Glioblastoma multiforme (GBM) is the most aggressive form of malignant primary brain tumors in adults with a survival of only 12-15 months. We previously showed that ZR2002, a chimeric aminoquinazoline designed to possess mixed EGFR tyrosine kinase (TK) inhibitory and DNA targeting properties exhibits potent activity against GBM established cell lines and brain tumor stem cells in vitro.
We analyzed the in vivo plasma and brain pharmacokinetics (PK) of ZR2002 using various doses and via different routes in CD-1 mice. Mice were sacrificed at 15 min, 30 min, 1 hr, 3 hr, 8 hr, 24 hr after drug administration to quantify the amount of ZR2002 in plasma and brain homogenate of mice using RB10 as an internal standard and HPLC-MS/MS method. For the in vivo efficacy of ZR2002, U87/EGFRvIII cells stably transduced to express luciferase were injected into the right corpus striatum of the brains of 4–6 week-old Nu/Nu nude mice. We monitored tumor growth by luciferase bioluminescence imaging and mice were randomized to receive ZR2002 or vehicle control.
Doses at 12.5 mg/kg IV, and 50 mg/kg PO ZR2002 did not cause any observable toxicity up to 24 h or in a subsequent experiment testing higher doses up to 150mg/kg PO compared to vehicle control with longer time follow-up over three weeks following drug administration. ZR2002 was detectable in the brain homogenate of mice at 3.58 µg/g or 2.76 µg/g for PO/50 mg/kg/3 hr (t max) or IV/12.5 mg/kg/5 min (t max), respectively. Our efficacy study showed that ZR2002 significantly improved the survival of intracranial U87/EGFRvIII tumor-bearing mice, compared to the control group (p value <0.0005).
We conclude that ZR2002 is able to cross the blood brain barrier and exhibits anti-tumor activity in U87/EGFRvIII orthotopic tumor mouse model, suggesting that this combi-molecule should be further developed in pre-clinical studies as a new treatment strategy in GBM.
McGill University
This research is partly funded by the Canadian Cancer Society grant #70217 (PK study) and Cancer Research Society grant#22716 (Efficacy Study)
All authors have declared no conflicts of interest.