Despite greater than 80% of children with acute myelogenous leukemia (AML) experiencing complete remission with the use of high-dose chemotherapy or transplantation, the long-term survival rate is approximately 50%. Further significant improvements in long-term outcome are not expected with conventional therapy alone. Thus novel agents and study designs in which new agents are added to conventional therapy will be needed. Receptor tyrosine kinases play important roles in normal physiological processes and control fundamental cellular activities including cell proliferation, differentiation, and survival. The increasing understanding of the biology of AML has implicated aberrant tyrosine kinase activation in the leukemogenic process. Thus, there has been substantial enthusiasm in adult AML for novel therapies that target oncogenic tyrosine kinase signaling. Our central hypothesis is that tyrosine kinase inhibitors (TKIs) will be effective for the treatment of childhood AML. Since cytarabine (Ara-C) is one of the most effective agents for the treatment of AML and is therefore included in every modern AML treatment regimen, novel agents such as TKIs will be administered with cytarabine-based regimens. New agents in AML must not interfere with the cellular uptake and retention of Ara-C and cytotoxic activity. In the current proposal, we outline three sets of related studies that will address the gaps in preclinical and clinical pharmacology to allow for the future rational incorporation of a promising multikinase inhibitor, sorafenib, in childhood AML. (1) To define the pharmacokinetics and pharmacodynamics of sorafenib in combination with Ara-C that is effective in vivo in murine models of AML. (2) To identify mechanisms by which sorafenib enhances the accumulation and antitumor activity of Ara-C in AML. (3) To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of sorafenib in children with AML receiving cytarabine-based regimens. The work described in this research project outlines a strategy to integrate sorafenib and other novel agents in the treatment of childhood AML, with an emphasis on optimal systemic and intratumoral drug exposure, and ultimately improve the survival of children with AML.
Despite greater than 80% of children with acute myelogenous leukemia (AML) experiencing complete remission with the use of high-dose chemotherapy or transplantation, the long-term survival rate is approximately 50%. Further significant improvements in long-term outcome are not expected with conventional therapy alone. Our studies are of direct human relevance as they will lead to the rational incorporation of a novel tyrosine kinase inhibitor, sorafenib, in childhood AML.
|Sprowl, Jason A; Ong, Su Sien; Gibson, Alice A et al. (2016) A phosphotyrosine switch regulates organic cation transporters. Nat Commun 7:10880|
|Drenberg, C D; Hu, S; Li, L et al. (2016) ABCC4 Is a Determinant of Cytarabine-Induced Cytotoxicity and Myelosuppression. Clin Transl Sci 9:51-9|
|Drenberg, Christina D; Buaboonnam, Jassada; Orwick, Shelley J et al. (2016) Evaluation of artemisinins for the treatment of acute myeloid leukemia. Cancer Chemother Pharmacol 77:1231-43|
|Zimmerman, Eric I; Gibson, Alice A; Hu, Shuiying et al. (2016) Multikinase Inhibitors Induce Cutaneous Toxicity through OAT6-Mediated Uptake and MAP3K7-Driven Cell Death. Cancer Res 76:117-26|
|Edginton, Andrea N; Zimmerman, Eric I; Vasilyeva, Aksana et al. (2016) Sorafenib metabolism, transport, and enterohepatic recycling: physiologically based modeling and simulation in mice. Cancer Chemother Pharmacol 77:1039-52|
|Drenberg, C D; Paugh, S W; Pounds, S B et al. (2016) Inherited variation in OATP1B1 is associated with treatment outcome in acute myeloid leukemia. Clin Pharmacol Ther 99:651-60|
|Vasilyeva, Aksana; Durmus, Selvi; Li, Lie et al. (2015) Hepatocellular Shuttling and Recirculation of Sorafenib-Glucuronide Is Dependent on Abcc2, Abcc3, and Oatp1a/1b. Cancer Res 75:2729-36|
|Nies, Anne T; Schaeffeler, Elke; van der Kuip, Heiko et al. (2014) Cellular uptake of imatinib into leukemic cells is independent of human organic cation transporter 1 (OCT1). Clin Cancer Res 20:985-94|
|Navid, Fariba; Christensen, Robbin; Inaba, Hiroto et al. (2013) Alternative formulations of sorafenib for use in children. Pediatr Blood Cancer 60:1642-6|
|Zimmerman, Eric I; Turner, David C; Buaboonnam, Jassada et al. (2013) Crenolanib is active against models of drug-resistant FLT3-ITD-positive acute myeloid leukemia. Blood 122:3607-15|
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