title: Polo-like Kinase Inhibitor Volasertib Exhibits Antitumor Activity and Synergy with Vincristine in Pediatric Malignancies.
abstract: BACKGROUND
  Polo-like kinase 1 (PLK1) controls the main cell-cycle checkpoints, suggesting utility of its inhibition for cancer treatment, including of highly proliferative pediatric cancer. This preclinical study explored the selective PLK1 inhibitor volasertib (BI 6727) alone and combined with chemotherapy in pediatric malignancies.
  
  
  METHODS
  Inhibition of proliferation was explored in vitro using dimethylthiazol carboxymethoxyphenyl sulfophenyl tetrazolium (MTS) assay. Mice bearing human xenografts were treated with weekly intravenous injections of volasertib.
  
  
  RESULTS
  Volasertib inhibited proliferation in all 40 cell lines tested, with a mean half-maximal growth inhibitory concentration of 313 nmol/l (range: 4-5000 nmol/l). Volasertib was highly active against RMS-1 alveolar rhabdomyosarcoma xenografts, resulting in 100% tumor regression. Activity was associated with complete and prolonged G2/M arrest and subsequent apoptotic cell death. Volasertib showed synergistic activity with vincristine but antagonistic effects with etoposide.
  
  
  CONCLUSIONS
  These findings support the further exploration of volasertib for pediatric malignancies, particularly alveolar rhabdomyosarcoma, and its combination with mitotic spindle poison.
authors: Vectorology and Anticancer Therapies, UMR 8203, CNRS, Paris-Sud University, Gustave Roussy Institute, Paris-Saclay University, Villejuif, France.
authors: Samuel
authors: S
authors: Abbou
authors: Department of Pediatric Hematology and Oncology, University Children's Hospital, Muenster, Germany.
authors: Claudia
authors: C
authors: Lanvers-Kaminsky
authors: Vectorology and Anticancer Therapies, UMR 8203, CNRS, Paris-Sud University, Gustave Roussy Institute, Paris-Saclay University, Villejuif, France.
authors: Estelle
authors: E
authors: Daudigeos-Dubus
authors: Vectorology and Anticancer Therapies, UMR 8203, CNRS, Paris-Sud University, Gustave Roussy Institute, Paris-Saclay University, Villejuif, France.
authors: Ludivine
authors: L
authors: LE Dret
authors: Gustave Roussy Institute, Optical Imaging and Flow Cytometry Platform, UMR8081 - IR4M, Villejuif, France.
authors: Corinne
authors: C
authors: Laplace-Builhe
authors: Amsterdam Medical Center, Amsterdam, the Netherlands.
authors: Jan
authors: J
authors: Molenaar
authors: Vectorology and Anticancer Therapies, UMR 8203, CNRS, Paris-Sud University, Gustave Roussy Institute, Paris-Saclay University, Villejuif, France.
authors: Gilles
authors: G
authors: Vassal
authors: Vectorology and Anticancer Therapies, UMR 8203, CNRS, Paris-Sud University, Gustave Roussy Institute, Paris-Saclay University, Villejuif, France birgit.geoerger@gustaveroussy.fr.
authors: Birgit
authors: B
authors: Geoerger
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009447:Neuroblastoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011621:Pteridines / Q000008:administration & dosage; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D014750:Vincristine; D000097869:Polo-Like Kinase 1; C541363:BI 6727
keywords: Cell-cycle checkpoint; childhood tumors; neuroblastoma; polo-like kinase 1 combination; rhabdomyosarcoma