title: Activity of the novel polo-like kinase 4 inhibitor CFI-400945 in pancreatic cancer patient-derived xenografts.
abstract: BACKGROUND
  Polo-like kinase 4 (PLK4) plays a key role in centriole replication. Hence PLK4 inhibition disrupts mitosis, and offers a novel approach to treating chromosomally unstable cancers, including pancreatic cancer. CFI-400945 is a first in class small molecule PLK4 inhibitor, currently undergoing early phase clinical trials.
  
  
  RESULTS
  Treatment with CFI-400945 significantly reduced tumor growth and increased survival in four out of the six models tested. Consistent with PLK4 inhibition, we observed reduced expression of the proliferation marker Ki-67 associated with an increase in nuclear diameter during treatment with CFI-400945. Additionally, treatment with CFI-400945 resulted in a significant reduction of tumor-initiating cells.
  
  
  CONCLUSIONS
  These results support the further investigation of PLK4 as a drug target in pancreatic cancer.
  
  
  METHODS
  Sensitivity to CFI-400945 was tested in a series of six patient-derived pancreatic cancer xenografts, selected to represent the range of growth characteristics, genetic features, and hypoxia found in pancreatic cancer patients.
authors.affiliation: Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Ines
authors.initials: I
authors.lastname: Lohse
authors.affiliation: Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Mason
authors.affiliation: Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Pinjiang Mary
authors.initials: PM
authors.lastname: Cao
authors.affiliation: Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Melania
authors.initials: M
authors.lastname: Pintilie
authors.affiliation: Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Bray
authors.affiliation: Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Medical Oncology and Haematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: David W
authors.initials: DW
authors.lastname: Hedley
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D007191:Indazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: C000592365:2-(3-(4-((2,6-dimethylmorpholino)methyl)styryl)-1H-indazol-6-yl)-5'-methoxyspiro(cyclopropane-1,3'-indolin)-2'-one; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007191:Indazoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; C490219:PLK4 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: CFI-400945; PLK4; pancreatic cancer; patient-derived pancreatic cancer xenografts; polo-like kinase 4