title: Personalizing the treatment of pediatric medulloblastoma: Polo-like kinase 1 as a molecular target in high-risk children.
abstract: Medulloblastoma is the most common malignant brain tumor in children. This disease is heterogeneous and is composed of four subtypes of medulloblastoma [WNT, Sonic Hedgehog (SHH), Group 3, and Group 4]. An immediate goal is to identify novel molecular targets for the most aggressive forms of medulloblastoma. Polo-like kinase 1 (PLK1) is an oncogenic kinase that controls cell cycle and proliferation, making it a strong candidate for medulloblastoma treatment. In this study, pediatric medulloblastomas were subtyped in two patient cohorts (discovery cohort, n = 63 patients; validation cohort, n = 57 patients) using NanoString nCounter analysis and PLK1 mRNA was assessed. We determined that the SHH and Group 3 subtypes were independently associated with poor outcomes in children as was PLK1 using Cox regression analyses. Furthermore, we screened a library of 129 compounds in clinical trials using a model of pediatric medulloblastoma and determined that PLK1 inhibitors were the most promising class of agents against the growth of medulloblastoma. In patient-derived primary medulloblastoma isolates, the PLK1 small-molecule inhibitor BI2536 suppressed the self-renewal of cells with high PLK1 but not low PLK1 expression. PLK1 inhibition prevented medulloblastoma cell proliferation, self-renewal, cell-cycle progression, and induced apoptosis. In contrast, the growth of normal neural stem cells was unaffected by BI2536. Finally, BI2536 extended survival in medulloblastoma-bearing mice with efficacy comparable with Headstart, a standard-of-care chemotherapy regimen. We conclude that patients with medulloblastoma expressing high levels of PLK1 are at elevated risk. These preclinical studies pave the way for improving the treatment of medulloblastoma through PLK1 inhibition.
authors.affiliation: Authors' Affiliations: Department of Pediatrics; Division of Anatomic Pathology, Department of Pathology and Laboratory Medicine; Division of Pediatric Neurosurgery, Department of Surgery, BC Children's Hospital, University of British Columbia; Department of Pathology and Laboratory Medicine, Centre for Applied Genomics, British Columbia Cancer Agency, Vancouver, British Columbia; Division of Neurosurgery, Department of Surgery, Faculty of Health Sciences, McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton; The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario; Pediatric Oncology Experimental Therapeutics Investigators Consortium (POETIC) Laboratory for Pre-Clinical and Drug Discovery Studies, Division of Pediatric Oncology, Alberta Children's Hospital, Calgary, Alberta, Canada; and Division of Pediatric Neuro-Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Joanna
authors.initials: J
authors.lastname: Triscott
authors.forename: Cathy
authors.initials: C
authors.lastname: Lee
authors.forename: Colleen
authors.initials: C
authors.lastname: Foster
authors.forename: Branavan
authors.initials: B
authors.lastname: Manoranjan
authors.forename: Mary Rose
authors.initials: MR
authors.lastname: Pambid
authors.forename: Rachel
authors.initials: R
authors.lastname: Berns
authors.forename: Abbas
authors.initials: A
authors.lastname: Fotovati
authors.forename: Chitra
authors.initials: C
authors.lastname: Venugopal
authors.forename: Katrina
authors.initials: K
authors.lastname: O'Halloran
authors.forename: Aru
authors.initials: A
authors.lastname: Narendran
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hawkins
authors.forename: Vijay
authors.initials: V
authors.lastname: Ramaswamy
authors.forename: Eric
authors.initials: E
authors.lastname: Bouffet
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Ash
authors.initials: A
authors.lastname: Singhal
authors.forename: Juliette
authors.initials: J
authors.lastname: Hukin
authors.forename: Rod
authors.initials: R
authors.lastname: Rassekh
authors.forename: Stephen
authors.initials: S
authors.lastname: Yip
authors.forename: Paul
authors.initials: P
authors.lastname: Northcott
authors.forename: Sheila K
authors.initials: SK
authors.lastname: Singh
authors.forename: Christopher
authors.initials: C
authors.lastname: Dunham
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Dunn
mesh_terms: D000293:Adolescent; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D006801:Humans; D007223:Infant; D008527:Medulloblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D057285:Precision Medicine / Q000379:methods*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D011621:Pteridines / Q000627:therapeutic use*; D012307:Risk Factors; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D000097869:Polo-Like Kinase 1; C518477:BI 2536