Summary of project PR001421

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001421. The data can be accessed directly via it's Project DOI: 10.21228/M81X41 This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

Project ID: PR001421
Project DOI:doi: 10.21228/M81X41
Project Title:De Novo Pyrimidine Synthesis is a Targetable Vulnerability in IDH Mutant Glioma
Project Type:LC-MS Quantitative Analysis
Project Summary:Mutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against leukemia, they appear less active in aggressive glioma, underscoring the need for alternative treatment strategies. Through a chemical synthetic lethality screen, we discovered that IDH1 mutant glioma cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). We developed a genetically engineered mouse model of mutant IDH1-driven astrocytoma and used it and multiple patient-derived models to show that the brain-penetrant DHODH inhibitor BAY 2402234 displays monotherapy efficacy against IDH mutant gliomas. Mechanistically, this reflects an obligate dependence of glioma cells on the de novo pyrimidine synthesis pathway and mutant IDH’s ability to sensitize to DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation.
Institute:UT Southwestern Medical Center
Department:Children's Research Institute
Laboratory:McBrayer Laboratory
Last Name:McBrayer
First Name:Samuel
Address:6000 Harry Hines Boulevard, NL11.110K, Dallas, Texas, 75235, USA
Email:samuel.mcbrayer@utsouthwestern.edu
Phone:(214)-648-3730

Summary of all studies in project PR001421

Study IDStudy TitleSpeciesInstituteAnalysis
(* : Contains Untargted data)
Release
Date
VersionSamplesDownload
(* : Contains raw data)
ST002231 Metabolomics Analysis of HOG-EV and HOG-R132H Cells with and without BAY 2402234 Treatment Homo sapiens UT Southwestern Medical Center MS 2022-07-28 1 67 Uploaded data (3.9G)*
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