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

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.

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BIMG-08. DEUTERIUM MAGNETIC RESONANCE SPECTROSCOPY USING 2H-PYRUVATE ALLOWS NON-INVASIVE IN VIVO IMAGING OF TERT EXPRESSION IN BRAIN TUMORS

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab024.007 ◽

2021 ◽

Vol 3 (Supplement_1) ◽

pp. i2-i2

Author(s):

Georgios Batsios ◽

Celine Taglang ◽

Meryssa Tran ◽

Anne Marie Gillespie ◽

Joseph Costello ◽

...

Keyword(s):

Magnetic Resonance ◽

Magnetic Resonance Spectroscopy ◽

In Vivo Imaging ◽

Lactate Production ◽

Telomere Maintenance ◽

Resonance Spectroscopy ◽

Low Grade ◽

Non Invasive ◽

Tert Expression

Abstract 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 (2H)-MRS has emerged as a novel, clinically translatable method of monitoring metabolic fluxes in vivo. However, to date, studies have solely examined 2H-glucose and the use of [U-2H]pyruvate for non-invasive 2H-MRS has not been tested. Following intravenous injection of a bolus of [U-2H]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-2H]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-2H]pyruvate for in vivo imaging. Importantly, since 2H-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.

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NIMG-51. DEUTERIUM METABOLIC IMAGING OF BRAIN TUMOR IMMORTALITY USING 2H-PYRUVATE

Neuro-Oncology ◽

10.1093/neuonc/noab196.549 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi140-vi141

Author(s):

Georgios Batsios ◽

Céline Taglang ◽

Meryssa Tran ◽

Anne Marie Gillespie ◽

Sabrina Ronen ◽

...

Keyword(s):

Brain Tumor ◽

Lactate Production ◽

Response To Therapy ◽

Telomere Maintenance ◽

Metabolic Imaging ◽

Resonance Spectroscopy ◽

Low Grade ◽

Tumor Proliferation ◽

Non Invasive ◽

Tert Expression

Abstract Telomere maintenance is essential for tumor immortality and sustained tumor proliferation. Most tumors, including high-grade glioblastomas and low-grade oligodendrogliomas achieve telomere maintenance via reactivation of the expression of telomerase reverse transcriptase (TERT), which is silenced in normal somatic cells. Due to this essential role, TERT is a therapeutic target and TERT inhibitors such as 6-thio-2’-deoxyguanosine are in clinical trials. Non-invasive methods of imaging TERT, therefore, have the potential to provide a readout of tumor proliferation and response to therapy. We previously showed that TERT expression is associated with elevated levels of NADH in gliomas. Since NADH is essential for the conversion of pyruvate to lactate, measuring pyruvate flux to lactate could be useful for imaging TERT expression. In this context, deuterium magnetic resonance spectroscopy (2H-MRS) recently emerged as a novel, clinically translatable method of monitoring metabolic fluxes. The goal of this study was to assess the potential of [U-2H]pyruvate for non-invasive imaging of TERT status in gliomas. Following intravenous injection of [U-2H]pyruvate, lactate production was significantly higher in mice bearing orthotopic oligodendroglioma (SF10417, BT88) or glioblastoma (GBM1, GBM6) tumors relative to tumor-free controls. 2D chemical shift imaging showed localization of lactate production to tumor vs. contralateral normal brain. Importantly, following treatment of mice bearing orthotopic GBM6 or BT88 tumors with the TERT inhibitor 6-thio-2’-deoxyguanosine, lactate production from [U-2H]pyruvate was significantly reduced at early timepoints when alterations in tumor volume could not be detected by anatomical imaging, pointing to the ability of [U-2H]pyruvate to report on pseudoprogression. Collectively, we have, for the first time, demonstrated the utility of [U-2H]pyruvate for metabolic imaging of brain tumor burden and treatment response in vivo. Importantly, since 2H-MRS can be implemented on clinical scanners, our results provide a novel, non-invasive method of integrating information regarding a fundamental tumor hallmark, i.e. TERT, into glioma patient management.

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NIMG-50. DEUTERIUM METABOLIC IMAGING OF THE ALTERNATIVE LENGTHENING OF TELOMERES PATHWAY REPORTS ON TUMOR BURDEN AND PSEUDOPROGRESSION IN LOW-GRADE GLIOMAS

Neuro-Oncology ◽

10.1093/neuonc/noab196.548 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi140-vi140

Author(s):

Céline Taglang ◽

Georgios Batsios ◽

Joydeep Mukherjee ◽

Meryssa Tran ◽

Anne Marie Gillespie ◽

...

