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.