Summary of Study ST002231

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.

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This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST002231
Study TitleMetabolomics Analysis of HOG-EV and HOG-R132H Cells with and without BAY 2402234 Treatment
Study TypeMetabolomics Analysis
Study SummaryHOG cells were plated in 6-well plates (0.5 × 10^6 cells per well). 24 hours later, HOG-EV or HOG-R132H cells were treated for 24 hours with 10 nM BAY 2402234 or DMSO. Cells were then harvested for LC-MS analysis.
Institute
UT Southwestern Medical Center
DepartmentChildren's Research Institute
LaboratoryMcBrayer Laboratory
Last NameMcBrayer
First NameSamuel
Address6000 Harry Hines Boulevard, NL10.110K, Dallas, TX 75235, USA
Emailsamuel.mcbrayer@utsouthwestern.edu
Phone(214)-648-3730
Submit Date2022-07-14
Num Groups4
Total Subjects1
Raw Data AvailableYes
Raw Data File Type(s)raw(Thermo)
Analysis Type DetailLC-MS
Release Date2022-07-28
Release Version1
Samuel McBrayer Samuel McBrayer
https://dx.doi.org/10.21228/M81X41
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:


Project:

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

Subject:

Subject ID:SU002317
Subject Type:Cultured cells
Subject Species:Homo sapiens
Taxonomy ID:9606
Genotype Strain:HOG
Gender:Male
Cell Strain Details:Human oligodendroglioma cell line
Cell Counts:500,000

Factors:

Subject type: Cultured cells; Subject species: Homo sapiens (Factor headings shown in green)

mb_sample_id local_sample_id Genotype Treatment
SA212572ML-11_NegativeHOG EV BAY2402234
SA212573ML-11_PositiveHOG EV BAY2402234
SA212574ML-12_PositiveHOG EV BAY2402234
SA212575ML-20_PositiveHOG EV BAY2402234
SA212576ML-20_NegativeHOG EV BAY2402234
SA212577ML-19_NegativeHOG EV BAY2402234
SA212578ML-19_PositiveHOG EV BAY2402234
SA212579ML-12_NegativeHOG EV BAY2402234
SA212580ML-27_NegativeHOG EV BAY2402234
SA212581ML-28_NegativeHOG EV BAY2402234
SA212582ML-28_PositiveHOG EV BAY2402234
SA212583ML-27_PositiveHOG EV BAY2402234
SA212584ML-03_NegativeHOG EV BAY2402234
SA212585ML-04_PositiveHOG EV BAY2402234
SA212586ML-04_NegativeHOG EV BAY2402234
SA212587ML-03_PositiveHOG EV BAY2402234
SA212588ML-17_PositiveHOG EV DMSO
SA212589ML-18_NegativeHOG EV DMSO
SA212590ML-26_NegativeHOG EV DMSO
SA212591ML-26_PositiveHOG EV DMSO
SA212592ML-25_PositiveHOG EV DMSO
SA212593ML-25_NegativeHOG EV DMSO
SA212594ML-18_PositiveHOG EV DMSO
SA212595ML-17_NegativeHOG EV DMSO
SA212596ML-10_PositiveHOG EV DMSO
SA212597ML-02_PositiveHOG EV DMSO
SA212598ML-10_NegativeHOG EV DMSO
SA212599ML-09_PositiveHOG EV DMSO
SA212600ML-09_NegativeHOG EV DMSO
SA212601ML-01_PositiveHOG EV DMSO
SA212602ML-02_NegativeHOG EV DMSO
SA212603ML-01_NegativeHOG EV DMSO
SA212604ML-07_NegativeHOG R132H BAY2402234
SA212605ML-24_NegativeHOG R132H BAY2402234
SA212606ML-24_PositiveHOG R132H BAY2402234
SA212607ML-32_PositiveHOG R132H BAY2402234
SA212608ML-31_NegativeHOG R132H BAY2402234
SA212609ML-31_PositiveHOG R132H BAY2402234
SA212610ML-32_NegativeHOG R132H BAY2402234
SA212611ML-23_NegativeHOG R132H BAY2402234
SA212612ML-23_PositiveHOG R132H BAY2402234
SA212613ML-16_PositiveHOG R132H BAY2402234
SA212614ML-08_PositiveHOG R132H BAY2402234
SA212615ML-16_NegativeHOG R132H BAY2402234
SA212616ML-07_PositiveHOG R132H BAY2402234
SA212617ML-08_NegativeHOG R132H BAY2402234
SA212618ML-15_PositiveHOG R132H BAY2402234
SA212619ML-15_NegativeHOG R132H BAY2402234
SA212620ML-29_NegativeHOG R132H DMSO
SA212621ML-14_NegativeHOG R132H DMSO
SA212622ML-29_PositiveHOG R132H DMSO
SA212623ML-30_PositiveHOG R132H DMSO
SA212624ML-14_PositiveHOG R132H DMSO
SA212625ML-30_NegativeHOG R132H DMSO
SA212626ML-05_NegativeHOG R132H DMSO
SA212627ML-21_NegativeHOG R132H DMSO
SA212628ML-22_PositiveHOG R132H DMSO
SA212629ML-22_NegativeHOG R132H DMSO
SA212630ML-13_NegativeHOG R132H DMSO
SA212631ML-06_PositiveHOG R132H DMSO
SA212632ML-13_PositiveHOG R132H DMSO
SA212633ML-05_PositiveHOG R132H DMSO
SA212634ML-06_NegativeHOG R132H DMSO
SA212635ML-21_PositiveHOG R132H DMSO
SA212636BlankN/A N/A
SA212637ML-33_NegativePooled Sample N/A
SA212638ML-33_PositivePooled Sample N/A
Showing results 1 to 67 of 67

