Evaluation of activity and combination strategies with the microtubule-targeting drug sagopilone in breast cancer cell lines

Julia Eschenbrenner, Sebastian Winsel, Stefanie Hammer, Anette Sommer, Kevin Mittelstaedt, Michael Drosch, Ulrich Klar, Christoph Sachse, Michael Hannus, Monika Seidel, Bertram Weiss, Claudia Merz, Gerhard Siemeister, Jens Hoffmann

Research output: Contribution to journalArticleScientificpeer-review

6 Citations (Scopus)

Abstract

Sagopilone, a fully synthetic epothilone, is a microtubule-stabilizing agent optimized for high in vitro and in vivo activity against a broad range of tumor models, including those resistant to paclitaxel and other systemic treatments. Sagopilone development is accompanied by translational research studies to evaluate the molecular mode of action, to recognize mechanisms leading to resistance, to identify predictive response biomarkers, and to establish a rationale for combination with different therapies. Here, we profiled sagopilone activity in breast cancer cell lines. To analyze the mechanisms of mitotic arrest and apoptosis and to identify additional targets and biomarkers, an siRNA-based RNAi drug modifier screen interrogating 300 genes was performed in four cancer cell lines. Defects of the spindle assembly checkpoint (SAC) were identified to cause resistance against sagopilone-induced mitotic arrest and apoptosis. Potential biomarkers for resistance could therefore be functional defects like polymorphisms or mutations in the SAC, particularly in the central SAC kinase BUB1B. Moreover, chromosomal heterogeneity and polyploidy are also potential biomarkers of sagopilone resistance since they imply an increased tolerance for aberrant mitosis. RNAi screening further demonstrated that the sagopilone-induced mitotic arrest can be enhanced by concomitant inhibition of mitotic kinesins, thus suggesting a potential combination therapy of sagopilone with a KIF2C (MCAK) kinesin inhibitor. However, the combination of sagopilone and inhibition of the prophase kinesin KIF11 (EG5) is antagonistic, indicating that the kinesin inhibitor has to be highly specific to bring about the required therapeutic benefit.
Original languageEnglish
JournalFrontiers in Oncology
DOIs
Publication statusPublished - 2012
MoE publication typeA1 Journal article-refereed

Fingerprint

Drug Delivery Systems
Microtubules
Breast Neoplasms
Cell Line
Kinesin
M Phase Cell Cycle Checkpoints
Biomarkers
RNA Interference
Epothilones
Apoptosis
Prophase
Polyploidy
Translational Medical Research
sagopilone
Excipients
Therapeutics
Paclitaxel
Mitosis
Small Interfering RNA
Neoplasms

Keywords

  • translational cancer research
  • breast cancer
  • microtubule-stabilizing agent
  • epothilone
  • sagopilone
  • RNAi screening
  • spindle assembly checkpoint
  • mitotic kinesins

Cite this

Eschenbrenner, Julia ; Winsel, Sebastian ; Hammer, Stefanie ; Sommer, Anette ; Mittelstaedt, Kevin ; Drosch, Michael ; Klar, Ulrich ; Sachse, Christoph ; Hannus, Michael ; Seidel, Monika ; Weiss, Bertram ; Merz, Claudia ; Siemeister, Gerhard ; Hoffmann, Jens. / Evaluation of activity and combination strategies with the microtubule-targeting drug sagopilone in breast cancer cell lines. In: Frontiers in Oncology. 2012.
@article{a5d5771b9d7d4dbc89312f88c35cb1d6,
title = "Evaluation of activity and combination strategies with the microtubule-targeting drug sagopilone in breast cancer cell lines",
abstract = "Sagopilone, a fully synthetic epothilone, is a microtubule-stabilizing agent optimized for high in vitro and in vivo activity against a broad range of tumor models, including those resistant to paclitaxel and other systemic treatments. Sagopilone development is accompanied by translational research studies to evaluate the molecular mode of action, to recognize mechanisms leading to resistance, to identify predictive response biomarkers, and to establish a rationale for combination with different therapies. Here, we profiled sagopilone activity in breast cancer cell lines. To analyze the mechanisms of mitotic arrest and apoptosis and to identify additional targets and biomarkers, an siRNA-based RNAi drug modifier screen interrogating 300 genes was performed in four cancer cell lines. Defects of the spindle assembly checkpoint (SAC) were identified to cause resistance against sagopilone-induced mitotic arrest and apoptosis. Potential biomarkers for resistance could therefore be functional defects like polymorphisms or mutations in the SAC, particularly in the central SAC kinase BUB1B. Moreover, chromosomal heterogeneity and polyploidy are also potential biomarkers of sagopilone resistance since they imply an increased tolerance for aberrant mitosis. RNAi screening further demonstrated that the sagopilone-induced mitotic arrest can be enhanced by concomitant inhibition of mitotic kinesins, thus suggesting a potential combination therapy of sagopilone with a KIF2C (MCAK) kinesin inhibitor. However, the combination of sagopilone and inhibition of the prophase kinesin KIF11 (EG5) is antagonistic, indicating that the kinesin inhibitor has to be highly specific to bring about the required therapeutic benefit.",
keywords = "translational cancer research, breast cancer, microtubule-stabilizing agent, epothilone, sagopilone, RNAi screening, spindle assembly checkpoint, mitotic kinesins",
author = "Julia Eschenbrenner and Sebastian Winsel and Stefanie Hammer and Anette Sommer and Kevin Mittelstaedt and Michael Drosch and Ulrich Klar and Christoph Sachse and Michael Hannus and Monika Seidel and Bertram Weiss and Claudia Merz and Gerhard Siemeister and Jens Hoffmann",
year = "2012",
doi = "10.3389/fonc.2011.00044",
language = "English",
journal = "Frontiers in Oncology",
issn = "2234-943X",
publisher = "Frontiers Media",

