Matches in SemOpenAlex for { <https://semopenalex.org/work/W4386819688> ?p ?o ?g. }
Showing items 1 to 87 of
87
with 100 items per page.
- W4386819688 abstract "Therapeutic resistance remains a major obstacle to successful clinical management of Diffuse Intrinsic Pontine Glioma (DIPG), a high-grade pediatric tumor of the brain stem. In nearly all patients, available therapies fail to prevent progression. Innovative combinatorial therapies that penetrate the blood-brain barrier and lead to long-term control of tumor growth are desperately needed. We identified mechanisms of resistance to radiotherapy, the standard of care for DIPG. Based on these findings, we rationally designed a brain-penetrant small molecule, MTX-241F, that is a highly selective inhibitor of EGFR and PI3 kinase family members, including the DNA repair protein DNA-PK. Preliminary studies demonstrated that micromolar levels of this inhibitor can be achieved in murine brain tissue and that MTX-241F exhibits promising single-agent efficacy and radiosensitizing activity in patient-derived DIPG neurospheres. Its physiochemical properties include high exposure in the brain, indicating excellent brain penetrance. Since radiotherapy results in double-strand breaks that are repaired by homologous recombination (HR) and non-homologous DNA end joining (NHEJ), we have tested the combination of MTX-241F with an inhibitor of ATM to achieve blockade of HR and NHEJ, respectively, with or without radiotherapy. When HR blockers were combined with MTX-241F and radiotherapy, synthetic lethality was observed, providing impetus to explore this combination in clinically relevant models of DIPG. Our data provide proof-of-concept evidence to support advanced development of MTX-241F for the treatment of DIPG. Future studies will be designed to inform rapid clinical translation to ultimately impact patients diagnosed with this devastating disease." @default.
- W4386819688 created "2023-09-19" @default.
- W4386819688 creator A5000162479 @default.
- W4386819688 creator A5001293585 @default.
- W4386819688 creator A5010918073 @default.
- W4386819688 creator A5013157173 @default.
- W4386819688 creator A5026975189 @default.
- W4386819688 creator A5034027819 @default.
- W4386819688 creator A5034340028 @default.
- W4386819688 creator A5052545112 @default.
- W4386819688 creator A5055574198 @default.
- W4386819688 creator A5057037751 @default.
- W4386819688 creator A5058753628 @default.
- W4386819688 creator A5072554260 @default.
- W4386819688 creator A5074328056 @default.
- W4386819688 creator A5092561588 @default.
- W4386819688 creator A5092892783 @default.
- W4386819688 date "2023-09-19" @default.
- W4386819688 modified "2023-10-17" @default.
- W4386819688 title "Targeting DNA Repair and Survival Signaling in Diffuse Intrinsic Pontine Gliomas to Prevent Tumor Recurrence" @default.
- W4386819688 doi "https://doi.org/10.1158/1535-7163.mct-23-0026" @default.
- W4386819688 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/37723046" @default.
- W4386819688 hasPublicationYear "2023" @default.
- W4386819688 type Work @default.
- W4386819688 citedByCount "0" @default.
- W4386819688 crossrefType "journal-article" @default.
- W4386819688 hasAuthorship W4386819688A5000162479 @default.
- W4386819688 hasAuthorship W4386819688A5001293585 @default.
- W4386819688 hasAuthorship W4386819688A5010918073 @default.
- W4386819688 hasAuthorship W4386819688A5013157173 @default.
- W4386819688 hasAuthorship W4386819688A5026975189 @default.
- W4386819688 hasAuthorship W4386819688A5034027819 @default.
- W4386819688 hasAuthorship W4386819688A5034340028 @default.
- W4386819688 hasAuthorship W4386819688A5052545112 @default.
- W4386819688 hasAuthorship W4386819688A5055574198 @default.
- W4386819688 hasAuthorship W4386819688A5057037751 @default.
- W4386819688 hasAuthorship W4386819688A5058753628 @default.
- W4386819688 hasAuthorship W4386819688A5072554260 @default.
- W4386819688 hasAuthorship W4386819688A5074328056 @default.
- W4386819688 hasAuthorship W4386819688A5092561588 @default.
- W4386819688 hasAuthorship W4386819688A5092892783 @default.
- W4386819688 hasBestOaLocation W43868196881 @default.
- W4386819688 hasConcept C102744134 @default.
- W4386819688 hasConcept C126322002 @default.
- W4386819688 hasConcept C134935766 @default.
- W4386819688 hasConcept C142724271 @default.
- W4386819688 hasConcept C143998085 @default.
- W4386819688 hasConcept C2779130545 @default.
- W4386819688 hasConcept C2780789225 @default.
- W4386819688 hasConcept C502942594 @default.
- W4386819688 hasConcept C509974204 @default.
- W4386819688 hasConcept C54355233 @default.
- W4386819688 hasConcept C552990157 @default.
- W4386819688 hasConcept C60644358 @default.
- W4386819688 hasConcept C71924100 @default.
- W4386819688 hasConcept C86803240 @default.
- W4386819688 hasConceptScore W4386819688C102744134 @default.
- W4386819688 hasConceptScore W4386819688C126322002 @default.
- W4386819688 hasConceptScore W4386819688C134935766 @default.
- W4386819688 hasConceptScore W4386819688C142724271 @default.
- W4386819688 hasConceptScore W4386819688C143998085 @default.
- W4386819688 hasConceptScore W4386819688C2779130545 @default.
- W4386819688 hasConceptScore W4386819688C2780789225 @default.
- W4386819688 hasConceptScore W4386819688C502942594 @default.
- W4386819688 hasConceptScore W4386819688C509974204 @default.
- W4386819688 hasConceptScore W4386819688C54355233 @default.
- W4386819688 hasConceptScore W4386819688C552990157 @default.
- W4386819688 hasConceptScore W4386819688C60644358 @default.
- W4386819688 hasConceptScore W4386819688C71924100 @default.
- W4386819688 hasConceptScore W4386819688C86803240 @default.
- W4386819688 hasLocation W43868196881 @default.
- W4386819688 hasLocation W43868196882 @default.
- W4386819688 hasOpenAccess W4386819688 @default.
- W4386819688 hasPrimaryLocation W43868196881 @default.
- W4386819688 hasRelatedWork W2083088629 @default.
- W4386819688 hasRelatedWork W2164137184 @default.
- W4386819688 hasRelatedWork W2166189554 @default.
- W4386819688 hasRelatedWork W2384708512 @default.
- W4386819688 hasRelatedWork W2888634671 @default.
- W4386819688 hasRelatedWork W2910737515 @default.
- W4386819688 hasRelatedWork W3178060103 @default.
- W4386819688 hasRelatedWork W4248161021 @default.
- W4386819688 hasRelatedWork W4250426713 @default.
- W4386819688 hasRelatedWork W4281934300 @default.
- W4386819688 isParatext "false" @default.
- W4386819688 isRetracted "false" @default.
- W4386819688 workType "article" @default.