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Efficacy of PARP Inhibitor Rucaparib in Orthotopic Glioblastoma Xenografts Is Limited by Ineffective Drug Penetration into the Central Nervous System

Lookup NU author(s): Dr James Murray, Julieann Sludden, Professor Alan Boddy, Professor Nicola Curtin

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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 patientderived 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. (C)2015 AACR.


Publication metadata

Author(s): Parrish KE, Cen L, Murray J, Calligaris D, Kizilbash S, Mittapalli RK, Carlson BL, Schroeder MA, Sludden J, Boddy AV, Agar NYR, Curtin NJ, Elmquist WF, Sarkaria JN

Publication type: Article

Publication status: Published

Journal: Molecular Cancer Therapeutics

Year: 2015

Volume: 14

Issue: 12

Pages: 2735-2743

Print publication date: 01/12/2015

Online publication date: 05/10/2015

Acceptance date: 14/09/2015

ISSN (print): 1535-7163

ISSN (electronic): 1538-8514

Publisher: American Association for Cancer Research

URL: http://dx.doi.org/10.1158/1535-7163.MCT-15-0553

DOI: 10.1158/1535-7163.MCT-15-0553


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