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BIMG-08. DEUTERIUM MAGNETIC RESONANCE SPECTROSCOPY USING (2)H-PYRUVATE ALLOWS NON-INVASIVE IN VIVO IMAGING OF TERT EXPRESSION IN BRAIN TUMORS
Telomere shortening constitutes a natural barrier to uncontrolled proliferation and all tumors must find a mechanism of maintaining telomere length. Most human tumors, including high-grade primary glioblastomas (GBMs) and low-grade oligodendrogliomas (LGOGs) achieve telomere maintenance via reactiva...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992203/ http://dx.doi.org/10.1093/noajnl/vdab024.007 |
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author | Batsios, Georgios Taglang, Celine Tran, Meryssa Gillespie, Anne Marie Costello, Joseph Ronen, Sabrina Viswanath, Pavithra |
author_facet | Batsios, Georgios Taglang, Celine Tran, Meryssa Gillespie, Anne Marie Costello, Joseph Ronen, Sabrina Viswanath, Pavithra |
author_sort | Batsios, Georgios |
collection | PubMed |
description | Telomere shortening constitutes a natural barrier to uncontrolled proliferation and all tumors must find a mechanism of maintaining telomere length. Most human tumors, including high-grade primary glioblastomas (GBMs) and low-grade oligodendrogliomas (LGOGs) achieve telomere maintenance via reactivation of the expression of telomerase reverse transcriptase (TERT), which is silenced in normal somatic cells. TERT expression is, therefore, a driver of tumor proliferation and, due to this essential role, TERT is also a therapeutic target. However, non-invasive methods of imaging TERT are lacking. The goal of this study was to identify magnetic resonance spectroscopy (MRS)-detectable metabolic biomarkers of TERT expression that will enable non-invasive visualization of tumor burden in LGOGs and GBMs. First, we silenced TERT expression by RNA interference in patient-derived LGOG (SF10417, BT88) and GBM (GS2) models. Our results linked TERT silencing to significant reductions in steady-state levels of NADH in all models. NADH is essential for the conversion of pyruvate to lactate, suggesting that measuring pyruvate flux to lactate could be useful for imaging TERT status. Recently, deuterium ((2)H)-MRS has emerged as a novel, clinically translatable method of monitoring metabolic fluxes in vivo. However, to date, studies have solely examined (2)H-glucose and the use of [U-(2)H]pyruvate for non-invasive (2)H-MRS has not been tested. Following intravenous injection of a bolus of [U-(2)H]pyruvate, lactate production was higher in mice bearing orthotopic LGOG (BT88 and SF10417) and GBM (GS2) tumor xenografts relative to tumor-free mice, suggesting that [U-(2)H]pyruvate has the potential to monitor TERT expression in vivo. In summary, our study, for the first time, shows the feasibility and utility of [U-(2)H]pyruvate for in vivo imaging. Importantly, since (2)H-MRS can be implemented on clinical scanners, our results provide a novel, non-invasive method of integrating information regarding a fundamental cancer hallmark, i.e. TERT, into glioma patient management. |
format | Online Article Text |
