Acute myeloid leukemia (AML) is the second most common form of childhood leukemia and has the worst prognosis of all major childhood cancers. The nucleoside analog, Cytarabine (ara-C), is the most effective and widely used chemotherapeutic agent used to treat AML. However, wide inter-patient variation in its treatment response, development of resistance, and severe toxicity remain major hurdles to effective ara-C chemotherapy. Inter-patient variation in expression and/or activity of ara-C pharmacokinetic (PK) and pharmacodynamic (PD) genes is likely to contribute to the variability observed in ara-C treatment outcomes. During the last funding period of this application, we evaluated 12 PK genes in ara-C metabolic pathway and identified genetic polymorphisms that could explain a substantial portion of the variability in ara-C clinical response and could be of similar prognosti relevance as currently used risk stratification factors in AML patients. We found that genetic variation in PK genes may explain 11% of variation in prognosis (event-free survival, EFS) after accounting for 6 well established prognostic factors that cumulatively explain 18% of variation in EFS. To more fully understand the mechanisms contributing to variability in ara-C treatment outcomes, we now propose to study genes involved in ara-C pharmacodynamic response, which unfortunately have not been well studied so far. We have developed a novel statistical method, PROMISE (Projection Onto the Most Interesting Statistical Evidence), which dramatically increases our power to make important pharmacogenomic discoveries by identifying genetic features with a biologically meaningful pattern of associations with multiple pharmacologic and clinical endpoints. As a first step, we will use PROMISE to identify diagnostic leukemic blast gene expression signatures associated with in vitro leukemic blast sensitivity to ara-C as well as multiple clinical outcomes in AML patients (Aim 1). Following functional validation of candidate ara-C PD genes, we will identify and validate the clinical and prognostic significance of polymorphisms in ara-C PD genes in AML patients from multiple independent cohorts (Aim 2). Since epigenetic mechanisms such as DNA methylation have been suggested to influence gene expression in AML, we shall also evaluate DNA methylation for its role in regulating expression of ara-C PK and PD genes, and in influencing clinical outcomes in AML patients treated with ara-C (Aim 3). Finally, we will identify, and validate in independent cohorts of AML patients, the pharmacogenetic and pharmacoepigenetic markers that supplement currently known prognostic factors in an integrated system of risk assignment for purposes of determining treatment intensity. Understanding the interplay of genetic and epigenetic factors in mediating ara-C response and their integration into current prognostic features would present an opportunity to increase our accuracy in forecasting therapeutic outcomes in AML and allow more tailored, risk-stratified treatment approaches - a major advancement over current strategy.

Public Health Relevance

Acute myeloid leukemia (AML) is the second most common childhood leukemia and has the worst outcome of all major childhood cancers. Cytarabine (Ara-C) is the main drug used in AML chemotherapy;however, wide inter-patient variation in treatment response, development of resistance, and severe toxicity remains major hurdles to effective ara-C chemotherapy. The proposed research seeks to explain inter-patient variation in ara- C pharmacokinetic (PK) and pharmacodynamic (PD) genes by studying the genetic and epigenetic markers predictive of ara-C response in pediatric AML patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA132946-07
Application #
8858835
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Jessup, John M
Project Start
2008-06-01
Project End
2019-04-30
Budget Start
2014-09-01
Budget End
2015-04-30
Support Year
7
Fiscal Year
2014
Total Cost
$322,539
Indirect Cost
$93,576
Name
University of Florida
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Elsayed, Abdelrahman H; Cao, Xueyuan; Crews, Kristine R et al. (2018) Comprehensive Ara-C SNP score predicts leukemic cell intracellular ara-CTP levels in pediatric acute myeloid leukemia patients. Pharmacogenomics 19:1101-1110
Stockard, Bradley; Garrett, Timothy; Guingab-Cagmat, Joy et al. (2018) Distinct Metabolic features differentiating FLT3-ITD AML from FLT3-WT childhood Acute Myeloid Leukemia. Sci Rep 8:5534
Bargal, Salma A; Rafiee, Roya; Crews, Kristine R et al. (2018) Genome-wide association analysis identifies SNPs predictive of in vitro leukemic cell sensitivity to cytarabine in pediatric AML. Oncotarget 9:34859-34875
Lamba, Jatinder K; Voigt, Andrew P; Chauhan, Lata et al. (2018) CD33 splicing SNP regulates expression levels of CD33 in normal regenerating monocytes in AML patients. Leuk Lymphoma 59:2250-2253
Lamba, Jatinder K; Cao, Xueyuan; Raimondi, Susana C et al. (2018) Integrated epigenetic and genetic analysis identifies markers of prognostic significance in pediatric acute myeloid leukemia. Oncotarget 9:26711-26723
Lamba, Jatinder K; Pounds, Stanley; Cao, Xueyuan et al. (2016) Clinical significance of in vivo cytarabine-induced gene expression signature in AML. Leuk Lymphoma 57:909-20
Cao, Xueyuan; Crews, Kristine R; Downing, James et al. (2016) CC-PROMISE effectively integrates two forms of molecular data with multiple biologically related endpoints. BMC Bioinformatics 17:382
Bhise, Neha S; Chauhan, Lata; Shin, Miyoung et al. (2015) MicroRNA-mRNA Pairs Associated with Outcome in AML: From In Vitro Cell-Based Studies to AML Patients. Front Pharmacol 6:324
Ghodke-Puranik, Yogita; Puranik, Amrutesh S; Shintre, Pooja et al. (2015) Folate metabolic pathway single nucleotide polymorphisms: a predictive pharmacogenetic marker of methotrexate response in Indian (Asian) patients with rheumatoid arthritis. Pharmacogenomics 16:2019-34
Bachanova, Veronika; Shanley, Ryan; Malik, Farhana et al. (2015) Cytochrome P450 2B6*5 Increases Relapse after Cyclophosphamide-Containing Conditioning and Autologous Transplantation for Lymphoma. Biol Blood Marrow Transplant 21:944-8

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