Biology subjects

Phoenix, T.

Publications and source records attributed to Phoenix, T..

3 recordsLinked to original sources

bioRxiv2025

Integrative Multi-Omics Analysis Identifies Nuclear Factor I as a Key Driver of Dysregulated Purine Metabolism in DIPG

Diffuse intrinsic pontine glioma (DIPG) is a devastating brainstem cancer in children, with a median survival of under one year and limited treatment options. Over 80% of DIPGs possess a H3K27M mutation. To identify metabolic vulnerabilities linked to this mutation, we utilized a multi-omics approach in H3K27M-expressing cells, patient-derived cell lines, and mouse models. We show that by reprogramming chromatin landscape the mutation aberrantly induces NFI transcriptional activity, leading to misregulated purine metabolism. The mutation amplifies purine biosynthesis and degradation via the enzymes ATIC and PNP, respectively. Unregulated purine degradation relieves the negative feedback of purines on their own synthesis allowing continuous synthesis, use and degradation making DIPGs reliant on purine biosynthesis. Targeting ATIC reduced tumor progression and improved survival in mice. We propose ATIC as a potential novel target in DIPG.

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↗