Effects of the aurora kinase inhibitors AZD1152-HQPA and ZM447439 on growth arrest and polyploidy in acute myeloid leukemia cell lines and primary blasts

Walsby, Elisabeth Jane; Walsh, V.; Pepper, Chris; Burnett, Alan Kenneth; Mills, Ken I.

doi:10.3324/haematol.12148

Cited by 78 publications

(68 citation statements)

References 26 publications

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“…73 In a separate study, the same group found that such CTL responses were not limited to the immunodominant WT1 [126][127][128][129][130][131][132][133][134] epitope, but could also be directed against other HLA-A*0201-restricted WT1-derived epitopes (WT1 [37][38][39][40][41][42][43][44][45] , WT1 [187][188][189][190][191][192][193][194][195] and WT1 [235][236][237][238][239][240][241][242][243] ). 88 A similar observation was made regarding PRAME, which is known to contain at least four different HLA-A*0201-restricted epitopes that can be naturally recognized (PRA [100][101][102][103][104][105][106][107][108] , PRA 142-151 , PRA 300-309 and PRA [425][426][427][428][429]...…”

Section: Criterion 4: Immunogenicity Humoral and Cellular Immune Respmentioning

confidence: 54%

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

2012

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The graft-versus-leukemia effect of allogeneic hematopoietic stem cell transplantation (HSCT) has shown that the immune system is capable of eradicating acute myeloid leukemia (AML). This knowledge, along with the identification of the target antigens against which antileukemia immune responses are directed, has provided a strong impetus for the development of antigen-targeted immunotherapy of AML. The success of any antigen-specific immunotherapeutic strategy depends critically on the choice of target antigen. Ideal molecules for immune targeting in AML are those that are: (1) leukemia-specific; (2) expressed in most leukemic blasts including leukemic stem cells; (3) important for the leukemic phenotype; (4) immunogenic; and (5) clinically effective. In this review, we provide a comprehensive overview on AML-related tumor antigens and assess their applicability for immunotherapy against the five criteria outlined above. In this way, we aim to facilitate the selection of appropriate target antigens, a task that has become increasingly challenging given the large number of antigens identified and the rapid pace at which new targets are being discovered. The information provided in this review is intended to guide the rational design of future antigen-specific immunotherapy trials, which will hopefully lead to new antileukemia therapies with more selectivity and higher efficacy.

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Section: Criterion 4: Immunogenicity Humoral and Cellular Immune Respmentioning

confidence: 54%

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

2012

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“…AZD1152 has been shown to significantly inhibit the growth of human colon, lung, and hematologic tumor xenografts in immunodeficient mice and as such has been selected for clinical evaluation (18,19). It has also shown tumoricidal activity against a panel of tumor cell lines including those of acute myeloid leukemia (AML) origin (20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

The FLT3 Internal Tandem Duplication Mutation Is a Secondary Target of the Aurora B Kinase Inhibitor AZD1152-HQPA in Acute Myelogenous Leukemia Cells