Collection:

Collection ID:CO002310
Collection Summary:Cells were washed with ice-cold saline and snap frozen in liquid nitrogen.
Sample Type:Cultured cells

Treatment:

Treatment ID:TR002329
Treatment Summary:HOG cells were plated in 6-well plates (0.5 × 10^6 cells per well). 24 hours later, HOG-EV or HOG-R132H cells were treated for 24 hours with 10 nM BAY 2402234 or DMSO.

Sample Preparation:

Sampleprep ID:SP002323
Sampleprep Summary:Metabolites were extracted in 80% methanol, vortexed for 20 min at 4°C, and centrifuged (21,100 × g for 10 min at 4°C). Metabolite samples were dried using a CentriVap (Labconco) or SpeedVac (Thermo Fisher) concentrator. Dried metabolites were resuspended in 40-50 µL 80% acetonitrile, vortexed for 20 min at 4°C, and centrifuged (21,100 × g for 10 min at 4°C). 10 µL was injected and analyzed with a Q-Exactive HF-X hybrid quadrupole-orbitrap mass spectrometer (Thermo Fisher) coupled to a Vanquish Flex UHPLC system (Thermo Fisher).

Combined analysis:

Analysis ID AN003640 AN003641
Analysis type MS MS
Chromatography type HILIC HILIC
Chromatography system Vanquish Flex UHPLC Vanquish Flex UHPLC
Column Millipore ZIC-pHILIC Millipore ZIC-pHILIC
MS Type ESI ESI
MS instrument type Orbitrap Orbitrap
MS instrument name Thermo Q Exactive HF-X Orbitrap Thermo Q Exactive HF-X Orbitrap
Ion Mode POSITIVE NEGATIVE
Units TIC-Corrected Peak Area TIC-Corrected Peak Area

Chromatography:

Chromatography ID:CH002695
Chromatography Summary:Chromatographic resolution of metabolites was achieved using on a Millipore ZIC-pHILIC column using a linear gradient of 10 mM ammonium formate pH 9.8 and acetonitrile.
Instrument Name:Vanquish Flex UHPLC
Column Name:Millipore ZIC-pHILIC
Chromatography Type:HILIC

MS:

MS ID:MS003391
Analysis ID:AN003640
Instrument Name:Thermo Q Exactive HF-X Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:Spectra were acquired with a resolving power of 60,000 full width at half maximum (FWHM), a scan range set to 80–1,200 m/z, and polarity switching. Data-dependent MS/MS data was acquired on unlabeled pooled samples to confirm metabolite IDs when necessary. Peaks were integrated using El-Maven 0.12.0 software (Elucidata) or TraceFinder 5.1 SP2 software (Thermo Fisher). Total ion counts were quantified using Freestyle 1.7 SP1 software (Thermo Fisher). Peaks were normalized to total ion counts using the R statistical programming language.
Ion Mode:POSITIVE
  
MS ID:MS003392
Analysis ID:AN003641
Instrument Name:Thermo Q Exactive HF-X Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:Spectra were acquired with a resolving power of 60,000 full width at half maximum (FWHM), a scan range set to 80–1,200 m/z, and polarity switching. Data-dependent MS/MS data was acquired on unlabeled pooled samples to confirm metabolite IDs when necessary. Peaks were integrated using El-Maven 0.12.0 software (Elucidata) or TraceFinder 5.1 SP2 software (Thermo Fisher). Total ion counts were quantified using Freestyle 1.7 SP1 software (Thermo Fisher). Peaks were normalized to total ion counts using the R statistical programming language.
Ion Mode:NEGATIVE
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