Pharmacometabolomics identifies dodecanamide and leukotriene B4 dimethylamide as a predictor of chemosensitivity for patients with acute myeloid leukemia treated with cytarabine and anthracycline

Abstract

Clinical responses to standard cytarabine plus anthracycline regimen in acute myeloid leukemia (AML) are heterogeneous and there is an unmet need for biological predictors of response to this regimen. Here, we applied a pharmacometabolomics approach to identify potential biomarkers associated with response to this regimen in AML patients. Based on clinical response the enrolled 82 patients were subdivided into two groups: complete remission(CR) responders (n=42) and non-responders (n=40). Metabolic profiles of pre-treatment serum from patients were analyzed by ultra-high performance liquid chromatography coupled with mass spectrometry and the metabolic differences between the two groups were investigated by multivariate statistical analysis. A metabolite panel containing dodecanamide and leukotriene B4 dimethylamide (LTB4-DMA) had the power capacity to differentiate the two groups of patients, yielding an area under the receiver operating characteristic of 0.945 (85.2% sensitivity and 88.9% specificity) in the training set and 0.944(84.6% sensitivity and 80.0% specificity) in the test set. The patients with high levels of LTB4-DMA and low amounts of dodecanamide had good sensitivity to chemotherapeutic agents. The possible reasons were that dodecanamide was produced by leukemic cells as a lipolytic factor to fuel their growth with a potential role in drug resistance and LTB4-DMA was a potent leukotriene B4 antagonist that could be applicable in the treatment of AML. These preliminary results demonstrates the feasibility of relating chemotherapy responses with pre-treatment metabolic profiles of AML patients, and pharmacometabolomics may be a useful tool to select patients that are more likely to benefit from cytarabine plus anthracycline chemotherapy.

Cellular Metabolomics Profiles Associated With Drug Chemosensitivity in AML

“…Of particular interest were also metabolites with a role in altered lipid and fatty acid metabolism associated with respect to doxorubicin chemosensitivity (low levels of LysoPC 16:1 and high levels of glycerol in doxorubicin resistant AML cell lines). Alterations to lipid metabolism are a common feature across multiple cancer types (41)(42)(43)(44)(45)(46), and a growing number of studies have shown its importance for AML as well (7,(47)(48)(49). One of the key alterations to lipid metabolism in AML is an increased dependence on lipid catabolism through fatty acid oxidation (FAO).…”

“…The growing field of metabolomics and its approaches allows full metabolic profile evaluation in AML patients and leukemic cell cultures to explore the relationship between metabolism and resistance. Metabolomics studies of leukemia cell lines have been targeted to an identify metabolic pathways of resistance in multiple forms of leukemia (6)(7)(8). One study specifically investigating chemo-sensitivity has further explored the alterations to glutamine, glucose, fatty acid metabolism, and oxidative phosphorylation in cells resistant to commonly used chemotherapy (9).…”

A Canadian Study of Cisplatin Metabolomics and Nephrotoxicity (ACCENT): A Clinical Research Protocol

“…Variable Importance in Projection (VIP) scores will be used to rank metabolites by their discriminating importance and metabolites with VIP score >1 (standard for untargeted metabolomics studies) will be identified as candidates. [74][75][76][77] Candidate metabolites will be subjected to multivariate analysis to exclude possible confounding with other clinical/ patient characteristics. Subsequently, a nested case-control approach will be used for quantitative metabolomics analysis to measure the absolute concentration of candidate metabolites on 120 repeated samples (60 adults, 60 children) from the discovery cohort (n = 20 no AKI, n = 20 KDIGO AKI, n = 20 NCI AKI).…”

Revealing the Mysteries of Acute Myeloid Leukemia: From Quantitative PCR through Next-Generation Sequencing and Systemic Metabolomic Profiling

“…Metabolomic profiling by ultra-high performance liquid-chromatography mass spectrometry was used to study the metabolome of FLT3-ITD positive AML [77], which until now has been poorly understood. Using ultra-high performance liquid-chromatographymass spectrometry, they identified a specific metabolomic signature in plasma and in leukemic cells according to FLT3 status, including lysophospholipid metabolism, cysteine/methionine metabolism, tryptophan metabolism, purine metabolism and biosynthesis and carnitine mediated fatty acid oxidation [77][78][79][80].…”