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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA138744-03
Application #
8207924
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Merritt, William D
Project Start
2010-03-10
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
3
Fiscal Year
2012
Total Cost
$338,142
Indirect Cost
$136,867
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
van Oosterwijk, Jolieke G; Buelow, Daelynn R; Drenberg, Christina D et al. (2018) Hypoxia-induced upregulation of BMX kinase mediates therapeutic resistance in acute myeloid leukemia. J Clin Invest 128:369-380
Fu, Qiang; Chen, Mingqing; Hu, Shuiying et al. (2018) Development and validation of an analytical method for regorafenib and its metabolites in mouse plasma. J Chromatogr B Analyt Technol Biomed Life Sci 1090:43-51
Bins, S; van Doorn, L; Phelps, M A et al. (2017) Influence of OATP1B1 Function on the Disposition of Sorafenib-?-D-Glucuronide. Clin Transl Sci 10:271-279
Park, I-K; Blum, W; Baker, S D et al. (2017) E3 ubiquitin ligase Cbl-b activates the p53 pathway by targeting Siva1, a negative regulator of ARF, in FLT3 inhibitor-resistant acute myeloid leukemia. Leukemia 31:502-505
Drenberg, Christina D; Gibson, Alice A; Pounds, Stanley B et al. (2017) OCTN1 Is a High-Affinity Carrier of Nucleoside Analogues. Cancer Res 77:2102-2111
Drenberg, Christina D; Buelow, Daelynn R; Pounds, Stanley B et al. (2017) Transcriptome profiling of patient derived xenograft models established from pediatric acute myeloid leukemia patients confirm maintenance of FLT3-ITD mutation. Leuk Lymphoma 58:247-250
Jarusiewicz, Jamie A; Jeon, Jae Yoon; Connelly, Michele C et al. (2017) Discovery of a Diaminopyrimidine FLT3 Inhibitor Active against Acute Myeloid Leukemia. ACS Omega 2:1985-2009
Jeon, Jae Yoon; Sparreboom, Alex; Baker, Sharyn D (2017) Kinase Inhibitors: The Reality Behind the Success. Clin Pharmacol Ther 102:726-730
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

Showing the most recent 10 out of 24 publications