TY - JOUR
T1 - Inhibition of survivin with YM155 induces durable tumor response in anaplastic thyroid cancer
AU - Mehta, Amit
AU - Zhang, Lisa
AU - Boufraqech, Myriem
AU - Liu-Chittenden, Yi
AU - Zhang, Yaqin
AU - Patel, Dhaval
AU - Davis, Sean
AU - Rosenberg, Avi
AU - Ylaya, Kris
AU - Aufforth, Rachel
AU - Li, Zhuyin
AU - Shen, Min
AU - Kebebew, Electron
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/9/15
Y1 - 2015/9/15
N2 - Purpose: Anaplastic thyroid cancer (ATC) is a rare but lethal malignancy without any effective therapy. The aim of this study is to use a high-throughput drug library screening to identify a novel therapeutic agent that targets dysregulated genes/pathways in ATC. Experimental Design: We performed quantitative highthroughput screening (qHTS) in ATC cell lines using a compound library of 3,282 drugs. Dysregulated genes in ATC were analyzed using genome-wide expression analysis and immunohistochemistry in human ATC tissue samples and ATC cell lines. In vitro and in vivo studies were performed for determining drug activity, effectiveness of targeting, and the mechanism of action. Results: qHTS identified 100 active compounds in three ATC cell lines. One of the most active agents was the first-in-class survivin inhibitor YM155. Genome-wide expression analysis and immunohistochemistry showed overexpression of survivin in human ATC tissue samples, and survivin was highly expressed in all ATC cell lines tested. YM155 significantly inhibited ATC cellular proliferation. Mechanistically, YM155 inhibited survivin expression in ATC cells. Furthermore, YM155 treatment reduced claspin expression, which was associated with S-phase arrest in ATC cells. In vivo, YM155 significantly inhibited growth and metastases and prolonged survival. Conclusions: Our data show that YM155 is a promising anticancer agent for ATC and that its target, survivin, is overexpressed in ATC. Our findings support the use of YM155 in clinical trials as a therapeutic option in advanced and metastatic ATC.
AB - Purpose: Anaplastic thyroid cancer (ATC) is a rare but lethal malignancy without any effective therapy. The aim of this study is to use a high-throughput drug library screening to identify a novel therapeutic agent that targets dysregulated genes/pathways in ATC. Experimental Design: We performed quantitative highthroughput screening (qHTS) in ATC cell lines using a compound library of 3,282 drugs. Dysregulated genes in ATC were analyzed using genome-wide expression analysis and immunohistochemistry in human ATC tissue samples and ATC cell lines. In vitro and in vivo studies were performed for determining drug activity, effectiveness of targeting, and the mechanism of action. Results: qHTS identified 100 active compounds in three ATC cell lines. One of the most active agents was the first-in-class survivin inhibitor YM155. Genome-wide expression analysis and immunohistochemistry showed overexpression of survivin in human ATC tissue samples, and survivin was highly expressed in all ATC cell lines tested. YM155 significantly inhibited ATC cellular proliferation. Mechanistically, YM155 inhibited survivin expression in ATC cells. Furthermore, YM155 treatment reduced claspin expression, which was associated with S-phase arrest in ATC cells. In vivo, YM155 significantly inhibited growth and metastases and prolonged survival. Conclusions: Our data show that YM155 is a promising anticancer agent for ATC and that its target, survivin, is overexpressed in ATC. Our findings support the use of YM155 in clinical trials as a therapeutic option in advanced and metastatic ATC.
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U2 - 10.1158/1078-0432.CCR-14-3251
DO - 10.1158/1078-0432.CCR-14-3251
M3 - Article
C2 - 25944801
AN - SCOPUS:84942925453
SN - 1078-0432
VL - 21
SP - 4123
EP - 4132
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 18
ER -