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 ID | Study Title | Species | Institute | Analysis (* : Contains Untargted data) |
Release Date | Version | Samples | Download (* : 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)* |
