Efficacy of PARP inhibitor rucaparib in orthotopic glioblastoma xenografts is limited by ineffective drug penetration into the central nervous system

Karen E. Parrish, Ling Cen, James Murray, David Calligaris, Sani Kizilbash, Rajendar K. Mittapalli, Brett L. Carlson, Mark A. Schroeder, Julieann Sludden, Alan V. Boddy, Nathalie Y R Agar, Nicola J. Curtin, William F. Elmquist, Jann N Sarkaria

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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, matrixassisted 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.

Original languageEnglish (US)
Pages (from-to)2735-2743
Number of pages9
JournalMolecular Cancer Therapeutics
Volume14
Issue number12
DOIs
StatePublished - Dec 1 2015

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temozolomide
Glioblastoma
Heterografts
Central Nervous System
Pharmaceutical Preparations
Brain
Pharmacokinetics
Central Nervous System Agents
Neoplasms
Madin Darby Canine Kidney Cells
Poly(ADP-ribose) Polymerase Inhibitors
rucaparib
Knockout Mice
Brain Neoplasms
Lasers

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Efficacy of PARP inhibitor rucaparib in orthotopic glioblastoma xenografts is limited by ineffective drug penetration into the central nervous system. / Parrish, Karen E.; Cen, Ling; Murray, James; Calligaris, David; Kizilbash, Sani; Mittapalli, Rajendar K.; Carlson, Brett L.; Schroeder, Mark A.; Sludden, Julieann; Boddy, Alan V.; Agar, Nathalie Y R; Curtin, Nicola J.; Elmquist, William F.; Sarkaria, Jann N.

In: Molecular Cancer Therapeutics, Vol. 14, No. 12, 01.12.2015, p. 2735-2743.

Research output: Contribution to journalArticle

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 2015, 'Efficacy of PARP inhibitor rucaparib in orthotopic glioblastoma xenografts is limited by ineffective drug penetration into the central nervous system', Molecular Cancer Therapeutics, vol. 14, no. 12, pp. 2735-2743. https://doi.org/10.1158/1535-7163.MCT-15-0553
Parrish, Karen E. ; Cen, Ling ; Murray, James ; Calligaris, David ; Kizilbash, Sani ; Mittapalli, Rajendar K. ; Carlson, Brett L. ; Schroeder, Mark A. ; Sludden, Julieann ; Boddy, Alan V. ; Agar, Nathalie Y R ; Curtin, Nicola J. ; Elmquist, William F. ; Sarkaria, Jann N. / Efficacy of PARP inhibitor rucaparib in orthotopic glioblastoma xenografts is limited by ineffective drug penetration into the central nervous system. In: Molecular Cancer Therapeutics. 2015 ; Vol. 14, No. 12. pp. 2735-2743.
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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, matrixassisted 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.",
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