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Clinical Cancer Research
Clinical Cancer Research

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Cancer Therapy: Preclinical

Survivin Is a Viable Target for the Treatment of Malignant Peripheral Nerve Sheath Tumors

Markus P. Ghadimi, Eric D. Young, Roman Belousov, Yiqun Zhang, Gonzalo Lopez, Kristelle Lusby, Christine Kivlin, Elizabeth G. Demicco, Chad J. Creighton, Alexander J. Lazar, Raphael E. Pollock and Dina Lev
Markus P. Ghadimi
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Eric D. Young
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Roman Belousov
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Yiqun Zhang
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Gonzalo Lopez
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Kristelle Lusby
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Christine Kivlin
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Elizabeth G. Demicco
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Chad J. Creighton
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Alexander J. Lazar
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Raphael E. Pollock
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Dina Lev
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DOI: 10.1158/1078-0432.CCR-11-2592 Published May 2012
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Abstract

Purpose: To examine the role of survivin as a therapeutic target in preclinical models of human malignant peripheral nerve sheath tumors (MPNST)

Experimental Design: Survivin protein expression levels and subcellular localization were examined immunohistochemically in an MPNST tissue microarray. Human MPNST cells were studied in vitro and in vivo; real-time PCR, Western blotting, and immunocytochemical analyses were used to evaluate survivin expression and localization activation. Cell culture assays were used to evaluate the impact of anti-survivin–specific siRNA inhibition on cell growth and cell-cycle progression and survival. The effect of the small-molecule survivin inhibitor YM155 on local and metastatic MPNST growth was examined in vivo.

Results: Survivin was found to be highly expressed in human MPNSTs; enhanced cytoplasmic subcellular localization differentiated MPNSTs from their plexiform neurofibroma premalignant counterparts. Human MPNST cell lines exhibited survivin mRNA and protein overexpression; expression in both nuclear and cytoplasmic compartments was noted. Survivin knockdown abrogated MPNST cell growth, inducing G2 cell-cycle arrest and marked apoptosis. YM155 inhibited human MPNST xenograft growth and metastasis in severe combined immunodeficient (SCID) mice. Antitumor effects were more pronounced in fast-growing xenografts.

Conclusions: Our studies show an important role for survivin in human MPNST biology. Patients with MPNSTs should be considered for ongoing or future clinical trials that evaluate anti-survivin therapeutic strategies. Most importantly, future investigations should evaluate additional pathways that can be targeted in combination with survivin for maximal synergistic anti-MPNST effects. Clin Cancer Res; 18(9); 2545–57. ©2012 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Received October 7, 2011.
  • Revision received February 7, 2012.
  • Accepted February 29, 2012.
  • ©2012 American Association for Cancer Research.
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Clinical Cancer Research: 18 (9)
May 2012
Volume 18, Issue 9
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Survivin Is a Viable Target for the Treatment of Malignant Peripheral Nerve Sheath Tumors
Markus P. Ghadimi, Eric D. Young, Roman Belousov, Yiqun Zhang, Gonzalo Lopez, Kristelle Lusby, Christine Kivlin, Elizabeth G. Demicco, Chad J. Creighton, Alexander J. Lazar, Raphael E. Pollock and Dina Lev
Clin Cancer Res May 1 2012 (18) (9) 2545-2557; DOI: 10.1158/1078-0432.CCR-11-2592

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Survivin Is a Viable Target for the Treatment of Malignant Peripheral Nerve Sheath Tumors
Markus P. Ghadimi, Eric D. Young, Roman Belousov, Yiqun Zhang, Gonzalo Lopez, Kristelle Lusby, Christine Kivlin, Elizabeth G. Demicco, Chad J. Creighton, Alexander J. Lazar, Raphael E. Pollock and Dina Lev
Clin Cancer Res May 1 2012 (18) (9) 2545-2557; DOI: 10.1158/1078-0432.CCR-11-2592
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Clinical Cancer Research
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