FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4362597193> ?p ?o ?g. }

• W4362597193 endingPage "2820" @default.
• W4362597193 startingPage "2820" @default.
• W4362597193 abstract "Abstract Diffuse midline gliomas (DMG) are an aggressive and treatment resistant form of brain cancer in urgent need of new and effective treatment strategies. Radiation therapy (RT) is the standard of care for DMGs, but these tumors often recur locally within the high-dose radiation field. Therefore, it is imperative to discover methods of overcoming RT resistance. DMGs are often characterized by the presence of driving mutation in the tail domain of histone H3 that converts the 27th residue from a lysine to a methionine (termed H3K27M). Using liquid chromatography/mass spectrometry “snapshot” metabolomics, we determined that human H3K27M-expressing cells (referred to as K27M cells going forward) possess altered metabolic profiles distinct from their H3-wildtype (H3WT) counterparts characterized by enrichment in metabolites associated with purine metabolism. RT-treated K27M isogenic-paired cells displayed K27M-specific increases in the abundance of both hypoxanthine and guanine and decreased abundance of guanosine, which can be degraded into guanine from mature guanylate species (GMP/GDP/GTP). Hypoxanthine and guanine are the substrates for HGPRT (encoded by HPRT1), the rate-limiting enzyme in purine salvage. Using publicly available data, pediatric high-grade gliomas (pHGG) expressing K27M were found to have decreased HPRT1 transcript compared to H3WT tumors, and we found decreased HGPRT protein expression in K27M cell lines compared to their isogenic H3WT counterparts. The decreased abundance of guanosine, increased abundance of both purine salvage metabolites following RT, and decreased expression of HGPRT suggest impaired guanylate purine salvage in K27M cells that is exacerbated by RT. We hypothesized that K27M cells are deficient in purine salvage and may rely on de novo purine synthesis (DNPS) for purine production following RT. Consistent with this hypothesis, we found that a clinically available, blood-brain penetrant inhibitor of DNPS increased RT-mediated killing of K27M neurospheres in vitro. Combination RT+DNPS inhibition (DNPSi) increased survival (38d post-implantation) over RT alone (31.5d post-implantation) in Rag1-KO mice bearing orthotopically implanted K27M tumors, but did not cure tumors. To understand potential mechanisms of treatment resistance, we interrogated metabolic pathway utilization with stable isotope tracing. Using 2,8-deuterium-hypoxanthine to interrogate purine salvage and 15N-glutamine to interrogate de novo purine synthesis, we found an RT-mediated increase in purine salvage that could mediate resistance to DNPSi inhibition. Future experiments will determine whether inhibition of purine salvage has efficacy for those tumors that recur or progress following treatment with RT and DNPSi inhibition. Citation Format: Erik R. Peterson, Peter Sajjakulnukit, Andrew Scott, Caleb Heaslip, Costas Lyssiotis, Maria G. Castro, Daniel R. Wahl. Defining the role of purine metabolism in radiation resistance in H3K27M–mutant diffuse midline glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2820." @default.
• W4362597193 created "2023-04-06" @default.
• W4362597193 creator A5000778757 @default.
• W4362597193 creator A5008672750 @default.
• W4362597193 creator A5020108774 @default.
• W4362597193 creator A5026775589 @default.
• W4362597193 creator A5040378393 @default.
• W4362597193 creator A5046406895 @default.
• W4362597193 creator A5049944456 @default.
• W4362597193 date "2023-04-04" @default.
• W4362597193 modified "2023-10-16" @default.
• W4362597193 title "Abstract 2820: Defining the role of purine metabolism in radiation resistance in H3K27M–mutant diffuse midline glioma" @default.
• W4362597193 doi "https://doi.org/10.1158/1538-7445.am2023-2820" @default.
• W4362597193 hasPublicationYear "2023" @default.
• W4362597193 type Work @default.
• W4362597193 citedByCount "0" @default.
• W4362597193 crossrefType "journal-article" @default.
• W4362597193 hasAuthorship W4362597193A5000778757 @default.
• W4362597193 hasAuthorship W4362597193A5008672750 @default.
• W4362597193 hasAuthorship W4362597193A5020108774 @default.
• W4362597193 hasAuthorship W4362597193A5026775589 @default.
• W4362597193 hasAuthorship W4362597193A5040378393 @default.
• W4362597193 hasAuthorship W4362597193A5046406895 @default.
• W4362597193 hasAuthorship W4362597193A5049944456 @default.
• W4362597193 hasConcept C104317684 @default.
• W4362597193 hasConcept C143065580 @default.
• W4362597193 hasConcept C169586020 @default.
• W4362597193 hasConcept C181199279 @default.
• W4362597193 hasConcept C185592680 @default.
• W4362597193 hasConcept C21565614 @default.
• W4362597193 hasConcept C2776476023 @default.
• W4362597193 hasConcept C2778301229 @default.
• W4362597193 hasConcept C2780912031 @default.
• W4362597193 hasConcept C2781116151 @default.
• W4362597193 hasConcept C502942594 @default.
• W4362597193 hasConcept C512185932 @default.
• W4362597193 hasConcept C515207424 @default.
• W4362597193 hasConcept C55493867 @default.
• W4362597193 hasConcept C60644358 @default.
• W4362597193 hasConcept C78179603 @default.
• W4362597193 hasConcept C86803240 @default.
• W4362597193 hasConceptScore W4362597193C104317684 @default.
• W4362597193 hasConceptScore W4362597193C143065580 @default.
• W4362597193 hasConceptScore W4362597193C169586020 @default.
• W4362597193 hasConceptScore W4362597193C181199279 @default.
• W4362597193 hasConceptScore W4362597193C185592680 @default.
• W4362597193 hasConceptScore W4362597193C21565614 @default.
• W4362597193 hasConceptScore W4362597193C2776476023 @default.
• W4362597193 hasConceptScore W4362597193C2778301229 @default.
• W4362597193 hasConceptScore W4362597193C2780912031 @default.
• W4362597193 hasConceptScore W4362597193C2781116151 @default.
• W4362597193 hasConceptScore W4362597193C502942594 @default.
• W4362597193 hasConceptScore W4362597193C512185932 @default.
• W4362597193 hasConceptScore W4362597193C515207424 @default.
• W4362597193 hasConceptScore W4362597193C55493867 @default.
• W4362597193 hasConceptScore W4362597193C60644358 @default.
• W4362597193 hasConceptScore W4362597193C78179603 @default.
• W4362597193 hasConceptScore W4362597193C86803240 @default.
• W4362597193 hasIssue "7_Supplement" @default.
• W4362597193 hasLocation W43625971931 @default.
• W4362597193 hasOpenAccess W4362597193 @default.
• W4362597193 hasPrimaryLocation W43625971931 @default.
• W4362597193 hasRelatedWork W1605437789 @default.
• W4362597193 hasRelatedWork W1972023176 @default.
• W4362597193 hasRelatedWork W1985654998 @default.
• W4362597193 hasRelatedWork W2001495358 @default.
• W4362597193 hasRelatedWork W2013157260 @default.
• W4362597193 hasRelatedWork W2023033821 @default.
• W4362597193 hasRelatedWork W2055143521 @default.
• W4362597193 hasRelatedWork W2086038894 @default.
• W4362597193 hasRelatedWork W2127998943 @default.
• W4362597193 hasRelatedWork W54361237 @default.
• W4362597193 hasVolume "83" @default.
• W4362597193 isParatext "false" @default.
• W4362597193 isRetracted "false" @default.
• W4362597193 workType "article" @default.