Biology subjects

Taglang, C.

Publications and source records attributed to Taglang, C..

7 recordsLinked to original sources

bioRxiv2026

GLP1R agonists and vorasidenib converge on peroxynitrite-mediated cytotoxicity in mutant IDH glioma

Mutations in isocitrate dehydrogenase 1 or 2 (mIDH) generate the oncometabolite D-2-hydroxyglutarate that drives tumorigenesis in a distinct molecular class of gliomas. The mIDH inhibitor vorasidenib slows tumor growth, but disease progression remains a challenge, identifying a need for strategies that deepen and prolong therapeutic response. Here, we show that glucagon-like peptide-1R (GLP1R) agonists synergize with vorasidenib in patient-derived and murine models of mIDH glioma. Mechanistically, GLP1R agonists activate cAMP-protein kinase A signaling and induce nitric oxide synthase 1-dependent nitric oxide production in mIDH glioma cells. Nitric oxide inhibits aconitase and ribonucleotide reductase via S-nitrosylation, thereby disrupting the tricarboxylic acid cycle, depleting deoxyribonucleotides, blocking DNA synthesis, and exerting a cytostatic inhibition of tumor cell proliferation. Concomitantly, vorasidenib relieves D-2HG-driven suppression of pyruvate dehydrogenase, thereby increasing mitochondrial superoxide production and suppressing proliferation without cytotoxicity. When combined, GLP1R agonist-induced nitric oxide and vorasidenib-induced superoxide converge to generate peroxynitrite, which damages lipids and DNA, and triggers apoptosis in mIDH glioma cells. Combining a GLP1R agonist with vorasidenib recapitulates these metabolic and pharmacodynamic effects in mice bearing intracranial mIDH tumors, induces tumor regression, and significantly prolongs survival relative to each monotherapy in vivo. Collectively, our studies demonstrate that GLP1R agonism and mIDH inhibition induce distinct alterations in mitochondrial redox metabolism that converge to produce synergistic cytotoxicity and provide a mechanistic basis for clinical evaluation of this therapeutic strategy in patients with mIDH glioma.

cancer biology↗

bioRxiv2025

Understanding and imaging PHGDH-driven intrinsic resistance to mutant IDH inhibition in gliomas

Mutations in isocitrate dehydrogenase (IDHm) define a distinct molecular class of gliomas. IDHm converts -ketoglutarate (-KG) to the oncometabolite D-2-hydroxyglutarate (D-2HG), which drives tumorigenesis. The IDHm inhibitor vorasidenib suppresses D-2HG production and extends progression-free survival in some, but not all, IDHm glioma patients. Here, using clinically relevant patient-derived IDHm models and patient tissue, we show that phosphoglycerate dehydrogenase (PHGDH) drives intrinsic resistance to vorasidenib by promiscuously converting -KG to D-2HG and maintaining D-2HG concentration despite IDHm inhibition. Silencing PHGDH sensitizes resistant models to vorasidenib, while conversely, overexpressing PHGDH induces vorasidenib resistance in sensitive models. Importantly, deuterium metabolic imaging of D-2HG production from diethyl-[3,3-2H]--ketoglutarate provides an early readout of response and resistance to vorasidenib that is not available by anatomical imaging in vivo. Collectively, we have identified PHGDH-driven D-2HG production as an intrinsic mechanism of resistance to vorasidenib and diethyl-[3,3-2H]-ketoglutarate as a non-invasive tracer for interrogating intrinsic resistance in IDHm gliomas. STATEMENT OF SIGNIFICANCEVorasidenib, which suppresses D-2HG production, is the first precision therapy to be approved for IDHm glioma patients. We show that PHGDH-driven restoration of D-2HG production mediates intrinsic resistance to vorasidenib in IDHm gliomas. Importantly, deuterium metabolic imaging of D-2HG production from diethyl-[3,3-2H]--ketoglutarate enables non-invasive assessment of resistance in IDHm gliomas.

cancer biology↗

bioRxiv2025

The 1p/19q co-deletion induces targetable and imageable vulnerabilities in glucose metabolism in oligodendrogliomas

