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Research ArticleDrug Discovery and Translational Medicine

Efficacy and Mechanism of Action of Volasertib, a Potent and Selective Inhibitor of Polo-Like Kinases, in Preclinical Models of Acute Myeloid Leukemia

Dorothea Rudolph, Maria Antonietta Impagnatiello, Claudia Blaukopf, Christoph Sommer, Daniel W. Gerlich, Mareike Roth, Ulrike Tontsch-Grunt, Andreas Wernitznig, Fabio Savarese, Marco H. Hofmann, Christoph Albrecht, Lena Geiselmann, Markus Reschke, Pilar Garin-Chesa, Johannes Zuber, Jürgen Moll, Günther R. Adolf and Norbert Kraut
Journal of Pharmacology and Experimental Therapeutics March 2015, 352 (3) 579-589; DOI: https://doi.org/10.1124/jpet.114.221150
Dorothea Rudolph
Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (D.R., M.A.I., U.T.-G., A.W., F.S., M.H.H., C.A., L.G., M.R., P.G.-C., J.M., G.R.A., N.K.); Institute of Molecular Biotechnology, Vienna, Austria (C.B., C.S., D.W.G.); and Research Institute of Molecular Pathology, Vienna, Austria (M.R., J.Z.)
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Maria Antonietta Impagnatiello
Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (D.R., M.A.I., U.T.-G., A.W., F.S., M.H.H., C.A., L.G., M.R., P.G.-C., J.M., G.R.A., N.K.); Institute of Molecular Biotechnology, Vienna, Austria (C.B., C.S., D.W.G.); and Research Institute of Molecular Pathology, Vienna, Austria (M.R., J.Z.)
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Claudia Blaukopf
Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (D.R., M.A.I., U.T.-G., A.W., F.S., M.H.H., C.A., L.G., M.R., P.G.-C., J.M., G.R.A., N.K.); Institute of Molecular Biotechnology, Vienna, Austria (C.B., C.S., D.W.G.); and Research Institute of Molecular Pathology, Vienna, Austria (M.R., J.Z.)
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Christoph Sommer
Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (D.R., M.A.I., U.T.-G., A.W., F.S., M.H.H., C.A., L.G., M.R., P.G.-C., J.M., G.R.A., N.K.); Institute of Molecular Biotechnology, Vienna, Austria (C.B., C.S., D.W.G.); and Research Institute of Molecular Pathology, Vienna, Austria (M.R., J.Z.)
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Daniel W. Gerlich
Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (D.R., M.A.I., U.T.-G., A.W., F.S., M.H.H., C.A., L.G., M.R., P.G.-C., J.M., G.R.A., N.K.); Institute of Molecular Biotechnology, Vienna, Austria (C.B., C.S., D.W.G.); and Research Institute of Molecular Pathology, Vienna, Austria (M.R., J.Z.)
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Mareike Roth
Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (D.R., M.A.I., U.T.-G., A.W., F.S., M.H.H., C.A., L.G., M.R., P.G.-C., J.M., G.R.A., N.K.); Institute of Molecular Biotechnology, Vienna, Austria (C.B., C.S., D.W.G.); and Research Institute of Molecular Pathology, Vienna, Austria (M.R., J.Z.)
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Ulrike Tontsch-Grunt
Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (D.R., M.A.I., U.T.-G., A.W., F.S., M.H.H., C.A., L.G., M.R., P.G.-C., J.M., G.R.A., N.K.); Institute of Molecular Biotechnology, Vienna, Austria (C.B., C.S., D.W.G.); and Research Institute of Molecular Pathology, Vienna, Austria (M.R., J.Z.)
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Andreas Wernitznig
Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (D.R., M.A.I., U.T.-G., A.W., F.S., M.H.H., C.A., L.G., M.R., P.G.-C., J.M., G.R.A., N.K.); Institute of Molecular Biotechnology, Vienna, Austria (C.B., C.S., D.W.G.); and Research Institute of Molecular Pathology, Vienna, Austria (M.R., J.Z.)
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Fabio Savarese
Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (D.R., M.A.I., U.T.-G., A.W., F.S., M.H.H., C.A., L.G., M.R., P.G.-C., J.M., G.R.A., N.K.); Institute of Molecular Biotechnology, Vienna, Austria (C.B., C.S., D.W.G.); and Research Institute of Molecular Pathology, Vienna, Austria (M.R., J.Z.)
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Marco H. Hofmann
Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (D.R., M.A.I., U.T.-G., A.W., F.S., M.H.H., C.A., L.G., M.R., P.G.-C., J.M., G.R.A., N.K.); Institute of Molecular Biotechnology, Vienna, Austria (C.B., C.S., D.W.G.); and Research Institute of Molecular Pathology, Vienna, Austria (M.R., J.Z.)
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Christoph Albrecht
Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (D.R., M.A.I., U.T.-G., A.W., F.S., M.H.H., C.A., L.G., M.R., P.G.-C., J.M., G.R.A., N.K.); Institute of Molecular Biotechnology, Vienna, Austria (C.B., C.S., D.W.G.); and Research Institute of Molecular Pathology, Vienna, Austria (M.R., J.Z.)
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Lena Geiselmann
Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (D.R., M.A.I., U.T.-G., A.W., F.S., M.H.H., C.A., L.G., M.R., P.G.-C., J.M., G.R.A., N.K.); Institute of Molecular Biotechnology, Vienna, Austria (C.B., C.S., D.W.G.); and Research Institute of Molecular Pathology, Vienna, Austria (M.R., J.Z.)
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Markus Reschke
Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (D.R., M.A.I., U.T.-G., A.W., F.S., M.H.H., C.A., L.G., M.R., P.G.-C., J.M., G.R.A., N.K.); Institute of Molecular Biotechnology, Vienna, Austria (C.B., C.S., D.W.G.); and Research Institute of Molecular Pathology, Vienna, Austria (M.R., J.Z.)
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Pilar Garin-Chesa
Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (D.R., M.A.I., U.T.-G., A.W., F.S., M.H.H., C.A., L.G., M.R., P.G.-C., J.M., G.R.A., N.K.); Institute of Molecular Biotechnology, Vienna, Austria (C.B., C.S., D.W.G.); and Research Institute of Molecular Pathology, Vienna, Austria (M.R., J.Z.)
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Johannes Zuber
Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (D.R., M.A.I., U.T.-G., A.W., F.S., M.H.H., C.A., L.G., M.R., P.G.-C., J.M., G.R.A., N.K.); Institute of Molecular Biotechnology, Vienna, Austria (C.B., C.S., D.W.G.); and Research Institute of Molecular Pathology, Vienna, Austria (M.R., J.Z.)
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Jürgen Moll
Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (D.R., M.A.I., U.T.-G., A.W., F.S., M.H.H., C.A., L.G., M.R., P.G.-C., J.M., G.R.A., N.K.); Institute of Molecular Biotechnology, Vienna, Austria (C.B., C.S., D.W.G.); and Research Institute of Molecular Pathology, Vienna, Austria (M.R., J.Z.)
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Günther R. Adolf
Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (D.R., M.A.I., U.T.-G., A.W., F.S., M.H.H., C.A., L.G., M.R., P.G.-C., J.M., G.R.A., N.K.); Institute of Molecular Biotechnology, Vienna, Austria (C.B., C.S., D.W.G.); and Research Institute of Molecular Pathology, Vienna, Austria (M.R., J.Z.)
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Norbert Kraut
Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (D.R., M.A.I., U.T.-G., A.W., F.S., M.H.H., C.A., L.G., M.R., P.G.-C., J.M., G.R.A., N.K.); Institute of Molecular Biotechnology, Vienna, Austria (C.B., C.S., D.W.G.); and Research Institute of Molecular Pathology, Vienna, Austria (M.R., J.Z.)
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Abstract