Keyword(s):

Magnetic Resonance ◽

Tumor Burden ◽

Telomere Maintenance ◽

Metabolic Imaging ◽

Glycolytic Flux ◽

Low Grade ◽

Non Invasive ◽

Glucose Flux ◽

Alternative Lengthening

Abstract Glioma patient management relies heavily on magnetic resonance imaging (MRI). However, MRI is often inadequate for assessment of tumor burden and pseudoprogression. Non-invasive methods that report on molecular pathways such as telomere maintenance that drive tumor proliferation are needed. Among brain tumors, low-grade astrocytomas (LGAs) use the alternative lengthening of telomeres (ALT) pathway for telomere maintenance. The goal of this study was to identify ALT-linked metabolic alterations that can be exploited for non-invasive magnetic resonance spectroscopy (MRS)-based imaging of LGAs. We examined the patient-derived BT257 model and compared neurospheres that are ALT-dependent (BT257 ALT+) with those in which the ALT pathway has been silenced (BT257 ALT-). Our studies suggest that expression and activity of the rate-limiting glycolytic enzyme phosphofructokinase-1 are significantly higher in BT257 ALT+ neurospheres relative to ALT-, an effect that is associated with elevated glucose flux to lactate. Studies indicate that poly(ADP-ribose) polymerase inhibitors such as niraparib selectively induce telomeric fusion and cell death in ALT-dependent cells. We find that the telomeric fusion-mediated cytotoxicity of niraparib is associated with significantly reduced glycolytic flux in BT257 ALT+ neurospheres. We then examined whether 2H-MRS using [6,6’-2H]-glucose, which is a clinically translatable method of imaging glycolytic flux, can be used to monitor the ALT pathway in vivo. [6,6’-2H]-glucose flux to lactate is elevated in tumor relative to normal brain in mice bearing orthotopic BT257 tumors. Importantly, following treatment of BT257 tumor-bearing mice with niraparib, lactate production from [6,6’-2H]-glucose is significantly reduced at early timepoints when alterations in tumor volume cannot be observed by MRI, pointing to the ability of [6,6’-2H]-glucose to report on pseudoprogression in vivo. Collectively, our studies mechanistically link the ALT pathway with elevated glycolytic flux via phosphofructokinase-1 and identify deuterium metabolic imaging as a novel, non-invasive method of imaging tumor burden and treatment response in LGAs in vivo.

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BIMG-02. IMAGING IMMORTALITY: TERT EXPRESSION ALTERS GLUCOSE METABOLISM IN LOW-GRADE GLIOMAS IN A MANNER THAT CAN BE LEVERAGED FOR NONINVASIVE METABOLIC IMAGING

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab024.001 ◽

2021 ◽

Vol 3 (Supplement_1) ◽

pp. i1-i1

Author(s):

Pavithra Viswanath ◽

Georgios Batsios ◽

Anne Marie Gillespie ◽

Hema Artee Luchman ◽

Joseph Costello ◽

...

Keyword(s):

