FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W1967015427> ?p ?o ?g. }

• W1967015427 endingPage "C81" @default.
• W1967015427 startingPage "C81" @default.
• W1967015427 abstract "Abstract Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and is associated with a poor prognosis. Progress in developing effective therapies for this disease is significantly limited by the blood-brain barrier (BBB), which limits the delivery of many anti-cancer agents to infiltrative tumor cells. In addition to physical barriers, such as tight junctions, the efflux proteins bcrp and P-gp in the BBB limit the brain distribution of numerous anti-cancer agents. Palbociclib (PD0332991) is a potent Cdk4/6 inhibitor which has shown remarkable efficacy in treating peripheral (non-brain) tumors. The Cdk4 pathway is dysregulated in approximately 75% of GBM; most commonly, the pathway is hyperactivated through the homozygous deletion of p16 (52%), amplification of Cdk4 (18%), or amplification of Cdk6 (1%). The purpose of this study is to define the role of the efflux transporters P-gp and bcrp in the brain distribution of palbociclib and to examine if an intact BBB limits efficacy. Palbociclib brain distribution studies were performed in FVB wild-type, P-gp knockout (PKO; Mdr1a/b(-/-)), bcrp knockout (BKO; Bcrp1(-/-)), and triple knockout (TKO; Mdr1a/b(-/-)Bcrp1(-/-)) mice after an oral dose (10mg/kg). The concentrations of palbociclib from all distribution studies were determined by a sensitive and specific LC-MS/MS assay. Survival studies were conducted in patient-derived primary GBM xenograft models in athymic nu/nu mice. The brain exposure of palbociclib (AUCbrain-to-AUCplasma ratio) was ∼ 33.5, 3.2, and 150-fold higher as compared to WT mice (WT: .044; PKO: 1.34; BKO: 0.13; TKO: 6.24). Further, the steady-state brain-to-plasma ratio (B/P) of palbociclib after a constant intra-peritoneal infusion of 10 µg/hr for 48hrs was ∼120-fold higher in the TKO mice than the WT mice [WT: (0.21 ± 0.07); PKO: (2.48 ± .13); BKO: (0.43 ± 0.12); TKO: (26.5 ± 5.4) p &lt; 0.0001]. Inhibition of P-gp and bcrp with elacridar (10 mg/kg IP) resulted in a marked increase in palbociclib brain distribution [control B/P (0.06 ± 0.02); elacridar treatment (2.0 ± 1.4)]. For survival studies, palbociclib was dosed at 150 mg/kg/day continuously. Consistent with limited brain penetration, palbociclib did not improve the median survival of an orthotopic GBM xenograft model. In contrast, treatment of GBM22 xenografts grown as flank tumors resulted in profound efficacy with a 70 day prolongation in the time for tumor volume to reach 1000mm3. These data suggest the clinical paradigm of a potent anti-cancer agent (for instance, palbociclib) used in the treatment of peripheral disease is less effective in the treatment of brain tumors due to the BBB and active efflux by P-gp and bcrp. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C81. Citation Format: Karen E. Parrish, Jenny L. Pokorny, Rajendar K. Mittapalli, Katrina Bakken, Jann N. Sarkaria, William F. Elmquist. BBB efflux pump activity limits brain penetration of palbociclib (PD0332991) in glioblastoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C81." @default.
• W1967015427 created "2016-06-24" @default.
• W1967015427 creator A5009433459 @default.
• W1967015427 creator A5013680777 @default.
• W1967015427 creator A5015247761 @default.
• W1967015427 creator A5037781231 @default.
• W1967015427 creator A5041279285 @default.
• W1967015427 creator A5077785086 @default.
• W1967015427 date "2013-11-01" @default.
• W1967015427 modified "2023-10-16" @default.
• W1967015427 title "Abstract C81: BBB efflux pump activity limits brain penetration of palbociclib (PD0332991) in glioblastoma." @default.
• W1967015427 doi "https://doi.org/10.1158/1535-7163.targ-13-c81" @default.
• W1967015427 hasPublicationYear "2013" @default.
• W1967015427 type Work @default.
• W1967015427 sameAs 1967015427 @default.
