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

Background: The 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.

Methods: We used stable isotope tracing, mass spectrometry, and genetic and pharmacological approaches to interrogate [U- C]-glucose metabolism in patient-derived oligodendroglioma models (SF10417, BT88, BT54, TS603, NCH612).

Combined inhibition of de novo glutathione and nucleotide biosynthesis is synthetically lethal in glioblastoma.

Understanding the mechanisms by which oncogenic events alter metabolism will help identify metabolic weaknesses that can be targeted for therapy. Telomerase reverse transcriptase (TERT) is essential for telomere maintenance in most cancers. Here, we show that TERT acts via the transcription factor forkhead box O1 (FOXO1) to upregulate glutamate-cysteine ligase (GCLC), the rate-limiting enzyme for de novo biosynthesis of glutathione (GSH, reduced) in multiple cancer models, including glioblastoma (GBM).

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

Unlabelled: 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- C]-glucose in DMGs.

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

Unlabelled: 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.

Imaging telomerase reverse transcriptase expression in oligodendrogliomas using hyperpolarized δ-[1-C]-gluconolactone.

Background: Telomere maintenance by telomerase reverse transcriptase (TERT) is essential for immortality in most cancers, including oligodendrogliomas. Agents that disrupt telomere maintenance such as the telomere uncapping agent 6-thio-2'-deoxyguanosine (6-thio-dG) are in clinical trials. We previously showed that TERT expression in oligodendrogliomas is associated with upregulation of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP).

Hyperpolarized δ-[1- C]gluconolactone imaging visualizes response to TERT or GABPB1 targeting therapy for glioblastoma.

TERT promoter mutations are a hallmark of glioblastoma (GBM). Accordingly, TERT and GABPB1, a subunit of the upstream mutant TERT promoter transcription factor GABP, are being considered as promising therapeutic targets in GBM. We recently reported that the expression of TERT or GABP1 modulates flux via the pentose phosphate pathway (PPP).

Deuterium Metabolic Imaging Reports on TERT Expression and Early Response to Therapy in Cancer.

Purpose: Telomere maintenance is a hallmark of cancer. Most tumors maintain telomere length via reactivation of telomerase reverse transcriptase (TERT) expression. Identifying clinically translatable imaging biomarkers of TERT can enable noninvasive assessment of tumor proliferation and response to therapy.

Deuterium magnetic resonance spectroscopy enables noninvasive metabolic imaging of tumor burden and response to therapy in low-grade gliomas.

Background: The alternative lengthening of telomeres (ALT) pathway is essential for tumor proliferation in astrocytomas. The goal of this study was to identify metabolic alterations linked to the ALT pathway that can be exploited for noninvasive magnetic resonance spectroscopy (MRS)-based imaging of astrocytomas in vivo.

Methods: Genetic and pharmacological methods were used to dissect the association between the ALT pathway and glucose metabolism in genetically engineered and patient-derived astrocytoma models.

Imaging 6-Phosphogluconolactonase Activity in Brain Tumors Using Hyperpolarized δ-[1-C]gluconolactone.

Introduction: The 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.

Imaging Brain Metabolism Using Hyperpolarized C Magnetic Resonance Spectroscopy.

Aberrant metabolism is a key factor in many neurological disorders. The ability to measure such metabolic impairment could lead to improved detection of disease progression, and development and monitoring of new therapeutic approaches. Hyperpolarized C magnetic resonance spectroscopy (MRS) is a developing imaging technique that enables non-invasive measurement of enzymatic activity in real time in living organisms.

Amino Acid-Derived Sensors for Specific Zn Detection Using Hyperpolarized C Magnetic Resonance Spectroscopy.

Alterations in Zn concentration are seen in normal tissues and in disease states, and for this reason imaging of Zn is an area of active investigation. Herein, enriched [1- C]cysteine and [1- C ]iminodiacetic acid were developed as Zn -specific imaging probes using hyperpolarized C magnetic resonance spectroscopy. [1- C]cysteine was used to accurately quantify Zn in complex biological mixtures.

Late-stage deuteration of C-enriched substrates for T prolongation in hyperpolarized C MRI.

A robust and selective late-stage deuteration methodology was applied to 13C-enriched amino and alpha hydroxy acids to increase spin-lattice relaxation constant T1 for hyperpolarized 13C magnetic resonance imaging. For the five substrates with 13C-labeling on the C1-position ([1-13C]alanine, [1-13C]serine, [1-13C]lactate, [1-13C]glycine, and [1-13C]valine), significant increase of their T1 was observed at 3 T with deuterium labeling (+26%, 22%, +16%, +25% and +29%, respectively). Remarkably, in the case of [2-13C]alanine, [2-13C]serine and [2-13C]lactate, deuterium labeling led to a greater than four fold increase in T1.

[C]Para-Aminobenzoic Acid: A Positron Emission Tomography Tracer Targeting Bacteria-Specific Metabolism.

Imaging studies are frequently used to support the clinical diagnosis of infection. These techniques include computed tomography (CT) and magnetic resonance imaging (MRI) for structural information and single photon emission computed tomography (SPECT) or positron emission tomography (PET) for metabolic data. However, frequently, there is significant overlap in the imaging appearance of infectious and noninfectious entities using these tools.

Ruthenium-catalyzed hydrogen isotope exchange of C(sp)-H bonds directed by a sulfur atom.

We present here the first example of C(sp)-H activation directed by a sulfur atom. Based on this transformation catalyzed by Ru/C, we have developed a hydrogen isotope exchange reaction for the deuterium and tritium labelling of thioether substructures in complex molecules.

Enantiospecific C-H Activation Using Ruthenium Nanocatalysts.

The activation of C-H bonds has revolutionized modern synthetic chemistry. However, no general strategy for enantiospecific C-H activation has been developed to date. We herein report an enantiospecific C-H activation reaction followed by deuterium incorporation at stereogenic centers.

Regioselective and stereospecific deuteration of bioactive aza compounds by the use of ruthenium nanoparticles.

An efficient H/D exchange method allowing the deuteration of pyridines, quinolines, indoles, and alkyl amines with D2 in the presence of Ru@PVP nanoparticles is described. By a general and simple procedure involving mild reaction conditions and simple filtration to recover the labeled product, the isotopic labeling of 22 compounds proceeded in good yield with high chemo- and regioselectivity. The viability of this procedure was demonstrated by the labeling of eight biologically active compounds.