title: Efficacy of PARP Inhibitor Rucaparib in Orthotopic Glioblastoma Xenografts Is Limited by Ineffective Drug Penetration into the Central Nervous System.
abstract: PARP inhibition can enhance the efficacy of temozolomide and prolong survival in orthotopic glioblastoma (GBM) xenografts. The aim of this study was to evaluate the combination of the PARP inhibitor rucaparib with temozolomide and to correlate pharmacokinetic and pharmacodynamic studies with efficacy in patient-derived GBM xenograft models. The combination of rucaparib with temozolomide was highly effective in vitro in short-term explant cultures derived from GBM12, and, similarly, the combination of rucaparib and temozolomide (dosed for 5 days every 28 days for 3 cycles) significantly prolonged the time to tumor regrowth by 40% in heterotopic xenografts. In contrast, the addition of rucaparib had no impact on the efficacy of temozolomide in GBM12 or GBM39 orthotopic models. Using Madin-Darby canine kidney (MDCK) II cells stably expressing murine BCRP1 or human MDR1, cell accumulation studies demonstrated that rucaparib is transported by both transporters. Consistent with the influence of these efflux pumps on central nervous system drug distribution, Mdr1a/b(-/-)Bcrp1(-/-) knockout mice had a significantly higher brain to plasma ratio for rucaparib (1.61 ± 0.25) than wild-type mice (0.11 ± 0.08). A pharmacokinetic and pharmacodynamic evaluation after a single dose confirmed limited accumulation of rucaparib in the brain is associated with substantial residual PARP enzymatic activity. Similarly, matrix-assisted laser desorption/ionization mass spectrometric imaging demonstrated significantly enhanced accumulation of drug in flank tumor compared with normal brain or orthotopic tumors. Collectively, these results suggest that limited drug delivery into brain tumors may significantly limit the efficacy of rucaparib combined with temozolomide in GBM.
authors.affiliation: Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Parrish
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Ling
authors.initials: L
authors.lastname: Cen
authors.affiliation: Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Murray
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: David
authors.initials: D
authors.lastname: Calligaris
authors.affiliation: Department of Medical Oncology Mayo Clinic, Rochester, Minnesota.
authors.forename: Sani
authors.initials: S
authors.lastname: Kizilbash
authors.affiliation: Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Rajendar K
authors.initials: RK
authors.lastname: Mittapalli
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Brett L
authors.initials: BL
authors.lastname: Carlson
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Schroeder
authors.affiliation: Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Julieann
authors.initials: J
authors.lastname: Sludden
authors.affiliation: Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Alan V
authors.initials: AV
authors.lastname: Boddy
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Nathalie Y R
authors.initials: NY
authors.lastname: Agar
authors.affiliation: Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Curtin
authors.affiliation: Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: William F
authors.initials: WF
authors.lastname: Elmquist
authors.affiliation: Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota. sarkaria.jann@mayo.edu.
authors.forename: Jann N
authors.initials: JN
authors.lastname: Sarkaria
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D002490:Central Nervous System / Q000187:drug effects*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004285:Dogs; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D018345:Mice, Knockout; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: C513055:ABCB1 protein, human; 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; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D003606:Dacarbazine; C531549:rucaparib; C095122:multidrug resistance protein 3; D000077204:Temozolomide