id | pubmed-7992203 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-79922032021-03-31 BIMG-08. DEUTERIUM MAGNETIC RESONANCE SPECTROSCOPY USING (2)H-PYRUVATE ALLOWS NON-INVASIVE IN VIVO IMAGING OF TERT EXPRESSION IN BRAIN TUMORS Batsios, Georgios Taglang, Celine Tran, Meryssa Gillespie, Anne Marie Costello, Joseph Ronen, Sabrina Viswanath, Pavithra Neurooncol Adv Supplement Abstracts Telomere shortening constitutes a natural barrier to uncontrolled proliferation and all tumors must find a mechanism of maintaining telomere length. Most human tumors, including high-grade primary glioblastomas (GBMs) and low-grade oligodendrogliomas (LGOGs) achieve telomere maintenance via reactivation of the expression of telomerase reverse transcriptase (TERT), which is silenced in normal somatic cells. TERT expression is, therefore, a driver of tumor proliferation and, due to this essential role, TERT is also a therapeutic target. However, non-invasive methods of imaging TERT are lacking. The goal of this study was to identify magnetic resonance spectroscopy (MRS)-detectable metabolic biomarkers of TERT expression that will enable non-invasive visualization of tumor burden in LGOGs and GBMs. First, we silenced TERT expression by RNA interference in patient-derived LGOG (SF10417, BT88) and GBM (GS2) models. Our results linked TERT silencing to significant reductions in steady-state levels of NADH in all models. NADH is essential for the conversion of pyruvate to lactate, suggesting that measuring pyruvate flux to lactate could be useful for imaging TERT status. Recently, deuterium ((2)H)-MRS has emerged as a novel, clinically translatable method of monitoring metabolic fluxes in vivo. However, to date, studies have solely examined (2)H-glucose and the use of [U-(2)H]pyruvate for non-invasive (2)H-MRS has not been tested. Following intravenous injection of a bolus of [U-(2)H]pyruvate, lactate production was higher in mice bearing orthotopic LGOG (BT88 and SF10417) and GBM (GS2) tumor xenografts relative to tumor-free mice, suggesting that [U-(2)H]pyruvate has the potential to monitor TERT expression in vivo. In summary, our study, for the first time, shows the feasibility and utility of [U-(2)H]pyruvate for in vivo imaging. Importantly, since (2)H-MRS can be implemented on clinical scanners, our results provide a novel, non-invasive method of integrating information regarding a fundamental cancer hallmark, i.e. TERT, into glioma patient management. Oxford University Press 2021-03-25 /pmc/articles/PMC7992203/ http://dx.doi.org/10.1093/noajnl/vdab024.007 Text en © The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Supplement Abstracts Batsios, Georgios Taglang, Celine Tran, Meryssa Gillespie, Anne Marie Costello, Joseph Ronen, Sabrina Viswanath, Pavithra BIMG-08. DEUTERIUM MAGNETIC RESONANCE SPECTROSCOPY USING (2)H-PYRUVATE ALLOWS NON-INVASIVE IN VIVO IMAGING OF TERT EXPRESSION IN BRAIN TUMORS |
title | BIMG-08. DEUTERIUM MAGNETIC RESONANCE SPECTROSCOPY USING (2)H-PYRUVATE ALLOWS NON-INVASIVE IN VIVO IMAGING OF TERT EXPRESSION IN BRAIN TUMORS |
title_full | BIMG-08. DEUTERIUM MAGNETIC RESONANCE SPECTROSCOPY USING (2)H-PYRUVATE ALLOWS NON-INVASIVE IN VIVO IMAGING OF TERT EXPRESSION IN BRAIN TUMORS |
title_fullStr | BIMG-08. DEUTERIUM MAGNETIC RESONANCE SPECTROSCOPY USING (2)H-PYRUVATE ALLOWS NON-INVASIVE IN VIVO IMAGING OF TERT EXPRESSION IN BRAIN TUMORS |
title_full_unstemmed | BIMG-08. DEUTERIUM MAGNETIC RESONANCE SPECTROSCOPY USING (2)H-PYRUVATE ALLOWS NON-INVASIVE IN VIVO IMAGING OF TERT EXPRESSION IN BRAIN TUMORS |
title_short | BIMG-08. DEUTERIUM MAGNETIC RESONANCE SPECTROSCOPY USING (2)H-PYRUVATE ALLOWS NON-INVASIVE IN VIVO IMAGING OF TERT EXPRESSION IN BRAIN TUMORS |
title_sort | bimg-08. deuterium magnetic resonance spectroscopy using (2)h-pyruvate allows non-invasive in vivo imaging of tert expression in brain tumors |
topic | Supplement Abstracts |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992203/ http://dx.doi.org/10.1093/noajnl/vdab024.007 |
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