Abstract 5464: Host variation in OATP1B1 is associated with treatment outcome in pediatric AML

Abstract

Abstract Improvements in survival have been achieved for children and adolescents with acute myeloid leukemia (AML), with the 5-year survival rate increasing between 1975 and 2010 from <20% to 70%. However in the past decade, outcome has not improved. Therapeutic approach in AML consists of intensive combination chemotherapy and hematopoietic stem cell transplantation. Although several prognostic factors have been identified, current predictive analysis remains inadequate. We performed a pharmacogenetic-association study on leukemic and/or germline DNA of 164 pediatric patients with AML receiving cytarabine (Ara-C), daunorubicin (Dauno), etoposide (VP16) and mitoxantrone (MTZ) using the DMET platform involving 1,936 variants in 225 genes related to drug metabolism and transport. After adjusting for age, risk group and treatment arm, among the top-ranking variants associated with event-free survival (P = 0.0060) and overall survival (P = 0.012) was a silent single-nucleotide polymorphism (SNP) in SLCO1B1 (c.597C>T), a gene encoding the hepatocellular uptake transporter OATP1B1. This SNP was not correlated with gene expression in leukemic blasts (P = 0.58), suggesting the association might be due to a host rather than a leukemia effect. Since this SNP is in strong linkage disequilibrium (P<0.0001) with two non-synonymous coding variants in SLCO1B1 that encode known functional variants OATP1B1*1B (Asn130Asp) and OATP1B1*5 (Val174Ala), we hypothesized that one or more of the AML drugs may be a substrate of OATP1B1. In vitro transport studies using mammalian cells stably transfected with OATP1B1*1A (wild-type) revealed that the intracellular uptake of Ara-C, Dauno, VP16 and MTZ was enhanced compared with control cells in a time- and concentration-dependent manner. Moreover, the efficiency of drug transport was impaired in cells expressing either OATP1B1*1B or OATP1B1*5, or both (OATP1B1*15) compared with OATP1B1*1A. To test whether Ara-C, Dauno, VP16 and/or MTZ are transported by OATP1B-type carriers in vivo, we determined the pharmacokinetic profile of these agents (1-100 mg/kg; i.v. or i.p.) in mice deficient in the ortholog transporter Oatp1b2 [Oatp1b2(-/-) mice]. We found the concentrations of Dauno, VP16 and MTZ in livers of Oatp1b2(-/-) mice were reduced (1.4-2.8 fold) compared to wild-type mice, and this phenomenon was accompanied by significant increases in plasma area under the curve. Despite being a transported substrate of OATP1B1*1A and Oatp1b2 in vitro (4.7-fold vs control), plasma concentrations of Ara-C were not affected by Oatp1b2 deficiency, which may reflect a differential contribution of the liver in drug elimination between different species. Collectively, these findings indicate an important role for OATP1B1 in the systemic pharmacokinetics of multiple drugs used in the treatment of pediatric AML and suggest that inherited variability in host transporter function may indirectly regulate the effectiveness of therapy. Citation Format: Christina D. Drenberg, Stanley Pounds, Lei Shi, Shelley Orwick, Lie Li, Shuiying Hu, Alice Gibson, Raul Ribeiro, Jeffrey Rubnitz, Alex Sparreboom, Sharyn D. Baker. Host variation in OATP1B1 is associated with treatment outcome in pediatric AML. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5464. doi:10.1158/1538-7445.AM2015-5464