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Inhibition of PLK1 by capped-dose volasertib exerts substantial efficacy in MDS and sAML while sparing healthy haematopoiesis

Standard

Inhibition of PLK1 by capped-dose volasertib exerts substantial efficacy in MDS and sAML while sparing healthy haematopoiesis. / Dill, Veronika; Kauschinger, Johanna; Hauch, Richard T; Buschhorn, Lars; Odinius, Timo O; Müller-Thomas, Catharina; Mishra, Ritu; Kyncl, Michele C; Schmidt, Burkhard; Prodinger, Peter M; Hempel, Dirk; Bellos, Frauke; Höllein, Alexander; Kern, Wolfgang; Haferlach, Torsten; Slotta-Huspenina, Julia; Bassermann, Florian; Peschel, Christian; Götze, Katharina S; Waizenegger, Irene C; Höckendorf, Ulrike; Jost, Philipp J; Jilg, Stefanie.

in: EUR J HAEMATOL, Jahrgang 104, Nr. 2, 22.11.2019, S. 125-137.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Dill, V, Kauschinger, J, Hauch, RT, Buschhorn, L, Odinius, TO, Müller-Thomas, C, Mishra, R, Kyncl, MC, Schmidt, B, Prodinger, PM, Hempel, D, Bellos, F, Höllein, A, Kern, W, Haferlach, T, Slotta-Huspenina, J, Bassermann, F, Peschel, C, Götze, KS, Waizenegger, IC, Höckendorf, U, Jost, PJ & Jilg, S 2019, 'Inhibition of PLK1 by capped-dose volasertib exerts substantial efficacy in MDS and sAML while sparing healthy haematopoiesis', EUR J HAEMATOL, Jg. 104, Nr. 2, S. 125-137. https://doi.org/10.1111/ejh.13354

APA

Dill, V., Kauschinger, J., Hauch, R. T., Buschhorn, L., Odinius, T. O., Müller-Thomas, C., Mishra, R., Kyncl, M. C., Schmidt, B., Prodinger, P. M., Hempel, D., Bellos, F., Höllein, A., Kern, W., Haferlach, T., Slotta-Huspenina, J., Bassermann, F., Peschel, C., Götze, K. S., ... Jilg, S. (2019). Inhibition of PLK1 by capped-dose volasertib exerts substantial efficacy in MDS and sAML while sparing healthy haematopoiesis. EUR J HAEMATOL, 104(2), 125-137. https://doi.org/10.1111/ejh.13354

Vancouver

Dill V, Kauschinger J, Hauch RT, Buschhorn L, Odinius TO, Müller-Thomas C et al. Inhibition of PLK1 by capped-dose volasertib exerts substantial efficacy in MDS and sAML while sparing healthy haematopoiesis. EUR J HAEMATOL. 2019 Nov 22;104(2):125-137. https://doi.org/10.1111/ejh.13354

Bibtex

@article{59a6f1907806459e831864dc843c06ec,
title = "Inhibition of PLK1 by capped-dose volasertib exerts substantial efficacy in MDS and sAML while sparing healthy haematopoiesis",
abstract = "INTRODUCTION: Targeting the cell cycle machinery represents a rational therapeutic approach in myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (sAML). Despite substantial response rates, clinical use of the PLK inhibitor volasertib has been hampered by elevated side effects such as neutropenia and infections.OBJECTIVES: The primary objective was to analyse whether a reduced dose of volasertib was able to limit toxic effects on the healthy haematopoiesis while retaining its therapeutic effect.METHODS: Bone marrow mononuclear cells (BMMNCs) of patients with MDS/sAML (n = 73) and healthy controls (n = 28) were treated with volasertib (1 μM to 1 nM) or vehicle control. Short-term viability analysis was performed by flow cytometry after 72 hours. For long-term viability analysis, colony-forming capacity was assessed after 14 days. Protein expression of RIPK3 and MCL-1 was quantified via flow cytometry.RESULTS: Reduced dose levels of volasertib retained high cell death-inducing efficacy in primary human stem and progenitor cells of MDS/sAML patients without affecting healthy haematopoiesis in vitro. Interestingly, volasertib reduced colony-forming capacity and cell survival independent of clinical stage or mutational status.CONCLUSIONS: Volasertib offers a promising therapeutic approach in patients with adverse prognostic profile. RIPK3 and MCL-1 might be potential biomarkers for sensitivity to volasertib treatment.",
keywords = "Adult, Aged, Aged, 80 and over, Bone Marrow Cells/metabolism, Cell Cycle Proteins/antagonists & inhibitors, Female, Gene Expression Regulation, Leukemic/drug effects, Hematopoiesis/drug effects, Humans, Leukemia, Myeloid, Acute/drug therapy, Male, Myelodysplastic Syndromes/drug therapy, Myeloid Cell Leukemia Sequence 1 Protein/biosynthesis, Protein-Serine-Threonine Kinases/antagonists & inhibitors, Proto-Oncogene Proteins/antagonists & inhibitors, Pteridines/administration & dosage, Receptor-Interacting Protein Serine-Threonine Kinases/biosynthesis",
author = "Veronika Dill and Johanna Kauschinger and Hauch, {Richard T} and Lars Buschhorn and Odinius, {Timo O} and Catharina M{\"u}ller-Thomas and Ritu Mishra and Kyncl, {Michele C} and Burkhard Schmidt and Prodinger, {Peter M} and Dirk Hempel and Frauke Bellos and Alexander H{\"o}llein and Wolfgang Kern and Torsten Haferlach and Julia Slotta-Huspenina and Florian Bassermann and Christian Peschel and G{\"o}tze, {Katharina S} and Waizenegger, {Irene C} and Ulrike H{\"o}ckendorf and Jost, {Philipp J} and Stefanie Jilg",
note = "{\textcopyright} 2019 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.",
year = "2019",
month = nov,
day = "22",
doi = "10.1111/ejh.13354",
language = "English",
volume = "104",
pages = "125--137",
journal = "EUR J HAEMATOL",
issn = "0902-4441",
publisher = "Wiley-Blackwell",
number = "2",