Polo-like kinase 1 (Plk1), a member of the Polo-like kinase family of serine/threonine kinases, is a key regulator of multiple steps in mitosis. Here we report on the pharmacological profile of volasertib, a potent and selective Plk inhibitor, in multiple preclinical models of acute myeloid leukemia (AML) including established cell lines, bone marrow samples from AML patients in short-term culture, and subcutaneous as well as disseminated in vivo models in immune-deficient mice. Our results indicate that volasertib is highly efficacious as a single agent and in combination with established and emerging AML drugs, including the antimetabolite cytarabine, hypomethylating agents (decitabine, azacitidine), and quizartinib, a signal transduction inhibitor targeting FLT3. Collectively, these preclinical data support the use of volasertib as a new therapeutic approach for the treatment of AML patients, and provide a foundation for combination approaches that may further improve and prolong clinical responses.

Footnotes

    • Received October 29, 2014.
    • Accepted January 5, 2015.
  • D.R., A.W., C.A., L.G., U.T.-G., M.A.I., P.G.-C., J.M., F.S., M.R., G.R.A., and N.K. are employees of Boehringer Ingelheim. D.W.G., C.B., and C.S. are employees of the Institute of Molecular Biotechnology, Austrian Academy of Sciences, and received funding for their research from Boehringer Ingelheim.

  • dx.doi.org/10.1124/jpet.114.221150.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 352 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 352, Issue 3
1 Mar 2015
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Research ArticleDrug Discovery and Translational Medicine

Efficacy of Volasertib in Preclinical Models of AML

Dorothea Rudolph, Maria Antonietta Impagnatiello, Claudia Blaukopf, Christoph Sommer, Daniel W. Gerlich, Mareike Roth, Ulrike Tontsch-Grunt, Andreas Wernitznig, Fabio Savarese, Marco H. Hofmann, Christoph Albrecht, Lena Geiselmann, Markus Reschke, Pilar Garin-Chesa, Johannes Zuber, Jürgen Moll, Günther R. Adolf and Norbert Kraut
Journal of Pharmacology and Experimental Therapeutics March 1, 2015, 352 (3) 579-589; DOI: https://doi.org/10.1124/jpet.114.221150

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Research ArticleDrug Discovery and Translational Medicine

Efficacy of Volasertib in Preclinical Models of AML

Dorothea Rudolph, Maria Antonietta Impagnatiello, Claudia Blaukopf, Christoph Sommer, Daniel W. Gerlich, Mareike Roth, Ulrike Tontsch-Grunt, Andreas Wernitznig, Fabio Savarese, Marco H. Hofmann, Christoph Albrecht, Lena Geiselmann, Markus Reschke, Pilar Garin-Chesa, Johannes Zuber, Jürgen Moll, Günther R. Adolf and Norbert Kraut
Journal of Pharmacology and Experimental Therapeutics March 1, 2015, 352 (3) 579-589; DOI: https://doi.org/10.1124/jpet.114.221150
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