts 6-phospho-δ-gluconolactone to 6-phosphogluconate (6PG), remains unclear. Furthermore, non-invasive methods of assessing PGLS activity are lacking. The goal of this study was to examine the role of PGLS in glioblastomas and assess the utility of probing PGLS activity using hyperpolarized δ-[1-13C]gluconolactone for non-invasive imaging.MethodsTo interrogate the function of PGLS in redox, PGLS expression was silenced in U87, U251 and GS2 glioblastoma cells by RNA interference and levels of NADPH and reduced glutathione (GSH) measured. Clonogenicity assays were used to assess the effect of PGLS silencing on glioblastoma proliferation. Hyperpolarized δ-[1-13C]gluconolactone metabolism to 6PG was assessed in live cells treated with the chemotherapeutic agent temozolomide (TMZ) or with vehicle control. 13C 2D echo-planar spectroscopic imaging (EPSI) studies of hyperpolarized δ-[1-13C]gluconolactone metabolism were performed on rats bearing orthotopic glioblastoma tumors or tumor-free controls on a 3T spectrometer. Longitudinal 2D EPSI studies of hyperpolarized δ-[1-13C]gluconolactone metabolism and T2-weighted magnetic resonance imaging (MRI) were performed in rats bearing orthotopic U251 tumors following treatment with TMZ to examine the ability of hyperpolarized δ-[1-13C]gluconolactone to report on treatment response.ResultsPGLS knockdown downregulated NADPH and GSH, elevated oxidative stress and inhibited clonogenicity in all models. Conversely, PGLS expression and activity and steady-state NADPH and GSH were higher in tumor tissues from rats bearing orthotopic glioblastoma xenografts relative to contralateral brain and tumor-free brain. Importantly, [1-13C]6PG production from hyperpolarized δ-[1-13C]gluconolactone was observed in live glioblastoma cells and was significantly reduced by treatment with TMZ. Furthermore, hyperpolarized δ-[1-13C]gluconolactone metabolism to [1-13C]6PG could differentiate tumor from contralateral normal brain in vivo. Notably, TMZ significantly reduced 6PG production from hyperpolarized δ-[1-13C]gluconolactone at an early timepoint prior to volumetric alterations as assessed by anatomical imaging.ConclusionsCollectively, we have, for the first time, identified a role for PGLS activity in glioblastoma proliferation and validated the utility of probing PGLS activity using hyperpolarized δ-[1-13C]gluconolactone for non-invasive in vivo imaging of glioblastomas and their response to therapy.

scholarly journals Beneficial effects of acute inhibition of the oxidative pentose phosphate pathway in the failing heart

2014 ◽  
Vol 306 (5) ◽  
pp. H709-H717 ◽  
Author(s):  
Claudio Vimercati ◽  
Khaled Qanud ◽  
Gianfranco Mitacchione ◽  
Danuta Sosnowska ◽  
Zoltan Ungvari ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pentose Phosphate Pathway ◽  
Tissue Concentration ◽  
Glucose Consumption ◽  
Pentose Phosphate ◽  
Oxidative Pentose Phosphate Pathway ◽  
Stroke Work ◽  
Failing Heart

In vitro studies suggested that glucose metabolism through the oxidative pentose phosphate pathway (oxPPP) can paradoxically feed superoxide-generating enzymes in failing hearts. We therefore tested the hypothesis that acute inhibition of the oxPPP reduces oxidative stress and enhances function and metabolism of the failing heart, in vivo. In 10 chronically instrumented dogs, congestive heart failure (HF) was induced by high-frequency cardiac pacing. Myocardial glucose consumption was enhanced by raising arterial glycemia to levels mimicking postprandial peaks, before and after intravenous administration of the oxPPP inhibitor 6-aminonicotinamide (80 mg/kg). Myocardial energy substrate metabolism was measured with radiolabeled glucose and oleic acid, and cardiac 8-isoprostane output was used as an index of oxidative stress. A group of five chronically instrumented, normal dogs served as control. In HF, raising glycemic levels from ∼80 to ∼170 mg/dL increased cardiac isoprostane output by approximately twofold, whereas oxPPP inhibition normalized oxidative stress and enhanced cardiac oxygen consumption, glucose oxidation, and stroke work. In normal hearts glucose infusion did not induce significant changes in cardiac oxidative stress. Myocardial tissue concentration of 6P-gluconate, an intermediate metabolite of the oxPPP, was significantly reduced by ∼50% in treated versus nontreated failing hearts, supporting the inhibitory effect of 6-aminonicotinamide. Our study indicates an important contribution of the oxPPP activity to cardiac oxidative stress in HF, which is particularly pronounced during common physiological changes such as postprandial glycemic peaks.

