title: Polo-like Kinase 1 as a potential therapeutic target in Diffuse Intrinsic Pontine Glioma.
abstract: Diffuse intrinsic pontine gliomas (DIPGs) are highly aggressive, fatal, childhood tumors that arise in the brainstem. DIPGs have no effective treatment, and their location and diffuse nature render them inoperable. Radiation therapy remains the only standard of care for this devastating disease. New therapeutic targets are needed to develop novel therapy for DIPG.
  
  
  
  We examined the expression of PLK1 mRNA in DIPG tumor samples through microarray analysis and found it to be up regulated versus normal pons. Using the DIPG tumor cells, we inhibited PLK1 using a clinically relevant specific inhibitor BI 6727 and evaluated the effects on, proliferation, apoptosis, induction of DNA damage and radio sensitization of the DIPG tumor cells.
  
  
  
  Treatment of DIPG cell lines with BI 6727, a new generation, highly selective inhibitor of PLK1, resulted in decreased cell proliferation and a marked increase in cellular apoptosis. Cell cycle analysis showed a significant arrest in G2-M phase and a substantial increase in cell death. Treatment also resulted in an increased γH2AX expression, indicating induction of DNA damage. PLK1 inhibition resulted in radiosensitization of DIPG cells.
  
  
  
  These findings suggest that targeting PLK1 with small-molecule inhibitors, in combination with radiation therapy, will hold a novel strategy in the treatment of DIPG that warrants further investigation.
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Anschutz Medical Campus, 12800 19th Ave, Aurora, CO, 80045, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Amani
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Anschutz Medical Campus, 12800 19th Ave, Aurora, CO, 80045, USA.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Prince
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Anschutz Medical Campus, 12800 19th Ave, Aurora, CO, 80045, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Alimova
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Anschutz Medical Campus, 12800 19th Ave, Aurora, CO, 80045, USA.
authors.forename: Ilango
authors.initials: I
authors.lastname: Balakrishnan
authors.affiliation: Department of Neurosurgery, University of Colorado, Anschutz Medical Campus, 12800 19th Ave, Aurora, CO, 80045, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Birks
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Anschutz Medical Campus, 12800 19th Ave, Aurora, CO, 80045, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Donson
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Anschutz Medical Campus, 12800 19th Ave, Aurora, CO, 80045, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Harris
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Anschutz Medical Campus, 12800 19th Ave, Aurora, CO, 80045, USA.|Children's Hospital Colorado, 13123 E 16th Ave, Aurora, CO, 80045, USA.
authors.forename: Jean M Mulcahy
authors.initials: JM
authors.lastname: Levy
authors.affiliation: Department of Neurosurgery, University of Colorado, Anschutz Medical Campus, 12800 19th Ave, Aurora, CO, 80045, USA.|Children's Hospital Colorado, 13123 E 16th Ave, Aurora, CO, 80045, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Handler
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Anschutz Medical Campus, 12800 19th Ave, Aurora, CO, 80045, USA.|Department of Neurosurgery, University of Colorado, Anschutz Medical Campus, 12800 19th Ave, Aurora, CO, 80045, USA.|Children's Hospital Colorado, 13123 E 16th Ave, Aurora, CO, 80045, USA.
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Foreman
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Anschutz Medical Campus, 12800 19th Ave, Aurora, CO, 80045, USA.
authors.forename: Sujatha
authors.initials: S
authors.lastname: Venkataraman
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Anschutz Medical Campus, 12800 19th Ave, Aurora, CO, 80045, USA. Rajeev.Vibhakar@ucdenver.edu.|Department of Neurosurgery, University of Colorado, Anschutz Medical Campus, 12800 19th Ave, Aurora, CO, 80045, USA. Rajeev.Vibhakar@ucdenver.edu.|Children's Hospital Colorado, 13123 E 16th Ave, Aurora, CO, 80045, USA. Rajeev.Vibhakar@ucdenver.edu.
authors.forename: Rajeev
authors.identifier: 0000-0002-5949-3896
authors.initials: R
authors.lastname: Vibhakar
mesh_terms: D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000235:genetics*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011621:Pteridines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D017422:Sequence Analysis, DNA / Q000379:methods; D015854:Up-Regulation / Q000187:drug effects; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D011838:Radiation-Sensitizing Agents; D000097869:Polo-Like Kinase 1; C541363:BI 6727
keywords: BI6727; DIPG; PLK1