}

Eschenbrenner, J, Winsel, S, Hammer, S, Sommer, A, Mittelstaedt, K, Drosch, M, Klar, U, Sachse, C, Hannus, M, Seidel, M, Weiss, B, Merz, C, Siemeister, G & Hoffmann, J 2012, 'Evaluation of activity and combination strategies with the microtubule-targeting drug sagopilone in breast cancer cell lines', Frontiers in Oncology. https://doi.org/10.3389/fonc.2011.00044

Evaluation of activity and combination strategies with the microtubule-targeting drug sagopilone in breast cancer cell lines. / Eschenbrenner, Julia; Winsel, Sebastian; Hammer, Stefanie; Sommer, Anette; Mittelstaedt, Kevin; Drosch, Michael; Klar, Ulrich; Sachse, Christoph; Hannus, Michael; Seidel, Monika; Weiss, Bertram; Merz, Claudia; Siemeister, Gerhard; Hoffmann, Jens.

In: Frontiers in Oncology, 2012.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Evaluation of activity and combination strategies with the microtubule-targeting drug sagopilone in breast cancer cell lines

AU - Eschenbrenner, Julia

AU - Winsel, Sebastian

AU - Hammer, Stefanie

AU - Sommer, Anette

AU - Mittelstaedt, Kevin

AU - Drosch, Michael

AU - Klar, Ulrich

AU - Sachse, Christoph

AU - Hannus, Michael

AU - Seidel, Monika

AU - Weiss, Bertram

AU - Merz, Claudia

AU - Siemeister, Gerhard

AU - Hoffmann, Jens

PY - 2012

Y1 - 2012

N2 - Sagopilone, a fully synthetic epothilone, is a microtubule-stabilizing agent optimized for high in vitro and in vivo activity against a broad range of tumor models, including those resistant to paclitaxel and other systemic treatments. Sagopilone development is accompanied by translational research studies to evaluate the molecular mode of action, to recognize mechanisms leading to resistance, to identify predictive response biomarkers, and to establish a rationale for combination with different therapies. Here, we profiled sagopilone activity in breast cancer cell lines. To analyze the mechanisms of mitotic arrest and apoptosis and to identify additional targets and biomarkers, an siRNA-based RNAi drug modifier screen interrogating 300 genes was performed in four cancer cell lines. Defects of the spindle assembly checkpoint (SAC) were identified to cause resistance against sagopilone-induced mitotic arrest and apoptosis. Potential biomarkers for resistance could therefore be functional defects like polymorphisms or mutations in the SAC, particularly in the central SAC kinase BUB1B. Moreover, chromosomal heterogeneity and polyploidy are also potential biomarkers of sagopilone resistance since they imply an increased tolerance for aberrant mitosis. RNAi screening further demonstrated that the sagopilone-induced mitotic arrest can be enhanced by concomitant inhibition of mitotic kinesins, thus suggesting a potential combination therapy of sagopilone with a KIF2C (MCAK) kinesin inhibitor. However, the combination of sagopilone and inhibition of the prophase kinesin KIF11 (EG5) is antagonistic, indicating that the kinesin inhibitor has to be highly specific to bring about the required therapeutic benefit.

AB - Sagopilone, a fully synthetic epothilone, is a microtubule-stabilizing agent optimized for high in vitro and in vivo activity against a broad range of tumor models, including those resistant to paclitaxel and other systemic treatments. Sagopilone development is accompanied by translational research studies to evaluate the molecular mode of action, to recognize mechanisms leading to resistance, to identify predictive response biomarkers, and to establish a rationale for combination with different therapies. Here, we profiled sagopilone activity in breast cancer cell lines. To analyze the mechanisms of mitotic arrest and apoptosis and to identify additional targets and biomarkers, an siRNA-based RNAi drug modifier screen interrogating 300 genes was performed in four cancer cell lines. Defects of the spindle assembly checkpoint (SAC) were identified to cause resistance against sagopilone-induced mitotic arrest and apoptosis. Potential biomarkers for resistance could therefore be functional defects like polymorphisms or mutations in the SAC, particularly in the central SAC kinase BUB1B. Moreover, chromosomal heterogeneity and polyploidy are also potential biomarkers of sagopilone resistance since they imply an increased tolerance for aberrant mitosis. RNAi screening further demonstrated that the sagopilone-induced mitotic arrest can be enhanced by concomitant inhibition of mitotic kinesins, thus suggesting a potential combination therapy of sagopilone with a KIF2C (MCAK) kinesin inhibitor. However, the combination of sagopilone and inhibition of the prophase kinesin KIF11 (EG5) is antagonistic, indicating that the kinesin inhibitor has to be highly specific to bring about the required therapeutic benefit.

KW - translational cancer research

KW - breast cancer

KW - microtubule-stabilizing agent

KW - epothilone

KW - sagopilone

KW - RNAi screening

KW - spindle assembly checkpoint

KW - mitotic kinesins

U2 - 10.3389/fonc.2011.00044

DO - 10.3389/fonc.2011.00044

M3 - Article

JO - Frontiers in Oncology

JF - Frontiers in Oncology

SN - 2234-943X

ER -