BackgroundThe 1p/19q co-deletion is a hallmark of oligodendrogliomas. The goal of this study was to exploit metabolic vulnerabilities induced by the 1p/19q co-deletion for oligodendroglioma therapy and non-invasive imaging. MethodsWe used stable isotope tracing, mass spectrometry, and genetic and pharmacological approaches to interrogate [U-13C]-glucose metabolism in patient-derived oligodendroglioma models (SF10417, BT88, BT54, TS603, NCH612). We examined whether tracing [6,6-2H]-glucose metabolism using deuterium metabolic imaging (DMI) provided an early readout of treatment response. ResultsThe expression of the glycolytic enzyme enolase 1 (ENO1; chromosome 1p36.23) was reduced in patient-derived oligodendroglioma cells and patient biopsies due to the 1p/19q co-deletion and histone hypermethylation. Conversely, ENO2 was upregulated, an effect that was driven by mitogen-activated protein kinase (MAPK) signaling and ERK1-mediated phosphorylation and inactivation of the CIC transcriptional repressor in oligodendrogliomas. Genetic ablation of ENO2 or pharmacological inhibition using POMHEX inhibited proliferation with nanomolar potency but was not cytotoxic to oligodendroglioma cells or tumor xenografts. Mechanistically, ENO2 loss abrogated [U-13C]-glucose metabolism to lactate but shunted glucose towards biosynthesis of serine and purine nucleotides, an effect that was driven by phosphoglycerate dehydrogenase (PHGDH). Importantly, the PHGDH inhibitor D8 was synthetically lethal in combination with POMHEX, and the combination induced tumor regression in vivo. Furthermore, DMI of lactate production from [6,6-2H]-glucose provided an early readout of response to combination therapy that preceded MRI-detectable alterations and reflected extended survival. ConclusionsWe have identified ENO2 and PHGDH as 1p/19q co-deletion-induced metabolic vulnerabilities in oligodendrogliomas and demonstrated that DMI reports on early response to therapy. KEY POINTSO_LIThe 1p/19q co-deletion upregulates ENO2 in oligodendrogliomas. C_LIO_LIENO2 inhibition inhibits glycolysis but upregulates serine and nucleotide biosynthesis via PHGDH. C_LIO_LICombined inhibition of ENO2 and PHGDH is lethal, an effect that can be visualized by DMI. C_LI IMPORTANCE OF THE STUDYOligodendrogliomas are devastating primary brain tumors with long-lasting and life-altering effects on physical and cognitive function. The presence of a 1p/19q co-deletion defines oligodendrogliomas. Here, using clinically relevant patient-derived models and patient tissue, we show that the 1p/19q co-deletion leads to loss of the glycolytic enzyme ENO1 and upregulation of ENO2 in oligodendrogliomas. This provides a unique therapeutic opportunity since most cells rely on ENO1 for glycolysis. Targeting ENO2 using the brain-penetrant inhibitor POMHEX abrogates glycolysis but redirects glucose toward serine and nucleotide biosynthesis, an effect that is driven by PHGDH, the rate-limiting enzyme for serine biosynthesis. Importantly, combined treatment with POMHEX and the PHGDH inhibitor D8 is synthetically lethal in vitro and in vivo. Furthermore, visualizing glucose metabolism using DMI provides an early readout of response to therapy that predicts extended survival in vivo. In summary, we have developed a unique integrated metabolic therapy and imaging approach for oligodendrogliomas.

cancer biology↗

bioRxiv2025

Lactylation fuels nucleotide biosynthesis and facilitates deuterium metabolic imaging of tumor proliferation in H3K27M-mutant gliomas

Oncogenes hyperactive lactate production, but the mechanisms by which lactate facilitates tumor growth are unclear. Here, we demonstrate that lactate is essential for nucleotide biosynthesis in pediatric diffuse midline gliomas (DMGs). The oncogenic histone H3K27M mutation upregulates phosphoglycerate kinase 1 (PGK1) and drives lactate production from [U-13C]-glucose in DMGs. Lactate activates the nucleoside diphosphate kinase NME1 via lactylation and promotes the synthesis of nucleoside triphosphates essential for tumor proliferation. Importantly, we show that this mechanistic link between glycolysis and nucleotide biosynthesis provides a unique opportunity for deuterium metabolic imaging of DMGs. Spatially mapping 2H-lactate production from [6,6-2H]-glucose allows visualization of the metabolically active tumor lesion and provides an early readout of response to standard-of-care radiation and targeted therapy that precedes extended survival and reflects pharmacodynamic alterations at the tissue level in preclinical DMG models in vivo at clinical field strength (3T). In essence, we have identified an H3K27M-lactate-NME1 axis that promotes DMG proliferation and facilitates non-invasive metabolic imaging of DMGs. STATEMENT OF SIGNIFICANCEThis study establishes a role for lactate in driving nucleotide biosynthesis in DMGs. Importantly, imaging lactate production from glucose using DMI provides a readout of tumor proliferation and early response to therapy in clinically relevant DMG models. Our studies lay the foundation for precision metabolic imaging of DMG patients.

cancer biology↗

bioRxiv2024

GABA production induced by imipridones is a targetable and imageable metabolic alteration in diffuse midline gliomas