Glucose Metabolism ◽

Response To Therapy ◽

Metabolic Imaging ◽

Additional Patient ◽

Low Grade ◽

Normal Brain ◽

G6pdh Activity ◽

Glucose Flux ◽

13C Mrs ◽

Tert Expression

Abstract Telomerase reverse transcriptase (TERT) is essential for tumor immortality and uncontrolled proliferation, including in low-grade oligodendrogliomas (LGOGs). Since it is silenced in somatic cells, TERT is also a therapeutic target. Non-invasive imaging of TERT can differentiate tumor from normal brain or lesions such as gliosis and allow assessment of response to therapy. The goal of this study was to identify magnetic resonance spectroscopy (MRS)-detectable metabolic alterations associated with TERT that can be leveraged for noninvasive imaging in LGOGs. We examined patient-derived BT54 neurospheres in which TERT expression was silenced by RNA interference. 1H-MRS showed that steady-state levels of NAD(P)/H, glutathione, aspartate and AXP were elevated in BT54TERT+ neurospheres relative to BT54TERT-. Glucose flux through the pentose phosphate pathway (PPP) is essential for generating NADPH, which maintains glutathione homeostasis. 13C-MRS confirmed that [2-13C]-glucose flux through the PPP was elevated in BT54TERT+ neurospheres relative to BT54TERT-, an effect associated with higher activity of the PPP enzyme glucose-6-phosphate dehydrogenase (G6PDH). Hyperpolarized 13C-MRS is a method of increasing the signal to noise ratio of 13C-MRS such that it can monitor metabolic fluxes noninvasively in cells, animals and patients. Consistent with elevated PPP flux and G6PDH activity, hyperpolarized [U-13C]-glucose metabolism via the PPP to 6-phosphogluconate (6-PG) was elevated in BT54TERT+ neurospheres relative to BT54TERT-. Importantly, examination of an additional patient-derived LGOG model, the SF10417 model which readily forms orthotopic tumor xenografts in rats, showed that 6-PG production from hyperpolarized [U-13C]-glucose demarcated tumor from normal brain. Furthermore, LGOG patient biopsies had elevated NAD(P)/H, glutathione, aspartate, AXP and G6PDH activity relative to gliosis biopsies, confirming the clinical validity of our observations. Collectively, we have identified a metabolic signature of TERT expression that can be leveraged via hyperpolarized [U-13C]-glucose to improve diagnosis and treatment response monitoring for LGOG patients.

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Application of Hyperpolarized 13C Magnetic Resonance Imaging to Detect Target Inhibition of NFkB Activation in Preclinical Patient-Derived Models of CNS Lymphoma

Blood ◽

10.1182/blood-2018-99-117625 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2840-2840

Author(s):

Huimin Geng ◽

Brice Tiret ◽

Hua-Xin Gao ◽

Cigall Kadoch ◽

Ming Lu ◽

...

Keyword(s):

Magnetic Resonance ◽

Research Funding ◽

Clinical Chemistry ◽

Lactate Production ◽

Xenograft Model ◽

Metabolic Imaging ◽

Cns Lymphoma ◽

Resonance Spectroscopy ◽

Non Invasive ◽

Myd88 L265p

Abstract To gain insights into the tumor microenvironment in primary and secondary CNS lymphomas, we applied LC/MS and GC/MS for differential metabolomic profiling of the cerebrospinal fluid (CSF) of CNS lymphoma patients compared to control subjects. Among 145 analytes identified, the majority were involved in energy metabolism; one of the most significantly upregulated metabolites in CNS lymphoma was lactate (1.8 fold, p<0.001). Subsequently we determined that baseline elevated CSF lactate, quantified by a Beckman Coulter Unicell Clinical Chemistry analyzer, correlated with short survival in three phase I investigations involving immunotherapy in relapsed CNS lymphoma (p<0.0001). (Blood Advances 2018). Given this, we hypothesize that tumor-associated lactate significantly contributes to the pathogenesis of CNS lymphoma as a potential mediator of tumor invasion as well as immunosuppression, and can serve as a novel biomarker in CNS lymphoma. To pursue this, we are testing the hypothesis that metabolic imaging techniques including proton magnetic resonance spectroscopy (MRS) and hyperpolarized (HP) 13C MRS can facilitate prognosis and response assessment to targeted therapies. Thus far we have applied these metabolic imaging approaches to preclinical murine models involving diffusely invasive, intracranial, patient-derived xenografts of CNS DLBCL in RAG-/- mice, to detect tumor-associated lactate production generated by infiltrating lymphoma. We demonstrated that each of these MRS approaches detect highly invasive lymphoma that is undetectable by conventional gadolinium-enhanced T1, T2 sequences, or diffusion-weighted imaging. Because of its ability to detect real-time changes in metabolic pathways, we focused on the application of HP13C pyruvate metabolic imaging as a non-invasive imaging tool for NF-kB pathway inhibition in CNS lymphoma using these models. We evaluated the metabolic response to AZ1495, a novel, CNS penetrant, orally-bioavailable inhibitor of IRAK4 kinase, comparing MYD88 wild type vs. MYD88 L265P mutant tumor models. Using a 14.1T imaging system for MR acquisition, we demonstrated similar tumor-associated production of HP 13C lactate in both MYD88wt and MY88 mutant tumors at 3 weeks post-implantation. We determined that while AZ1495 did not significantly impact lactate production in MYD88wt lymphoma, this agent significantly down-regulated tumor-associated HP pyruvate to lactate conversion (>47%) within 2 days in MYD88 mutant CNS lymphoma (p<0.02). (Figure 1). In parallel, we determined that AZ1495 potently antagonized phosphorylation of p65 REL-A selectively in intracranial xenografts harboring L265P MYD88 mutation. Transcriptional profiling by RNA-Seq demonstrated > 2-fold down-modulation of NF-kB gene expression at 4h of AZ1495 therapy, including transcripts encoding LDH-A as well as the catalytic subunit of PI3K, suggesting interaction with the B cell receptor pathway. Combination AZ1495 plus ibrutinib starting d+5 was synergistic in survival prolongation compared to AZ1495 monotherapy (p<0.003), ibrutinib monotherapy (p<0.005), or control gavage (p<0.002) in a MYD88 L265P mutant, clinically refractory patient-derived intracranial DLBCL xenograft model. Taken together, these data demonstrate the ability of HP13C MRI metabolic imaging to identify highly infiltrative CNS lymphoma, not detectable by conventional MR sequences, as well as its potential to provide an early, non-invasive pharmacodynamic biomarker of response in an NFkB pathway-specific manner, and to facilitate precision medicine in CNS lymphoma. Supported by the National Cancer Institute, the Leukemia and Lymphoma Society and by the Sandler Program for Breakthrough Biomedical Research. Disclosures Gao: Glaxo Smith Kline: Employment. Drew:AstraZeneca: Employment. Degorce:Astra Zeneca: Employment. Mayo:Astra Zeneca: Employment. Dillman:Astra Zeneca: Employment. Anjum:Astra Zeneca: Employment. Bloecher:Astra Zeneca: Employment. Rubenstein:Celgene: Research Funding; Genentech: Research Funding.