Grundy

Seedhouse

Shang

et al. 2010

Molecular Cancer Therapeutics

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Aurora kinases play an essential role in orchestrating chromosome alignment, segregation, and cytokinesis during mitotic progression and both aurora-A and B are frequently overexpressed in a variety of human malignancies. In this study, we report the effects of AZD1152-HQPA, a highly selective inhibitor of aurora-B kinase, in acute myeloid leukemia (AML) cell lines and primary samples. We show that AZD1152-HQPA inhibits the phosphorylation of Histone H3 (pHH3) on serine 10 resulting in polyploid cells, apoptosis, and loss of viability in a panel of AML cell lines. We also show that AZD1152-HQPA sensitivity in our cell lines is irrespective of p53 status and the FLT3-ITD-expressing MOLM-13 and MV4-11 cell lines are particularly sensitive to AZD1152-HQPA. Internal tandem duplications (ITD) within the FLT3 tyrosine kinase receptor are found in ∼25% of AML patients and are associated with a poor prognosis. Here, we report that AZD1152-HQPA directly targets phosphorylated FLT3 along with inhibiting its downstream target phospho-signal transducer and activator of transcription 5 (STAT5) in the FLT3-ITD cell lines. We show pHH3 expression in primary AML blasts and its inhibition by AZD1152-HQPA at low doses in all of our primary samples tested. AZD1152-HQPA inhibits the clonogenic potential of primary AML samples, with FLT3-ITD samples being the most sensitive (P = 0.029). FLT3-ITD primary samples are also more sensitive to pHH3 inhibition (P = 0.022) and are particularly sensitive to pSTAT5 downregulation after treatment with AZD1152-HQPA compared with FLT3 wild-type samples (P = 0.007). We conclude that mutant FLT3 is a secondary target of AZD1152-HQPA and that FLT3-ITD primary samples are particularly sensitive to the drug. Mol Cancer Ther; 9(3); 661-72. ©2010 AACR.

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“…9,10 Barasertib (AZD1152) is a selective inhibitor of Aurora B kinase that can inhibit the growth of tumor cells, including those of AML origin. [11][12][13][14][15] Furthermore, barasertib has been shown to significantly inhibit the growth of human colon, lung, and hematologic tumor xenografts. 12,16 Barasertib was generally well tolerated in a phase 1 study in patients with advanced solid tumors, with neutropenia being the most frequently reported adverse event (AE).…”

Section: Introductionmentioning

confidence: 99%

Phase 1/2 study to assess the safety, efficacy, and pharmacokinetics of barasertib (AZD1152) in patients with advanced acute myeloid leukemia

Löwenberg

Muus

Ossenkoppele

et al. 2011

Blood

112

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The primary objective of this 2-part phase 1/2 study was to determine the maximumtolerated dose (MTD) of the potent and selective Aurora B kinase inhibitor barasertib (AZD1152) in patients with newly diagnosed or relapsed acute myeloid leukemia (AML). Part A determined the MTD of barasertib administered as a continuous 7-day infusion every 21 days. In part B, the efficacy of barasertib was evaluated at the MTD. In part A, 32 patients were treated with barasertib 50 mg (n ‫؍‬ 3), 100 mg (n ‫؍‬ 3), 200 mg (n ‫؍‬ 3), 400 mg (n ‫؍‬ 4), 800 mg (n ‫؍‬ 7), 1200 mg (n ‫؍‬ 6), and 1600 mg (n ‫؍‬ 6). Dose-limiting toxicities (stomatitis/mucosal inflammation events) were reported in the 800 mg (n ‫؍‬ 1), 1200 mg (n ‫؍‬ 1), and 1600 mg (n ‫؍‬ 2) groups. The MTD was defined as 1200 mg. In part B, 32 patients received barasertib 1200 mg. In each part of the study, 8 of 32 patients had a hematologic response according to Cheson AML criteria. The most commonly reported grade > 3 events were febrile neutropenia (n ‫؍‬ 24) and stomatitis/mucosal inflammation (n ‫؍‬ 16). We concluded that the MTD of barasertib is 1200 mg in patients with relapsed or newly diagnosed AML. Toxicity was manageable and barasertib treatment resulted in an overall hematologic response rate of 25%. This study is registered at www.ClinicalTrials.gov as NCT00497991. (Blood. 2011;118(23): 6030-6036)

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Effects of the aurora kinase inhibitors AZD1152-HQPA and ZM447439 on growth arrest and polyploidy in acute myeloid leukemia cell lines and primary blasts

Cited by 78 publications

References 26 publications

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

The FLT3 Internal Tandem Duplication Mutation Is a Secondary Target of the Aurora B Kinase Inhibitor AZD1152-HQPA in Acute Myelogenous Leukemia Cells

Phase 1/2 study to assess the safety, efficacy, and pharmacokinetics of barasertib (AZD1152) in patients with advanced acute myeloid leukemia

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