Physiologic and Metabolic Magnetic Resonance Imaging in Gliomas

2006 ◽  
Vol 24 (8) ◽  
pp. 1228-1235 ◽  
Author(s):  
Yue Cao ◽  
Pia C. Sundgren ◽  
Christina I. Tsien ◽  
Thomas T. Chenevert ◽  
Larry Junck
Keyword(s):  
Magnetic Resonance ◽  
Cerebral Blood Volume ◽  
Radiation Treatment ◽  
Malignant Gliomas ◽  
Response To Therapy ◽  
Metabolic Imaging ◽  
Treatment Modalities ◽  
Tissue Properties ◽  
Metabolic Properties

Magnetic resonance (MR) imaging provides excellent soft tissue differentiation and in vivo assessment of physiologic and metabolic properties of tissue. As new and more aggressive treatment modalities and combined modalities are being investigated for brain tumor treatment, it is becoming more important to accurately define tumor volumes for treatment planning, to determine the most aggressive tumor regions for intensified radiation treatment, to identify early regional response to therapy for reoptimization of treatment, and to detect early indicators of developing normal tissue toxicity. Readily available MR techniques of physiologic and metabolic imaging can currently provide useful information regarding tumor tissue properties including chemical composition, cerebral blood volume, perfusion, vascular permeability, and water mobility. This article will focus on the potential value of MR physiologic and metabolic imaging in the clinical management of malignant gliomas.

In Vivo Detection by31P NMR of Pentose Phosphate Pathway Block Secondary to Biochemical Modulation

1996 ◽  
Vol 9 (3) ◽  
pp. 114-120 ◽  
Author(s):  
U. Mahmood ◽  
J. C. Street ◽  
C. Matei ◽  
D. Ballon ◽  
D. S. Martin ◽  
...  
Keyword(s):  
Pentose Phosphate Pathway ◽  
Pentose Phosphate ◽  
Biochemical Modulation ◽  
In Vivo Detection

scholarly journals LINC00941 Promotes Progression of Non-Small Cell Lung Cancer by Sponging miR-877-3p to Regulate VEGFA Expression

2021 ◽  
Vol 11 ◽  
Author(s):  
Min-Huan Ren ◽  
Si Chen ◽  
Liang-Ge Wang ◽  
Wen-Xiu Rui ◽  
Pei Li
Keyword(s):  
Umbilical Vein ◽  
Tumor Development ◽  
Luciferase Assay ◽  
Small Cell Lung ◽  
Tumor Tissues ◽  
Umbilical Vein Endothelial Cells ◽  
First Time ◽  
Development Of Gastric Cancer

Long noncoding RNAs (lncRNAs) play critical roles in carcinoma occurrence and metastasis. LINC00941 has been found to mediate the development of gastric cancer, and LINC00941 was negatively associated with the longer overall survival of lung adenocarcinoma patients. Herein, our aim was to investigate the effects and mechanisms of LINC00941 in NSCLC progression. Microarray was used to identify the change lncRNAs in NSCLC, LINC00941 was found to increase in tumor tissues and patients’ plasma. Knockdown of LINC00941 didn’t modulate the proliferation of NSCLC cells, but inhibition of LINC00941 in NSCLC cells suppressed the angiogenesis ability of human umbilical vein endothelial cells (HUVECs). Moreover, LINC00941 promoted tumorigenesis in vivo, while si-LINC00941 inhibited tumor development of NSCLC. VEGFA was should to be significantly modulated by LINC00941 in NSCLC cells, then luciferase assay proved that LINC00941 regulated VEGFA expression via interacting with miR-877-3p. Followed functional experiments indicated that overexpression of LINC00941 accelerated angiogenesis and NSCLC tumor progression via miR-877-3p/VEGFA axis both in vitro and in vivo. In conclusion, our results clarified the LINC00941 function for the first time, and LINC00941 promoted the progression of NSCLC, which was mediated by miR-877-3p/VEGFA axis. This study might provide new understanding and targets for NSCLC diagnosis and treatment.

scholarly journals CBMT-41. IMAGING A HALLMARK OF CANCER: HYPERPOLARIZED 13C-MAGNETIC RESONANCE SPECTROSCOPY CAN NON-INVASIVELY MONITOR TERT EXPRESSION IN LOW-GRADE GLIOMAS IN VIVO