Diffuse midline gliomas (DMGs) are lethal primary brain tumors in children. The imipridones ONC201 and ONC206 induce mitochondrial dysfunction and have emerged as promising therapies for DMG patients. However, efficacy as monotherapy is limited, identifying a need for strategies that enhance response. Another hurdle is the lack of biomarkers that report on drug-target engagement at an early timepoint after treatment onset. Here, using 1H-magnetic resonance spectroscopy, which is a non-invasive method of quantifying metabolite pool sizes, we show that accumulation of {psi}-aminobutyric acid (GABA) is an early metabolic biomarker that can be detected within a week of ONC206 treatment, when anatomical alterations are absent, in mice bearing orthotopic xenografts. Mechanistically, imipridones activate the mitochondrial protease ClpP and upregulate the stress-responsive transcription factor ATF4. ATF4, in turn, upregulates glutamate decarboxylase, which synthesizes GABA, and downregulates ABAT, which degrades GABA, leading to GABA accumulation in DMG cells and tumors. Functionally, GABA secreted by imipridone-treated cells acts in an autocrine manner via the GABAB receptor to induce expression of superoxide dismutase (SOD1), which mitigates imipridone-induced oxidative stress and, thereby, curbs apoptosis. Importantly, blocking autocrine GABA signaling using the clinical stage GABAB receptor antagonist SGS-742 exacerbates oxidative stress and synergistically induces apoptosis in combination with imipridones in DMG cells and orthotopic tumor xenografts. Collectively, we identify GABA as a unique metabolic adaptation to imipridones that can be leveraged for non-invasive assessment of drug-target engagement and therapy. Clinical translation of our studies has the potential to enable precision metabolic therapy and imaging for DMG patients. One Sentence SummaryImipridones induce GABA accumulation in diffuse midline gliomas, an effect that can be leveraged for therapy and non-invasive imaging.

cancer biology↗

bioRxiv2023

Telomerase reverse transcriptase induces targetable alterations in glutathione and nucleotide biosynthesis in glioblastomas

Telomerase reverse transcriptase (TERT) is essential for glioblastoma (GBM) proliferation. Delineating metabolic vulnerabilities induced by TERT can lead to novel GBM therapies. We previously showed that TERT upregulates glutathione (GSH) pool size in GBMs. Here, we show that TERT acts via the FOXO1 transcription factor to upregulate expression of the catalytic subunit of glutamate-cysteine ligase (GCLC), the rate-limiting enzyme of de novo GSH synthesis. Inhibiting GCLC using siRNA or buthionine sulfoximine (BSO) reduces synthesis of 13C-GSH from [U-13C]-glutamine and inhibits clonogenicity. However, GCLC inhibition does not induce cell death, an effect that is associated with elevated [U-13C]-glutamine metabolism to glutamate and pyrimidine nucleotide biosynthesis. Mechanistically, GCLC inhibition activates MYC and leads to compensatory upregulation of two key glutamine-utilizing enzymes i.e., glutaminase (GLS), which generates glutamate from glutamine, and CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotatase), the enzyme that converts glutamine to the pyrimidine nucleotide precursor dihydroorotate. We then examined the therapeutic potential of inhibiting GLS and CAD in combination with GCLC. 6-diazo-5-oxy-L-norleucin (DON) is a potent inhibitor of glutamine-utilizing enzymes including GLS and CAD. The combination of BSO and DON suppresses GSH and pyrimidine nucleotide biosynthesis and is synergistically lethal in GBM cells. Importantly, in vivo stable isotope tracing indicates that combined treatment with JHU-083 (a brain-penetrant prodrug of DON) and BSO abrogates synthesis of GSH and pyrimidine nucleotides from [U-13C]-glutamine and induces tumor shrinkage in mice bearing intracranial GBM xenografts. Collectively, our studies exploit a mechanistic understanding of TERT biology to identify synthetically lethal metabolic vulnerabilities in GBMs. SIGNIFICANCEUsing in vivo stable isotope tracing, metabolomics, and loss-of-function studies, we demonstrate that TERT expression is associated with metabolic alterations that can be synergistically targeted for therapy in glioblastomas.

cancer biology↗

bioRxiv2021

Pan-cancer imaging of TERT expression using deuterium magnetic resonance spectroscopy-based assessment of pyruvate metabolism

Telomerase reverse transcriptase (TERT) expression is indispensable for tumor immortality. Non-invasive methods of imaging TERT can, therefore, report on tumor proliferation and response to therapy. Here, we show that TERT expression is associated with elevated levels of the redox metabolite NADH in multiple cancers, including glioblastoma, oligodendroglioma, melanoma, neuroblastoma, and hepatocellular carcinoma. Mechanistically, TERT acts via the metabolic regulator FOXO1 to upregulate nicotinamide phosphoribosyl transferase, which is the key enzyme for NADH biosynthesis. Importantly, deuterium magnetic resonance spectroscopy (2H-MRS), which is a novel, clinically translatable metabolic imaging modality, can be leveraged for imaging TERT-linked NADH in preclinical tumor models in vivo. Since NADH is essential for pyruvate flux to lactate, 2H-MRS following administration of 2H-labeled pyruvate non-invasively visualizes TERT expression and reports on early response to therapy. Collectively, our study provides insights into the mechanisms of TERT-linked metabolic reprogramming and, importantly, establishes 2H-MRS as a pan-cancer strategy for imaging tumor immortality.

cancer biology↗