}

RIS

TY - JOUR

T1 - Inhibition of PLK1 by capped-dose volasertib exerts substantial efficacy in MDS and sAML while sparing healthy haematopoiesis

AU - Dill, Veronika

AU - Kauschinger, Johanna

AU - Hauch, Richard T

AU - Buschhorn, Lars

AU - Odinius, Timo O

AU - Müller-Thomas, Catharina

AU - Mishra, Ritu

AU - Kyncl, Michele C

AU - Schmidt, Burkhard

AU - Prodinger, Peter M

AU - Hempel, Dirk

AU - Bellos, Frauke

AU - Höllein, Alexander

AU - Kern, Wolfgang

AU - Haferlach, Torsten

AU - Slotta-Huspenina, Julia

AU - Bassermann, Florian

AU - Peschel, Christian

AU - Götze, Katharina S

AU - Waizenegger, Irene C

AU - Höckendorf, Ulrike

AU - Jost, Philipp J

AU - Jilg, Stefanie

N1 - © 2019 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.

PY - 2019/11/22

Y1 - 2019/11/22

N2 - INTRODUCTION: Targeting the cell cycle machinery represents a rational therapeutic approach in myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (sAML). Despite substantial response rates, clinical use of the PLK inhibitor volasertib has been hampered by elevated side effects such as neutropenia and infections.OBJECTIVES: The primary objective was to analyse whether a reduced dose of volasertib was able to limit toxic effects on the healthy haematopoiesis while retaining its therapeutic effect.METHODS: Bone marrow mononuclear cells (BMMNCs) of patients with MDS/sAML (n = 73) and healthy controls (n = 28) were treated with volasertib (1 μM to 1 nM) or vehicle control. Short-term viability analysis was performed by flow cytometry after 72 hours. For long-term viability analysis, colony-forming capacity was assessed after 14 days. Protein expression of RIPK3 and MCL-1 was quantified via flow cytometry.RESULTS: Reduced dose levels of volasertib retained high cell death-inducing efficacy in primary human stem and progenitor cells of MDS/sAML patients without affecting healthy haematopoiesis in vitro. Interestingly, volasertib reduced colony-forming capacity and cell survival independent of clinical stage or mutational status.CONCLUSIONS: Volasertib offers a promising therapeutic approach in patients with adverse prognostic profile. RIPK3 and MCL-1 might be potential biomarkers for sensitivity to volasertib treatment.

AB - INTRODUCTION: Targeting the cell cycle machinery represents a rational therapeutic approach in myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (sAML). Despite substantial response rates, clinical use of the PLK inhibitor volasertib has been hampered by elevated side effects such as neutropenia and infections.OBJECTIVES: The primary objective was to analyse whether a reduced dose of volasertib was able to limit toxic effects on the healthy haematopoiesis while retaining its therapeutic effect.METHODS: Bone marrow mononuclear cells (BMMNCs) of patients with MDS/sAML (n = 73) and healthy controls (n = 28) were treated with volasertib (1 μM to 1 nM) or vehicle control. Short-term viability analysis was performed by flow cytometry after 72 hours. For long-term viability analysis, colony-forming capacity was assessed after 14 days. Protein expression of RIPK3 and MCL-1 was quantified via flow cytometry.RESULTS: Reduced dose levels of volasertib retained high cell death-inducing efficacy in primary human stem and progenitor cells of MDS/sAML patients without affecting healthy haematopoiesis in vitro. Interestingly, volasertib reduced colony-forming capacity and cell survival independent of clinical stage or mutational status.CONCLUSIONS: Volasertib offers a promising therapeutic approach in patients with adverse prognostic profile. RIPK3 and MCL-1 might be potential biomarkers for sensitivity to volasertib treatment.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Bone Marrow Cells/metabolism

KW - Cell Cycle Proteins/antagonists & inhibitors

KW - Female

KW - Gene Expression Regulation, Leukemic/drug effects

KW - Hematopoiesis/drug effects

KW - Humans

KW - Leukemia, Myeloid, Acute/drug therapy

KW - Male

KW - Myelodysplastic Syndromes/drug therapy

KW - Myeloid Cell Leukemia Sequence 1 Protein/biosynthesis

KW - Protein-Serine-Threonine Kinases/antagonists & inhibitors

KW - Proto-Oncogene Proteins/antagonists & inhibitors

KW - Pteridines/administration & dosage

KW - Receptor-Interacting Protein Serine-Threonine Kinases/biosynthesis

U2 - 10.1111/ejh.13354

DO - 10.1111/ejh.13354

M3 - SCORING: Journal article

C2 - 31758597

VL - 104

SP - 125

EP - 137

JO - EUR J HAEMATOL

JF - EUR J HAEMATOL

SN - 0902-4441

IS - 2

ER -