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.
Bibliographical noteFunding Information:
This work was supported in part by grants to J.N. Sarkaria from the Mayo Foundation, the NIH (CA141121 and CA127716) and the Brain Tumor Funders Consortium. This work was also supported in part by grants to W.F. Elmquist from the NIH (CA138437) and to both J.N. Sarkaria and W.F. Elmquist from the NIH (NS077921). N.Y.R. Agar was funded by the National Institute of Health Director''s New Innovator Award (1DP2OD007383-01), Dana-Farber PLGA Foundation, and Daniel E. Ponton fund for the Neurosciences. K.E. Parrish was supported by the Ronald J. Sawchuk, Edward G. Rippie and American Foundation for Pharmaceutical Education Pre-Doctoral Fellowships. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.