Matches in SemOpenAlex for { <https://semopenalex.org/work/W4281684140> ?p ?o ?g. }
Showing items 1 to 70 of
70
with 100 items per page.
- W4281684140 endingPage "i169" @default.
- W4281684140 startingPage "i169" @default.
- W4281684140 abstract "Abstract INTRODUCTION: CDK4/6 inhibitors have shown promise against central nervous system (CNS) tumors in vitro. This class of drugs relies on long-term exposure. Their use in early phase clinical studies in children with CNS tumors has defined dose limitations due to systemic toxicity. We have sought to circumvent these limitations in using CDK4/6 inhibitors for pediatric CNS tumors by first demonstrating enhanced efficiency with long-term administration and exploiting prolonged intrathecal delivery (IT). METHODS: Pediatric CNS tumor cell lines were used for cell viability assays: ATRT (BT-12, BT-16), CPC (CCHE-45), diffuse midline glioma (DIPG-XIII, HSJD-007), and medulloblastoma (DAOY); the assays were conducted at 24h, 72h, and 7d post-administration of CDK4/6 inhibitors (abemaciclib, palbociclib, ribociclib). Half maximal growth inhibitory concentrations (GI50) and areas under the curve (AUC) were compared for short-term (24h, 72h) and long-term (7d) dose-response curves. Toxicity with chronic IT administration was assessed using a neurobehavioral safety profile of 7-day continuous infusion of 2.5mM palbociclib (n = 5) into the mouse lateral ventricle compared with vehicle (n = 4). RESULTS: Our results demonstrate increased CDK4/6 inhibitor potency with longer administration. The greatest reductions in short-term to long-term GI50 were observed in ATRT, CPC, and DIPG across all inhibitors. The most pronounced time-dependent efficacy was observed with palbociclib for ATRT and abemaciclib for CPC and DIPG. AUCs significantly decreased (P < 0.05) with increasing drug exposure time across all inhibitors. 7-day intraventricular palbociclib infusion was equivalent in safety to PBS at doses ranging from 1,000 to 10,000-fold the in vitro GI50. CONCLUSIONS: The efficiency of CDK4/6 inhibitors in pediatric CNS tumors is enhanced with prolonged exposure. Long-term IT administration can achieve high CNS doses without associated systemic toxicities. Translational efforts using a metronomic IT strategy are logical to explore for pediatric CNS tumors which have potential for a leptomeningeal disease pattern." @default.
- W4281684140 created "2022-06-13" @default.
- W4281684140 creator A5014278257 @default.
- W4281684140 creator A5025854258 @default.
- W4281684140 creator A5030685339 @default.
- W4281684140 creator A5036314628 @default.
- W4281684140 creator A5061498093 @default.
- W4281684140 creator A5066386615 @default.
- W4281684140 date "2022-06-01" @default.
- W4281684140 modified "2023-10-14" @default.
- W4281684140 title "MODL-05 Metronomic Intrathecal Delivery of CDK4/6 Inhibitors in Preclinical Models of Pediatric Brain Tumors" @default.
- W4281684140 doi "https://doi.org/10.1093/neuonc/noac079.628" @default.
- W4281684140 hasPublicationYear "2022" @default.
- W4281684140 type Work @default.
- W4281684140 citedByCount "0" @default.
- W4281684140 crossrefType "journal-article" @default.
- W4281684140 hasAuthorship W4281684140A5014278257 @default.
- W4281684140 hasAuthorship W4281684140A5025854258 @default.
- W4281684140 hasAuthorship W4281684140A5030685339 @default.
- W4281684140 hasAuthorship W4281684140A5036314628 @default.
- W4281684140 hasAuthorship W4281684140A5061498093 @default.
- W4281684140 hasAuthorship W4281684140A5066386615 @default.
- W4281684140 hasBestOaLocation W42816841401 @default.
- W4281684140 hasConcept C121608353 @default.
- W4281684140 hasConcept C126322002 @default.
- W4281684140 hasConcept C143998085 @default.
- W4281684140 hasConcept C2775930923 @default.
- W4281684140 hasConcept C2778227246 @default.
- W4281684140 hasConcept C2779744173 @default.
- W4281684140 hasConcept C2780789225 @default.
- W4281684140 hasConcept C29730261 @default.
- W4281684140 hasConcept C31760486 @default.
- W4281684140 hasConcept C502942594 @default.
- W4281684140 hasConcept C530470458 @default.
- W4281684140 hasConcept C71924100 @default.
- W4281684140 hasConcept C98274493 @default.
- W4281684140 hasConceptScore W4281684140C121608353 @default.
- W4281684140 hasConceptScore W4281684140C126322002 @default.
- W4281684140 hasConceptScore W4281684140C143998085 @default.
- W4281684140 hasConceptScore W4281684140C2775930923 @default.
- W4281684140 hasConceptScore W4281684140C2778227246 @default.
- W4281684140 hasConceptScore W4281684140C2779744173 @default.
- W4281684140 hasConceptScore W4281684140C2780789225 @default.
- W4281684140 hasConceptScore W4281684140C29730261 @default.
- W4281684140 hasConceptScore W4281684140C31760486 @default.
- W4281684140 hasConceptScore W4281684140C502942594 @default.
- W4281684140 hasConceptScore W4281684140C530470458 @default.
- W4281684140 hasConceptScore W4281684140C71924100 @default.
- W4281684140 hasConceptScore W4281684140C98274493 @default.
- W4281684140 hasIssue "Supplement_1" @default.
- W4281684140 hasLocation W42816841401 @default.
- W4281684140 hasLocation W42816841402 @default.
- W4281684140 hasOpenAccess W4281684140 @default.
- W4281684140 hasPrimaryLocation W42816841401 @default.
- W4281684140 hasRelatedWork W1965490017 @default.
- W4281684140 hasRelatedWork W2307888536 @default.
- W4281684140 hasRelatedWork W2668040617 @default.
- W4281684140 hasRelatedWork W3203106735 @default.
- W4281684140 hasRelatedWork W4210431936 @default.
- W4281684140 hasRelatedWork W4236092729 @default.
- W4281684140 hasRelatedWork W4248161021 @default.
- W4281684140 hasRelatedWork W4361929397 @default.
- W4281684140 hasRelatedWork W4362403339 @default.
- W4281684140 hasRelatedWork W4362432756 @default.
- W4281684140 hasVolume "24" @default.
- W4281684140 isParatext "false" @default.
- W4281684140 isRetracted "false" @default.
- W4281684140 workType "article" @default.