Activity of the kinesin spindle protein inhibitor ispinesib (SB-715992) in models of breast cancer

James W. Purcell, Jefferson Davis, Mamatha Reddy, Shamra Martin, Kimberly Samayoa, Hung Vo, Karen Thomsen, Peter Bean, Wen Lin Kuo, Safiyyah Ziyad, Jessica Billig, Heidi Feiler, Joe Gray, Kenneth W. Wood, Sylvaine Cases

Research output: Contribution to journalArticle

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Abstract

Purpose: Ispinesib (SB-715992) is a potent inhibitor of kinesin spindle protein, a kinesin motor protein essential for the formation of a bipolar mitotic spindle and cell cycle progression through mitosis. Clinical studies of ispinesib have shown a 9% response rate in patients with locally advanced or meta-static breast cancer and a favorable safety profile without significant neurotoxicities, gastrointestinal toxicities, or hair loss. To better understand the potential of ispinesib in the treatment of breast cancer, we explored the activity of ispinesib alone and in combination with several therapies approved for the treatment of breast cancer. Experimental Design: We measured the ispinesib sensitivity and pharmacodynamic response of breast cancer cell lines representative of various subtypes in vitro and as xenografts in vivo and tested the ability of ispinesib to enhance the antitumor activity of approved therapies. Results: In vitro, ispinesib displayed broad antiproliferative activity against a panel of 53 breast cell lines. In vivo, ispinesib produced regressions in each of five breast cancer models and tumor-free survivors in three of these models. The effects of ispinesib treatment on pharmacodynamic markers of mitosis and apoptosis were examined in vitro and in vivo, revealing a greater increase in both mitotic and apoptotic markers in the MDA-MB-468 model than in the less sensitive BT-474 model. In vivo, ispinesib enhanced the antitumor activity of trastuzumab, lapatinib, doxorubicin, and capecitabine and exhibited activity comparable with paclitaxel and ixabepilone. Conclusions: These findings support further clinical exploration of kinesin spindle protein inhibitors for the treatment of breast cancer.

Original languageEnglish (US)
Pages (from-to)566-576
Number of pages11
JournalClinical Cancer Research
Volume16
Issue number2
DOIs
StatePublished - Jan 15 2010
Externally publishedYes

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Kinesin
Breast Neoplasms
Proteins
Mitosis
ispinesib
Therapeutics
Cell Line
Spindle Apparatus
Alopecia
Paclitaxel
Heterografts
Doxorubicin
Survivors
Cell Cycle
Breast
Research Design

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Purcell, J. W., Davis, J., Reddy, M., Martin, S., Samayoa, K., Vo, H., ... Cases, S. (2010). Activity of the kinesin spindle protein inhibitor ispinesib (SB-715992) in models of breast cancer. Clinical Cancer Research, 16(2), 566-576. https://doi.org/10.1158/1078-0432.CCR-09-1498

Activity of the kinesin spindle protein inhibitor ispinesib (SB-715992) in models of breast cancer. / Purcell, James W.; Davis, Jefferson; Reddy, Mamatha; Martin, Shamra; Samayoa, Kimberly; Vo, Hung; Thomsen, Karen; Bean, Peter; Kuo, Wen Lin; Ziyad, Safiyyah; Billig, Jessica; Feiler, Heidi; Gray, Joe; Wood, Kenneth W.; Cases, Sylvaine.

In: Clinical Cancer Research, Vol. 16, No. 2, 15.01.2010, p. 566-576.

Research output: Contribution to journalArticle

Purcell, JW, Davis, J, Reddy, M, Martin, S, Samayoa, K, Vo, H, Thomsen, K, Bean, P, Kuo, WL, Ziyad, S, Billig, J, Feiler, H, Gray, J, Wood, KW & Cases, S 2010, 'Activity of the kinesin spindle protein inhibitor ispinesib (SB-715992) in models of breast cancer', Clinical Cancer Research, vol. 16, no. 2, pp. 566-576. https://doi.org/10.1158/1078-0432.CCR-09-1498
Purcell, James W. ; Davis, Jefferson ; Reddy, Mamatha ; Martin, Shamra ; Samayoa, Kimberly ; Vo, Hung ; Thomsen, Karen ; Bean, Peter ; Kuo, Wen Lin ; Ziyad, Safiyyah ; Billig, Jessica ; Feiler, Heidi ; Gray, Joe ; Wood, Kenneth W. ; Cases, Sylvaine. / Activity of the kinesin spindle protein inhibitor ispinesib (SB-715992) in models of breast cancer. In: Clinical Cancer Research. 2010 ; Vol. 16, No. 2. pp. 566-576.
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AU - Davis, Jefferson

AU - Reddy, Mamatha

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AU - Samayoa, Kimberly

AU - Vo, Hung

AU - Thomsen, Karen

AU - Bean, Peter

AU - Kuo, Wen Lin

AU - Ziyad, Safiyyah

AU - Billig, Jessica

AU - Feiler, Heidi

AU - Gray, Joe

AU - Wood, Kenneth W.

AU - Cases, Sylvaine

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N2 - Purpose: Ispinesib (SB-715992) is a potent inhibitor of kinesin spindle protein, a kinesin motor protein essential for the formation of a bipolar mitotic spindle and cell cycle progression through mitosis. Clinical studies of ispinesib have shown a 9% response rate in patients with locally advanced or meta-static breast cancer and a favorable safety profile without significant neurotoxicities, gastrointestinal toxicities, or hair loss. To better understand the potential of ispinesib in the treatment of breast cancer, we explored the activity of ispinesib alone and in combination with several therapies approved for the treatment of breast cancer. Experimental Design: We measured the ispinesib sensitivity and pharmacodynamic response of breast cancer cell lines representative of various subtypes in vitro and as xenografts in vivo and tested the ability of ispinesib to enhance the antitumor activity of approved therapies. Results: In vitro, ispinesib displayed broad antiproliferative activity against a panel of 53 breast cell lines. In vivo, ispinesib produced regressions in each of five breast cancer models and tumor-free survivors in three of these models. The effects of ispinesib treatment on pharmacodynamic markers of mitosis and apoptosis were examined in vitro and in vivo, revealing a greater increase in both mitotic and apoptotic markers in the MDA-MB-468 model than in the less sensitive BT-474 model. In vivo, ispinesib enhanced the antitumor activity of trastuzumab, lapatinib, doxorubicin, and capecitabine and exhibited activity comparable with paclitaxel and ixabepilone. Conclusions: These findings support further clinical exploration of kinesin spindle protein inhibitors for the treatment of breast cancer.

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