Abstract 3617: The multikinase inhibitor sorafenib enhances the activity of cytarabine in a mouse xenograft model of acute myeloid leukemia (AML)

Abstract

Abstract AML is a genetically heterogeneous cancer frequently showing aberrant kinase signaling. Sorafenib, an inhibitor of multiple receptor and intracellular kinases, is in clinical development for the treatment of AML. Although initial anti-leukemic activity has been encouraging, responses have not been durable. We hypothesized that sorafenib was more likely to be effective when administered in combination with cytarabine, one of the most effective agents for the treatment of AML. We previously showed that sorafenib did not negatively influence the intracellular activation of cytarabine to its triphosphate form, and enhanced the activity of cytarabine in 7 AML cell lines and in 25 primary childhood AML blast samples (Niu, AACR, 2009). In the current study, we evaluated the activity of sorafenib in combination with cytarabine versus either agent alone in a mouse xenograft model of AML. 1 × 104 Luciferase + U937 cells (monocytic, CALM-AF10 chimera) were injected intravenously into the dorsolateral tail vein of NOD-SCID-IL2Rrnull mice and cohorts of 10-12 mice were treated. Sorafenib pharmacokinetics studies were conducted in the same mouse strain to determine a dose that produced human equivalent exposure. Tumor engraftment and progression were evaluated by biophotonic imaging and anti-leukemic activity was determined by monitoring survival time and performing histological studies in colonized tissues (bone marrow, spleen, and liver). Sorafenib 60 mg/kg administered orally twice daily achieved a clinically relevant steady-state exposure of 10 µM and was given on a daily for 5 out of 7 days schedule for 4 weeks; cytarabine 6.25 mg/kg was administered intraperitoneally once daily on the same schedule for 4 weeks alone or in combination with twice daily oral sorafenib. Sorafenib in combination with cytarabine delayed tumor progression and significantly (P<0.001) prolonged median survival compared to cytarabine alone, sorafenib alone or controls (median survival: 46 vs 34 vs 21 vs 19 days, respectively). Histological studies revealed smaller spleen size (0.05 ± 0.01 g vs 0.2 ± 0.1 g) and lower percentage of spleen colonized with U937 cells (0-30% vs 75-90%) in mice treated with the drug combination vs those treated with cytarabine alone. Studies in bone marrow showed a greater percentage of cells undergoing apoptosis (89% vs 75% Annexin V positive) and less U937 cells (0.6% vs 3.4% hCD45+) in the combination vs cytarabine treated groups. In conclusion, our studies demonstrate the in vivo activity of sorafenib in combination with cytarabine in AML and support our current efforts to evaluate this promising multikinase inhibitor in combination with cytarabine-based regimens in childhood AML. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3617.