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Characterization of astrocytomas, meningiomas, and pituitary adenomas by phosphorus magnetic resonance spectroscopy

Journal of Neurosurgery ◽

10.3171/jns.1991.74.3.0447 ◽

1991 ◽

Vol 74 (3) ◽

pp. 447-453 ◽

Cited By ~ 34

Author(s):

Douglas L. Arnold ◽

Joseph F. Emrich ◽

Eric A. Shoubridge ◽

Jean-Guy Villemure ◽

William Feindel

Keyword(s):

Magnetic Resonance ◽

Pituitary Adenomas ◽

Resonance Spectroscopy ◽

Low Grade ◽

Normal Brain ◽

Tumor Type ◽

Content Type ◽

Tumor Types ◽

Fine Print

✓ Phosphorus magnetic resonance (MR) spectroscopy allows noninvasive measurement of phosphate-containing compounds and pH within brain cells. The authors obtained localized phosphorus MR spectra from 10 normal brains, four low-grade astrocytomas, six glioblastomas, four meningiomas, and three pituitary adenomas and found differences in the spectra of each tumor type. Compared to normal brain, the spectra from low-grade astrocytomas showed a significant reduction of the phosphodiester (PDE) peak. Glioblastomas were characterized by a significant reduction of the PDE peak, elevation of the phosphomonoester (PME) peak, and a relatively alkaline intracellular pH. The spectra from meningiomas and pituitary adenomas were markedly different from the glial tumors. Meningiomas showed significant reductions in phosphocreatine, PDE, and inorganic phosphate, as well as a relatively alkaline pH. Pituitary adenomas resembled meningiomas, but had a much higher PME peak. Although the number of tumors studied was small, there appears to be a characteristic spectrum associated with these different tumor types. The present findings can be useful in the preoperative identification of these tumors and in furthering understanding of their growth and metabolism in vivo.

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Imaging toxin-induced neuroinflammation in mice using hyperpolarized13C magnetic resonance spectroscopy

10.1101/605568 ◽

2019 ◽

Author(s):

Lydia M Le Page ◽

Caroline Guglielmetti ◽

Chloé Najac ◽

Brice Tiret ◽

Myriam M Chaumeil

Keyword(s):