• W1967015427 citedByCount "8" @default.
• W1967015427 countsByYear W19670154272014 @default.
• W1967015427 countsByYear W19670154272015 @default.
• W1967015427 countsByYear W19670154272016 @default.
• W1967015427 countsByYear W19670154272018 @default.
• W1967015427 countsByYear W19670154272019 @default.
• W1967015427 crossrefType "journal-article" @default.
• W1967015427 hasAuthorship W1967015427A5009433459 @default.
• W1967015427 hasAuthorship W1967015427A5013680777 @default.
• W1967015427 hasAuthorship W1967015427A5015247761 @default.
• W1967015427 hasAuthorship W1967015427A5037781231 @default.
• W1967015427 hasAuthorship W1967015427A5041279285 @default.
• W1967015427 hasAuthorship W1967015427A5077785086 @default.
• W1967015427 hasConcept C110121322 @default.
• W1967015427 hasConcept C121608353 @default.
• W1967015427 hasConcept C124320809 @default.
• W1967015427 hasConcept C126322002 @default.
• W1967015427 hasConcept C134306372 @default.
• W1967015427 hasConcept C185592680 @default.
• W1967015427 hasConcept C199649820 @default.
• W1967015427 hasConcept C200082930 @default.
• W1967015427 hasConcept C2775930923 @default.
• W1967015427 hasConcept C2776194525 @default.
• W1967015427 hasConcept C2779744173 @default.
• W1967015427 hasConcept C29537977 @default.
• W1967015427 hasConcept C33923547 @default.
• W1967015427 hasConcept C502942594 @default.
• W1967015427 hasConcept C530470458 @default.
• W1967015427 hasConcept C55493867 @default.
• W1967015427 hasConcept C71924100 @default.
• W1967015427 hasConcept C98274493 @default.
• W1967015427 hasConceptScore W1967015427C110121322 @default.
• W1967015427 hasConceptScore W1967015427C121608353 @default.
• W1967015427 hasConceptScore W1967015427C124320809 @default.
• W1967015427 hasConceptScore W1967015427C126322002 @default.
• W1967015427 hasConceptScore W1967015427C134306372 @default.
• W1967015427 hasConceptScore W1967015427C185592680 @default.
• W1967015427 hasConceptScore W1967015427C199649820 @default.
• W1967015427 hasConceptScore W1967015427C200082930 @default.
• W1967015427 hasConceptScore W1967015427C2775930923 @default.
• W1967015427 hasConceptScore W1967015427C2776194525 @default.
• W1967015427 hasConceptScore W1967015427C2779744173 @default.
• W1967015427 hasConceptScore W1967015427C29537977 @default.
• W1967015427 hasConceptScore W1967015427C33923547 @default.
• W1967015427 hasConceptScore W1967015427C502942594 @default.
• W1967015427 hasConceptScore W1967015427C530470458 @default.
• W1967015427 hasConceptScore W1967015427C55493867 @default.
• W1967015427 hasConceptScore W1967015427C71924100 @default.
• W1967015427 hasConceptScore W1967015427C98274493 @default.
• W1967015427 hasIssue "11_Supplement" @default.
• W1967015427 hasLocation W19670154271 @default.
• W1967015427 hasOpenAccess W1967015427 @default.
• W1967015427 hasPrimaryLocation W19670154271 @default.
• W1967015427 hasRelatedWork W2001394696 @default.
• W1967015427 hasRelatedWork W2196273533 @default.
• W1967015427 hasRelatedWork W2885602815 @default.
• W1967015427 hasRelatedWork W2887176600 @default.
• W1967015427 hasRelatedWork W3125289280 @default.
• W1967015427 hasRelatedWork W3193135661 @default.
• W1967015427 hasRelatedWork W4200334245 @default.
• W1967015427 hasRelatedWork W4250227300 @default.
• W1967015427 hasRelatedWork W4281670981 @default.
• W1967015427 hasRelatedWork W4282837629 @default.
• W1967015427 hasVolume "12" @default.
• W1967015427 isParatext "false" @default.
• W1967015427 isRetracted "false" @default.
• W1967015427 magId "1967015427" @default.
• W1967015427 workType "article" @default.