title: ABCB1, ABCG2, and PTEN determine the response of glioblastoma to temozolomide and ABT-888 therapy.
abstract: OBJECTIVE
  Little is known about the optimal clinical use of ABT-888 (veliparib) for treatment of glioblastoma. ABT-888 is a PARP inhibitor undergoing extensive clinical evaluation in glioblastoma, because it may synergize with the standard-of-care temozolomide (TMZ). We have elucidated important factors controlling ABT-888 efficacy in glioblastoma.
  
  
  METHODS
  We used genetically engineered spontaneous glioblastoma mouse models and allograft models that were orthotopically transplanted into wild-type (WT) and Abcb1/Abcg2-deficient (KO) recipients.
  
  
  RESULTS
  ABT-888/TMZ is not efficacious against p53;p16(Ink4a)/p19(Arf);K-Ras(v12);LucR allografts in wild-type recipients, indicating inherent resistance. Abcb1/Abcg2 mediated efflux of ABT-888 at the blood-brain barrier (BBB) causes a 5-fold reduction of ABT-888 brain penetration (P < 0.0001) that was fully reversible by elacridar. Efficacy studies in WT and KO recipients and/or concomitant elacridar demonstrate that Abcb1/Abcg2 at the BBB and in tumor cells impair TMZ/ABT-888 combination treatment efficacy. Elacridar also markedly improved TMZ/ABT-888 combination treatment in the spontaneous p53;p16(Ink4a)/p19(Arf);K-Ras(v12);LucR glioblastoma model. Importantly, ABT-888 does enhance TMZ efficacy in Pten deficient glioblastoma allografts and spontaneous tumors, even in Abcb1/Abcg2 proficient wild-type mice. Loss of PTEN occurs frequently in glioblastoma (36%) and in silico analysis on patient with glioblastoma samples revealed that it is associated with a worse overall survival (310 days vs. 620 days, n = 117).
  