Magnetic Resonance ◽

Magnetic Resonance Spectroscopy ◽

Mouse Brain ◽

Lactate Production ◽

Contralateral Side ◽

Resonance Spectroscopy ◽

Activated Microglia ◽

Non Invasive ◽

Induced Changes

AbstractLipopolysaccharide (LPS) is a commonly used agent for induction of neuroinflammation in preclinical studies. Upon injection, LPS causes activation of microglia and astrocytes, whose metabolism alters to favor glycolysis. Assessingin vivoneuroinflammation and its modulation following therapy remains challenging, and new non-invasive methods allowing for longitudinal monitoring would be greatly valuable. Hyperpolarized (HP)13C magnetic resonance spectroscopy (MRS) is a promising technique for assessingin vivometabolism. In addition to applications in oncology, the most commonly used probe of [1-13C] pyruvate has shown potential in assessing neuroinflammation-linked metabolism in mouse models of multiple sclerosis and traumatic brain injury. Here, we wished to investigate LPS-induced neuroinflammatory changes using HP [1-13C] pyruvate and HP13C urea.2D chemical shift imaging following simultaneous intravenous injection of HP [1-13C] pyruvate and HP13C urea was performed at baseline (day 0), day 3 and day 7 post intracranial injection of LPS (n=6) or saline (n=5). Immunofluorescence (IF) analyses were performed for Iba1 (resting and activated microglia/macrophages), GFAP (resting and reactive astrocytes) and CD68 (activated microglia/macrophages).A significant increase in HP [1-13C] lactate production was observed in the injected (ipsilateral) side at 3 and 7 days of the LPS-treated mouse brain, but not in either the contralateral side or saline-injected animals. HP13C lactate/pyruvate ratio, without and with normalization to urea, was also significantly increased in the ipsilateral LPS-injected brain at 7 days compared to baseline. IF analyses showed a significant increase in CD68 and GFAP at 3 days, followed by increased numbers of Iba1 and GFAP positive cells at 7 days post-LPS injection.In conclusion, we can detect LPS-induced changes in the mouse brain using HP13C MRS, in alignment with increased numbers of microglia/macrophages and astrocytes. This study demonstrates that HP13C spectroscopy holds much potential for providing non-invasive information on neuroinflammation.

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Non-invasive assessment of telomere maintenance mechanisms in brain tumors

Nature Communications ◽

10.1038/s41467-020-20312-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Pavithra Viswanath ◽

Georgios Batsios ◽

Joydeep Mukherjee ◽

Anne Marie Gillespie ◽

Peder E. Z. Larson ◽

...

Keyword(s):

Genetically Engineered ◽

Telomere Maintenance ◽

Imaging Biomarker ◽

Response Monitoring ◽

Resonance Spectroscopy ◽

Low Grade ◽

Non Invasive ◽

Alternative Lengthening ◽

Metabolic Biomarkers ◽

Tert Expression

AbstractTelomere maintenance is a universal hallmark of cancer. Most tumors including low-grade oligodendrogliomas use telomerase reverse transcriptase (TERT) expression for telomere maintenance while astrocytomas use the alternative lengthening of telomeres (ALT) pathway. Although TERT and ALT are hallmarks of tumor proliferation and attractive therapeutic targets, translational methods of imaging TERT and ALT are lacking. Here we show that TERT and ALT are associated with unique 1H-magnetic resonance spectroscopy (MRS)-detectable metabolic signatures in genetically-engineered and patient-derived glioma models and patient biopsies. Importantly, we have leveraged this information to mechanistically validate hyperpolarized [1-13C]-alanine flux to pyruvate as an imaging biomarker of ALT status and hyperpolarized [1-13C]-alanine flux to lactate as an imaging biomarker of TERT status in low-grade gliomas. Collectively, we have identified metabolic biomarkers of TERT and ALT status that provide a way of integrating critical oncogenic information into non-invasive imaging modalities that can improve tumor diagnosis and treatment response monitoring.

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EXTH-20. HYPERPOLARIZED [2-13C] PYRUVATE TO [5-13C] GLUTAMATE AS BIOMARKERS OF IDH1 MUTANT GLIOMA RESPONSE TO TEMOZOLOMIDE THERAPY

Neuro-Oncology ◽

10.1093/neuonc/noz175.354 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi86-vi86 ◽

Cited By ~ 1

Author(s):

Elavarasan Subramani ◽

Chloe Najac ◽

Georgios Batsios ◽

Pavithra Viswanath ◽

Marina Radoul ◽

...

