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

Abstract

<div>Abstract<p><b>Purpose:</b> To examine the role of survivin as a therapeutic target in preclinical models of human malignant peripheral nerve sheath tumors (MPNST)</p><p><b>Experimental Design:</b> Survivin protein expression levels and subcellular localization were examined immunohistochemically in an MPNST tissue microarray. Human MPNST cells were studied <i>in vitro</i> and <i>in vivo</i>; 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 <i>in vivo</i>.</p><p><b>Results:</b> 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 G<sub>2</sub> 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.</p><p><b>Conclusions:</b> 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. <i>Clin Cancer Res; 18(9); 2545–57. ©2012 AACR</i>.</p></div>