  
  CONCLUSIONS
  The potential of ABT-888 in glioblastoma can best be demonstrated in patients with PTEN null tumors. Therefore, clinical trials with ABT-888 should evaluate these patients as a separate group. Importantly, inhibition of ABCB1 and ABCG2 (by elacridar) may improve the efficacy of TMZ/ABT-888 therapy in all glioblastoma patients.
authors.affiliation: Authors' Affiliations: General Clinical Lab/Mouse Cancer Clinic, The Netherlands Cancer Institute; Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy; Utrecht University, Utrecht; Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute; Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania; Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands; and Molecular Neurogenetics Unit, Departments of Neurology and Radiology, Massachusetts General Hospital, and Neuroscience Program, Harvard Medical School, Boston, Massachusetts.
authors.forename: Fan
authors.initials: F
authors.lastname: Lin
authors.affiliation: Authors' Affiliations: General Clinical Lab/Mouse Cancer Clinic, The Netherlands Cancer Institute; Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy; Utrecht University, Utrecht; Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute; Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania; Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands; and Molecular Neurogenetics Unit, Departments of Neurology and Radiology, Massachusetts General Hospital, and Neuroscience Program, Harvard Medical School, Boston, MassachusettsAuthors' Affiliations: General Clinical Lab/Mouse Cancer Clinic, The Netherlands Cancer Institute; Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy; Utrecht University, Utrecht; Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute; Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania; Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands; and Molecular Neurogenetics Unit, Departments of Neurology and Radiology, Massachusetts General Hospital, and Neuroscience Program, Harvard Medical School, Boston, Massachusetts.
authors.forename: Mark C
authors.initials: MC
authors.lastname: de Gooijer
authors.affiliation: Authors' Affiliations: General Clinical Lab/Mouse Cancer Clinic, The Netherlands Cancer Institute; Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy; Utrecht University, Utrecht; Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute; Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania; Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands; and Molecular Neurogenetics Unit, Departments of Neurology and Radiology, Massachusetts General Hospital, and Neuroscience Program, Harvard Medical School, Boston, Massachusetts.
authors.forename: Eloy Moreno
authors.initials: EM
authors.lastname: Roig
authors.affiliation: Authors' Affiliations: General Clinical Lab/Mouse Cancer Clinic, The Netherlands Cancer Institute; Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy; Utrecht University, Utrecht; Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute; Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania; Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands; and Molecular Neurogenetics Unit, Departments of Neurology and Radiology, Massachusetts General Hospital, and Neuroscience Program, Harvard Medical School, Boston, Massachusetts.
authors.forename: Levi C M
authors.initials: LC
authors.lastname: Buil
authors.affiliation: Authors' Affiliations: General Clinical Lab/Mouse Cancer Clinic, The Netherlands Cancer Institute; Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy; Utrecht University, Utrecht; Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute; Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania; Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands; and Molecular Neurogenetics Unit, Departments of Neurology and Radiology, Massachusetts General Hospital, and Neuroscience Program, Harvard Medical School, Boston, Massachusetts.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Christner
authors.affiliation: Authors' Affiliations: General Clinical Lab/Mouse Cancer Clinic, The Netherlands Cancer Institute; Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy; Utrecht University, Utrecht; Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute; Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania; Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands; and Molecular Neurogenetics Unit, Departments of Neurology and Radiology, Massachusetts General Hospital, and Neuroscience Program, Harvard Medical School, Boston, MassachusettsAuthors' Affiliations: General Clinical Lab/Mouse Cancer Clinic, The Netherlands Cancer Institute; Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy; Utrecht University, Utrecht; Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute; Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania; Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands; and Molecular Neurogenetics Unit, Departments of Neurology and Radiology, Massachusetts General Hospital, and Neuroscience Program, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Beumer
authors.affiliation: Authors' Affiliations: General Clinical Lab/Mouse Cancer Clinic, The Netherlands Cancer Institute; Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy; Utrecht University, Utrecht; Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute; Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania; Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands; and Molecular Neurogenetics Unit, Departments of Neurology and Radiology, Massachusetts General Hospital, and Neuroscience Program, Harvard Medical School, Boston, MassachusettsAuthors' Affiliations: General Clinical Lab/Mouse Cancer Clinic, The Netherlands Cancer Institute; Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy; Utrecht University, Utrecht; Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute; Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania; Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands; and Molecular Neurogenetics Unit, Departments of Neurology and Radiology, Massachusetts General Hospital, and Neuroscience Program, Harvard Medical School, Boston, Massachusetts.
authors.forename: Thomas
authors.initials: T
authors.lastname: Würdinger
authors.affiliation: Authors' Affiliations: General Clinical Lab/Mouse Cancer Clinic, The Netherlands Cancer Institute; Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy; Utrecht University, Utrecht; Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute; Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania; Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands; and Molecular Neurogenetics Unit, Departments of Neurology and Radiology, Massachusetts General Hospital, and Neuroscience Program, Harvard Medical School, Boston, MassachusettsAuthors' Affiliations: General Clinical Lab/Mouse Cancer Clinic, The Netherlands Cancer Institute; Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy; Utrecht University, Utrecht; Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute; Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania; Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands; and Molecular Neurogenetics Unit, Departments of Neurology and Radiology, Massachusetts General Hospital, and Neuroscience Program, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.affiliation: Authors' Affiliations: General Clinical Lab/Mouse Cancer Clinic, The Netherlands Cancer Institute; Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy; Utrecht University, Utrecht; Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute; Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania; Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands; and Molecular Neurogenetics Unit, Departments of Neurology and Radiology, Massachusetts General Hospital, and Neuroscience Program, Harvard Medical School, Boston, Massachusetts o.v.tellingen@nki.nl.
authors.forename: Olaf
authors.initials: O
authors.lastname: van Tellingen
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000166:Acridines / Q000008:administration & dosage / Q000493:pharmacokinetics; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D001562:Benzimidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004285:Dogs; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D018374:LLC-PK1 Cells; D061985:Madin Darby Canine Kidney Cells; D008657:Metabolic Clearance Rate; D018345:Mice, Knockout; D008819:Mice, Nude; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D013552:Swine; D000077204:Temozolomide; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D000166:Acridines; D001562:Benzimidazoles; D044005:Tetrahydroisoquinolines; C521013:veliparib; D003606:Dacarbazine; D051059:PTEN Phosphohydrolase; C507084:Abcb1b protein, mouse; C083501:Elacridar; D000077204:Temozolomide