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi42-vi42
Author(s):  
Pavithra Viswanath ◽  
Georgios Batsios ◽  
Anne Marie Gillespie ◽  
Russell O Pieper ◽  
Sabrina Ronen
Keyword(s):  
Lactate Production ◽  
Metabolic Imaging ◽  
Imaging Biomarkers ◽  
Resonance Spectroscopy ◽  
Low Grade ◽  
Normal Brain ◽  
Non Invasive ◽  
Glucose Flux ◽  
Tert Expression

Abstract Telomerase reverse transcriptase (TERT) expression is a hallmark of cancer, including in primary glioblastomas and low-grade oligodendrogliomas. Since TERT is essential for glioma proliferation and is an attractive therapeutic target, metabolic imaging of TERT status can inform on tumor progression and response to therapy. To that end, the goal of this study was to identify non-invasive, translational, hyperpolarized 13C-magnetic resonance spectroscopy-detectable metabolic imaging biomarkers of TERT in low-grade oligodendrogliomas. Unbiased metabolomic analysis of immortalized normal human astrocytes without (NHAcontrol) and with TERT (NHAtert) indicated that TERT induced unique metabolic reprogramming. Notably, TERT increased NADPH and NADH levels. Glucose flux through the pentose phosphate pathway (PPP) is a major producer of NADPH. Non-invasive imaging of PPP flux using hyperpolarized [U-13C,U-2H]-glucose indicated that production of the PPP metabolite 6-phosphogluconate (6-PG) was elevated in NHAtert cells relative to NHAcontrol. Importantly, hyperpolarized [U-13C,U-2H]-glucose flux to 6-PG clearly differentiated tumor from normal brain in orthotopic NHAtert tumor xenografts. Next, we exploited the observation that TERT expression increased NADH, which is essential for the metabolism of hyperpolarized [1-13C]-alanine to lactate. Lactate production from hyperpolarized [1-13C]-alanine was higher in NHAtert cells relative to NHAcontrol. Importantly, hyperpolarized [1-13C]-alanine imaging in orthotopic NHAtert tumors revealed pronounced differences in lactate production between tumor tissue and normal brain. Mechanistically, TERT increased expression of glucose-6-phosphate dehydrogenase (G6PDH), the rate-limiting enzyme for 6-PG and NADPH production, and of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme for NADH biosynthesis. Silencing TERT reversed G6PDH and NAMPT expression and normalized hyperpolarized [U-13C,U-2H]-glucose and [1-13C]-alanine metabolism, validating our imaging biomarkers. Finally, hyperpolarized [U-13C,U-2H]-glucose and [1-13C]-alanine could monitor TERT status in the clinically relevant, patient-derived BT54 oligodendroglioma model. In summary, we demonstrate, for the first time, non-invasive in vivo imaging of TERT status in gliomas that can enable longitudinal analysis of tumor burden and treatment response in the clinic.

scholarly journals 89Zr-Labeled AR20.5: A MUC1-Targeting ImmunoPET Probe

Molecules ◽  
2020 ◽  
Vol 25 (10) ◽  
pp. 2315 ◽  
Author(s):  
Kimberly Fung ◽  
Delphine Vivier ◽  
Outi Keinänen ◽  
Elaheh Khozeimeh Sarbisheh ◽  
Eric W. Price ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Tissue ◽  
Activity Concentration ◽  
Poor Response ◽  
Response To Therapy ◽  
In Vivo Evaluation ◽  
In Vivo Experiments ◽  
Positron Emission ◽  
Tumor Types

High expression levels of the tumor-associated antigen MUC1 have been correlated with tumor aggressiveness, poor response to therapy, and poor survival in several tumor types, including breast, pancreatic, and epithelial ovarian cancer. Herein, we report the synthesis, characterization, and in vivo evaluation of a novel radioimmunoconjugate for the immuno-positron emission tomography (immunoPET) imaging of MUC1 expression based on the AR20.5 antibody. To this end, we modified AR20.5 with the chelator desferrioxamine (DFO) and labeled it with the positron-emitting radiometal zirconium-89 (t1/2 ~3.3 d) to produce [89Zr]Zr-DFO-AR20.5. In subsequent in vivo experiments in athymic nude mice bearing subcutaneous MUC1-expressing ovarian cancer xenografts, [89Zr]Zr-DFO-AR20.5 clearly delineated tumor tissue, producing a tumoral activity concentration of 19.1 ± 6.4 percent injected dose per gram (%ID/g) at 120 h post-injection and a tumor-to-muscle activity concentration ratio of 42.4 ± 10.6 at the same time point. Additional PET imaging experiments in mice bearing orthotopic MUC1-expressing ovarian cancer xenografts likewise demonstrated that [89Zr]Zr-DFO-AR20.5 enables the visualization of tumor tissue—including metastatic lesions—with promising tumor-to-background contrast.

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