Abstract LB-210: Impact of ABC-transporters in the blood-brain barrier on the efficacy of the PARP inhibitor ABT-888 against transplanted and spontaneous murine brain tumors

Abstract

Abstract Introduction: ABT-888 (veliparib) is a potent PARP inhibitor and is currently in phase 2 clinical trials. PARP inhibitors enhance the activity of DNA damaging therapies, due to the critical function of PARP-1 and PARP-2 in DNA repair. Combination of ABT-888 with radiation-temozolomide (TMZ) chemotherapy for glioma patient treatment is receiving considerable interest because this combination has shown promise in preclinical models. High-grade glioma patients have a very poor prognosis. Complete resection of the tumor is always impossible and many remaining tumor cells reside in surrounding normal brain tissue where the blood-brain barrier (BBB) is still functional. We have shown that ABCB1 and ABCG2 limit the brain penetration of ABT-888. We have extended our pharmacokinetic studies and are investigating the impact of ABC-transporters in the BBB on the efficacy of ABT-888/TMZ combination therapy using sophisticated murine glioma models. Methods: Drug disposition after i.v. and p.o. administration of 10 mg/kg has been determined in wildtype (WT), single and compound ABC-transporter knockout (KO) mice. ABT-888 was given alone or in combination with elacridar. Drug concentrations were determined by LC-MS/MS. The impact of ABC-transporters on the efficacy of ABT-888 (10 or 25 mg/kg/bid for 5 consecutive days) in combination with TMZ (100 mg/kg/dayx5) was studied using WT and Abcb1/Abcg2 KO recipient mice that were grafted intracranially with a murine glioma derived cell line. Furthermore, efficacy studies were conducted using a transgenic spontaneous glioma model by giving ABT-888 and TMZ with or without elacridar (50 mg/kg bidaily). Results: AUCs of ABT-888 in plasma, liver, kidney, spleen, lung and heart of WT vs single Abcb1, single Abcg2, or compound Abcb1;Abcg2 knockout mice after i.v. administration of 10 mg/kg were not different. However, the AUCs in brains were 4.6, 1.2 and 6.9-fold higher for Abcb1, Abcg2, and Abcb1;Abcg2 KO mice respectively, compared to WT mice. The oral bioavailability of ABT-888 was also similar in WT and KO mice. Co-administration of elacridar increased t-max, but this had only a minor effect on the plasma AUC. ABT-888 (10 mg/kg) potentiated the efficacy of TMZ against glioma cells implanted in Abcb1;Abcg2 KO mice. In WT mice, potentiating of TMZ was seen at 25 mg/kg, but not at 10 mg/kg. Spontaneous tumors treated with elacridar in combination with TMZ and ABT-888 (10 mg/kg) responded better than without elacridar, however, concomitant elacridar also appeared to enhance toxicity. Conclusions: ABC-transporters do not affect systemic clearance or oral bioavailability of ABT-888, however, the brain penetration of ABT-888 is 7-fold reduced by the action of Abcb1 and Abcg2. Efficacy studies indicate that these ABC-transporters may compromise the effects of ABT-888 in potentiating TMZ efficacy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-210. doi:10.1158/1538-7445.AM2011-LB-210