title: Polo-like kinase 1 is a therapeutic target in high-risk neuroblastoma.
abstract: OBJECTIVE
  High-risk neuroblastoma remains a therapeutic challenge for pediatric oncologists. The Polo-like kinase 1 (PLK1) is highly expressed in many human cancers and is a target of the novel small-molecule inhibitor BI 2536, which has shown promising anticancer activity in adult malignancies. Here, we investigated the effect of BI 2536 on neuroblastoma cells in vitro and in vivo to explore PLK1 as a potential target in high-risk neuroblastoma therapy.
  
  
  METHODS
  PLK1 transcript levels were analyzed by microarrays in 476 primary neuroblastoma specimens, and correlation with prognostic markers and patient outcome was examined. To explore the effect of PLK1 inhibition on neuroblastoma cells, 7 cell lines were treated with BI 2536 and changes in growth properties were determined. Furthermore, nude mice with IMR-32 and SK-N-AS xenografts were treated with BI 2536.
  
  
  RESULTS
  PLK1 is highly expressed in unfavorable neuroblastoma and in neuroblastoma cell lines. Expression of PLK1 is associated with unfavorable prognostic markers such as stage 4, age >18 months, MYCN amplification, unfavorable gene expression-based classification, and adverse patient outcome (P < 0.001 each). On treatment with nanomolar doses of BI 2536, all neuroblastoma cell lines analyzed showed significantly reduced proliferation, cell cycle arrest, and cell death. Moreover, BI 2536 abrogated growth of neuroblastoma xenografts in nude mice.
  
  
  CONCLUSIONS
  Elevated PLK1 expression is significantly associated with high-risk neuroblastoma and unfavorable patient outcome. Inhibition of PLK1 using BI 2536 exhibits strong antitumor activity on human neuroblastoma cells in vitro and in vivo, opening encouraging new perspectives for the treatment of high-risk neuroblastoma.
authors.affiliation: Children's Hospital, Department of Pediatric Oncology and Hematology and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ackermann
authors.forename: Felix
authors.initials: F
authors.lastname: Goeser
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Schulte
authors.forename: Alexander
authors.initials: A
authors.lastname: Schramm
authors.forename: Volker
authors.initials: V
authors.lastname: Ehemann
authors.forename: Barbara
authors.initials: B
authors.lastname: Hero
authors.forename: Angelika
authors.initials: A
authors.lastname: Eggert
authors.forename: Frank
authors.initials: F
authors.lastname: Berthold
authors.forename: Matthias
authors.initials: M
authors.lastname: Fischer
mesh_terms: D000293:Adolescent; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D051379:Mice; D008819:Mice, Nude; D015999:Multivariate Analysis; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000188:drug therapy / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011621:Pteridines / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000235:genetics; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000187:drug effects; D015854:Up-Regulation; D055815:Young Adult; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D000097869:Polo-Like Kinase 1; C518477:BI 2536