title: Inhibition of Survivin with YM155 Induces Durable Tumor Response in Anaplastic Thyroid Cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  We performed quantitative high-throughput 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.
authors.affiliation: Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland. Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: Amit
authors.initials: A
authors.lastname: Mehta
authors.affiliation: Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Lisa
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Myriem
authors.initials: M
authors.lastname: Boufraqech
authors.affiliation: Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu-Chittenden
authors.affiliation: National Center for Advancing Translational Sciences, NIH, Bethesda, Maryland.
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Dhaval
authors.initials: D
authors.lastname: Patel
authors.affiliation: Cancer Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Sean
authors.initials: S
authors.lastname: Davis
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Avi
authors.initials: A
authors.lastname: Rosenberg
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Kris
authors.initials: K
authors.lastname: Ylaya
authors.affiliation: Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Rachel
authors.initials: R
authors.lastname: Aufforth
authors.affiliation: National Center for Advancing Translational Sciences, NIH, Bethesda, Maryland.
authors.forename: Zhuyin
authors.initials: Z
authors.lastname: Li
authors.affiliation: National Center for Advancing Translational Sciences, NIH, Bethesda, Maryland.
authors.forename: Min
authors.initials: M
authors.lastname: Shen
authors.affiliation: Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland. kebebewe@mail.nih.gov.
authors.forename: Electron
authors.initials: E
authors.lastname: Kebebew
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry; D000818:Animals; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D051379:Mice; D009285:Naphthoquinones / Q000737:chemistry*; D009362:Neoplasm Metastasis; D034741:RNA, Small Interfering / Q000378:metabolism; D016196:S Phase; D000077022:Survivin; D065646:Thyroid Carcinoma, Anaplastic / Q000188:drug therapy* / Q000276:immunology*; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C107489:BIRC5 protein, human; C488158:CLSPN protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D034741:RNA, Small Interfering; D000077022:Survivin; C523798:sepantronium