title: ABCG2 and ABCB1 Limit the Efficacy of Dasatinib in a PDGF-B-Driven Brainstem Glioma Model.
abstract: Dasatinib is a multikinase inhibitor in clinical trials for glioma, and thus far has failed to demonstrate significant efficacy. We investigated whether the ABC efflux transporters ABCG2 and ABCB1 expressed in the blood-brain barrier (BBB), are limiting the efficacy of dasatinib in the treatment of glioma using genetic and pharmacologic approaches. We utilized a genetic brainstem glioma mouse model driven by platelet-derived growth factor-B and p53 loss using abcg2/abcb1 wild-type (ABC WT) or abcg2/abcb1 knockout mice (ABC KO). First, we observed that brainstem glioma tumor latency is significantly prolonged in ABC KO versus ABC WT mice (median survival of 47 vs. 34 days). Dasatinib treatment nearly doubles the survival of brainstem glioma-bearing ABC KO mice (44 vs. 80 days). Elacridar, an ABCG2 and ABCB1 inhibitor, significantly increases the efficacy of dasatinib in brainstem glioma-bearing ABC WT mice (42 vs. 59 days). Pharmacokinetic analysis demonstrates that dasatinib delivery into the normal brain, but not into the tumor core, is significantly increased in ABC KO mice compared with ABC WT mice. Surprisingly, elacridar did not significantly increase dasatinib delivery into the normal brain or the tumor core of ABC WT mice. Next, we demonstrate that the tight junctions of the BBB of this model are compromised as assessed by tissue permeability to Texas Red dextran. Finally, elacridar increases the cytotoxicity of dasatinib independent of ABCG2 and ABCB1 expression in vitro In conclusion, elacridar improves the efficacy of dasatinib in a brainstem glioma model without significantly increasing its delivery to the tumor core. Mol Cancer Ther; 15(5); 819-29. ©2016 AACR.
authors.affiliation: Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Rajendar K
authors.initials: RK
authors.lastname: Mittapalli
authors.affiliation: Department of Pediatrics, Duke University, Durham, North Carolina. Department of Pathology, Duke University, Durham, North Carolina. Preston Robert Tisch Brain Tumor Center, Durham, North Carolina.
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Chung
authors.affiliation: Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Parrish
authors.affiliation: Department of Pediatrics, Duke University, Durham, North Carolina. Department of Pathology, Duke University, Durham, North Carolina. Preston Robert Tisch Brain Tumor Center, Durham, North Carolina.
authors.forename: Donna
authors.initials: D
authors.lastname: Crabtree
authors.affiliation: Department of Pediatrics, Duke University, Durham, North Carolina. Department of Pathology, Duke University, Durham, North Carolina. Preston Robert Tisch Brain Tumor Center, Durham, North Carolina. Department of Surgery, Division of Neurological Surgery, Duke University, Durham, North Carolina.
authors.forename: Kyle G
authors.initials: KG
authors.lastname: Halvorson
authors.affiliation: Department of Pediatrics, Duke University, Durham, North Carolina. Department of Pathology, Duke University, Durham, North Carolina. Preston Robert Tisch Brain Tumor Center, Durham, North Carolina.
authors.forename: Guo
authors.initials: G
authors.lastname: Hu
authors.affiliation: Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: William F
authors.initials: WF
authors.lastname: Elmquist
authors.affiliation: Department of Pediatrics, Duke University, Durham, North Carolina. Department of Pathology, Duke University, Durham, North Carolina. Preston Robert Tisch Brain Tumor Center, Durham, North Carolina. oren.becher@duke.edu.
authors.forename: Oren J
authors.initials: OJ
authors.lastname: Becher
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics / Q000378:metabolism*; D000166:Acridines / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism; D020295:Brain Stem Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D000069439:Dasatinib / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D004357:Drug Synergism; D015870:Gene Expression; D005910:Glioma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000166:Acridines; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D044005:Tetrahydroisoquinolines; C083501:Elacridar; D000069439:Dasatinib