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Effect of STAT3 inhibitor in chronic myeloid leukemia associated signaling pathway: a mathematical modeling, simulation and systems biology study.

ABSTRACT: Chronic myeloid leukemia (CML) is a hematopoietic stem-cell disorder which proliferates due to abnormal growth of basophil cells. Several proangiogenic molecules have been reported to be associated in CML progression, including the hepatocyte growth factor (HGF). However, detail mechanism about the cellular distribution and function of HGF in CML is yet to be revealed. The proliferation of hematopoietic cells are regulated by some of the growth factors like interleukin 3 (IL-3), IL-6, erythropoietin, thrombopoietin, etc. In this study IL-6 pathways have been taken into consideration which induces JAK/STAT and MAPK pathways to decipher the CML progression stages. An attempt has been made to model these pathways with the help of ordinary differential equations (ODEs) and estimating unknown parameters through fminsearch optimization algorithm. Some of the specific component like STAT3, of the pathway has been analyzed in detail and their role in CML progression has been elucidated. The roles of STAT3 inhibitors into the treatment of CML have been thoroughly studied and optimum concentration of the inhibitors have been predicted.

SUBMITTER: Kumar H

PROVIDER: S-EPMC4729759 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Effect of STAT3 inhibitor in chronic myeloid leukemia associated signaling pathway: a mathematical modeling, simulation and systems biology study.

Kumar Himansu H Tichkule Swapnil S Raj Utkarsh U Gupta Saurabh S Srivastava Swati S Varadwaj Pritish Kumar PK

3 Biotech 20160127 1

Chronic myeloid leukemia (CML) is a hematopoietic stem-cell disorder which proliferates due to abnormal growth of basophil cells. Several proangiogenic molecules have been reported to be associated in CML progression, including the hepatocyte growth factor (HGF). However, detail mechanism about the cellular distribution and function of HGF in CML is yet to be revealed. The proliferation of hematopoietic cells are regulated by some of the growth factors like interleukin 3 (IL-3), IL-6, erythropoi ...[more]

PMID: 28330111

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Project description:BackgroundAsciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant. The safety and antileukemic activity of asciminib in patients with Philadelphia chromosome-positive leukemia are unknown.MethodsIn this phase 1, dose-escalation study, we enrolled 141 patients with chronic-phase and 9 with accelerated-phase chronic myeloid leukemia (CML) who had resistance to or unacceptable side effects from at least two previous ATP-competitive tyrosine kinase inhibitors (TKIs). The primary objective was to determine the maximum tolerated dose or the recommended dose (or both) of asciminib. Asciminib was administered once or twice daily (at doses of 10 to 200 mg). The median follow-up was 14 months.ResultsPatients were heavily pretreated; 70% (105 of 150 patients) had received at least three TKIs. The maximum tolerated dose of asciminib was not reached. Among patients with chronic-phase CML, 34 (92%) with a hematologic relapse had a complete hematologic response; 31 (54%) without a complete cytogenetic response at baseline had a complete cytogenetic response. A major molecular response was achieved or maintained by 12 months in 48% of patients who could be evaluated, including 8 of 14 (57%) deemed to have resistance to or unacceptable side effects from ponatinib. A major molecular response was achieved or maintained by 12 months in 5 patients (28%) with a T315I mutation at baseline. Clinical responses were durable; a major molecular response was maintained in 40 of 44 patients. Dose-limiting toxic effects included asymptomatic elevations in the lipase level and clinical pancreatitis. Common adverse events included fatigue, headache, arthralgia, hypertension, and thrombocytopenia.ConclusionsAsciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ponatinib had failed and those with a T315I mutation. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02081378.).

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Effect of STAT3 inhibitor in chronic myeloid leukemia associated signaling pathway: a mathematical modeling, simulation and systems biology study.

Publications

Effect of STAT3 inhibitor in chronic myeloid leukemia associated signaling pathway: a mathematical modeling, simulation and systems biology study.

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