Keyword(s):

Tca Cycle ◽

Response To Therapy ◽

Response To Treatment ◽

Metabolic Imaging ◽

Imaging Biomarkers ◽

Resonance Spectroscopy ◽

Low Grade ◽

1H Mrs ◽

Hyperpolarized 13C ◽

13C Mrs

Abstract Low-grade gliomas, driven by mutations in the cytosolic isocitrate dehydrogenase 1 (IDH1) gene, are less aggressive than primary glioblastoma, but nonetheless always recur and ultimately lead to patient death. The treatment of IDH1 mutant patients with Temozolomide (TMZ) improves survival, but there remains a need for complementary imaging methods to assess response to therapy at an early time point. The goal of this study was, therefore, to determine the value of magnetic resonance spectroscopy (MRS)-based metabolic imaging biomarkers for detection of response to treatment. To this end we investigated NHA and U87 cells expressing IDH1 R132H mutant gene (NHAIDHmut and U87IDHmut) and first used 1H MRS combined with chemometrics to examined the metabolic alterations that occurred following treatment with the IC50 value of TMZ. We observed a significant increase in 2-hydroxyglutarate (2-HG), glutamate, and glutamine, and metabolic pathway analysis showed tricarboxylic acid (TCA) cycle and pyruvate metabolism to be significantly altered pathways following TMZ treatment compared to DMSO control. To confirm changes in TCA cycle flux and to assess the metabolic pathways contributing to the increase in 2-HG and glutamate/glutamine, cells were then labelled with [1-13C] glucose and [3-13C] glutamine. Our data indicated that both glucose flux via the TCA to glutamate and 2HG, and the contribution of glutamine to glutamate and 2HG were increased following TMZ treatment. Finally, we used hyperpolarized 13C-MRS to dynamically probe the metabolism of hyperpolarized [2-13C] pyruvate and its conversion to hyperpolarized [5-13C] glutamate via the TCA cycle. Consistent with our previous findings, we observed that hyperpolarized [5-13C] glutamate synthesis was significantly higher in TMZ-treated cells compared to controls. Collectively, our findings identify 1H MRS-detectable elevation of 2-HG and glutamate/glutamine as well as hyperpolarized 13C-MRS-detectable [5-13C] glutamate production from [2-13C] pyruvate as potentially translatable metabolic biomarkers of response to TMZ therapy in mutant IDH1 glioma.

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Early Detection of Pancreatic Intraepithelial Neoplasias (PanINs) in Transgenic Mouse Model by Hyperpolarized 13C Metabolic Magnetic Resonance Spectroscopy

International Journal of Molecular Sciences ◽

10.3390/ijms21103722 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3722

Author(s):

Prasanta Dutta ◽

Susana Castro Pando ◽

Marilina Mascaro ◽

Erick Riquelme ◽

Michelle Zoltan ◽

...

Keyword(s):

Pancreatic Cancer ◽

Magnetic Resonance ◽

Early Detection ◽

Ex Vivo ◽

Premalignant Lesions ◽

Metabolic Imaging ◽

Resonance Spectroscopy ◽

Low Grade ◽

High Risk Populations

While pancreatic cancer (PC) survival rates have recently shown modest improvement, the disease remains largely incurable. Early detection of pancreatic cancer may result in improved outcomes and therefore, methods for early detection of cancer, even premalignant lesions, may provide more favorable outcomes. Pancreatic intraepithelial neoplasias (PanINs) have been identified as premalignant precursor lesions to pancreatic cancer. However, conventional imaging methods used for screening high-risk populations do not have the sensitivity to detect PanINs. Here, we have employed hyperpolarized metabolic imaging in vivo and nuclear magnetic resonance (1H-NMR) metabolomics ex vivo to identify and understand metabolic changes, towards enabling detection of early PanINs and progression to advanced PanINs lesions that precede pancreatic cancer formation. Progression of disease from tissue containing predominantly low-grade PanINs to tissue with high-grade PanINs showed a decreasing alanine/lactate ratio from high-resolution NMR metabolomics ex vivo. Hyperpolarized magnetic resonance spectroscopy (HP-MRS) allows over 10,000-fold sensitivity enhancement relative to conventional magnetic resonance. Real-time HP-MRS was employed to measure non-invasively changes of alanine and lactate metabolites with disease progression and in control mice in vivo, following injection of hyperpolarized [1-13C] pyruvate. The alanine-to-lactate signal intensity ratio was found to decrease as the disease progressed from low-grade PanINs to high-grade PanINs. The biochemical changes of alanine transaminase (ALT) and lactate dehydrogenase (LDH) enzyme activity were assessed. These results demonstrate that there are significant alterations of ALT and LDH activities during the transformation from early to advanced PanINs lesions. Furthermore, we demonstrate that real-time conversion kinetic rate constants (kPA and kPL) can be used as metabolic imaging biomarkers of pancreatic premalignant lesions. Findings from this emerging HP-MRS technique can be translated to the clinic for detection of pancreatic premalignant lesion in high-risk populations.

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