title: Pyrvinium Targets CD133 in Human Glioblastoma Brain Tumor-Initiating Cells.
abstract: OBJECTIVE
  Clonal evolution of cancer may be regulated by determinants of stemness, specifically self-renewal, and current therapies have not considered how genetic perturbations or properties of stemness affect such functional processes. Glioblastoma-initiating cells (GICs), identified by expression of the cell surface marker CD133, are shown to be chemoradioresistant. In the current study, we sought to elucidate the functional role of CD133 in self-renewal and identify compounds that can specifically target this CD133(+) treatment-refractory population.
  
  
  METHODS
  Using gain/loss-of-function studies for CD133 we assessed the in vitro self-renewal and in vivo tumor formation capabilities of patient-derived glioblastoma cells. We generated a CD133 signature combined with an in silico screen to find compounds that target GICs. Self-renewal and proliferation assays on CD133-sorted samples were performed to identify the preferential action of hit compounds. In vivo efficacy of the lead compound pyrvinium was assessed in intracranial GIC xenografts and survival studies. Lastly, microarray analysis was performed on pyrvinium-treated GICs to discover core signaling events involved.
  
  
  RESULTS
  We discovered pyrvinium, a small-molecule inhibitor of GIC self-renewal in vitro and in vivo, in part through inhibition of Wnt/β-catenin signaling and other essential stem cell regulatory pathways. We provide a therapeutically tractable strategy to target self-renewing, chemoradioresistant, and functionally important CD133(+) stem cells that drive glioblastoma relapse and mortality.
  
  
  CONCLUSIONS
  Our study provides an integrated approach for the eradication of clonal populations responsible for cancer progression, and may apply to other aggressive and heterogeneous cancers.
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Chitra
authors.initials: C
authors.lastname: Venugopal
authors.affiliation: McMaster Centre for Functional Genomics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Robin
authors.initials: R
authors.lastname: Hallett
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Parvez
authors.initials: P
authors.lastname: Vora
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada. Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada. Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Branavan
authors.initials: B
authors.lastname: Manoranjan
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Sujeivan
authors.initials: S
authors.lastname: Mahendram
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada. Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Maleeha A
authors.initials: MA
authors.lastname: Qazi
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Nicole
authors.initials: N
authors.lastname: McFarlane
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Minomi
authors.initials: M
authors.lastname: Subapanditha
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Nolte
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada. Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Mohini
authors.initials: M
authors.lastname: Singh
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada. Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Bakhshinyan
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Neha
authors.initials: N
authors.lastname: Garg
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Thusyanth
authors.initials: T
authors.lastname: Vijayakumar
authors.affiliation: Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Boleslaw
authors.initials: B
authors.lastname: Lach
authors.affiliation: Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: John P
authors.initials: JP
authors.lastname: Provias
authors.affiliation: Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Kesava
authors.initials: K
authors.lastname: Reddy
authors.affiliation: Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Naresh K
authors.initials: NK
authors.lastname: Murty
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada. Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Bradley W
authors.initials: BW
authors.lastname: Doble
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada. Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Mickie
authors.initials: M
authors.lastname: Bhatia
authors.affiliation: McMaster Centre for Functional Genomics, McMaster University, Hamilton, Ontario, Canada. Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: John A
authors.initials: JA
authors.lastname: Hassell
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada. Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada. Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada. ssingh@mcmaster.ca.
authors.forename: Sheila K
authors.initials: SK
authors.lastname: Singh
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D049109:Cell Proliferation; D000066673:Cell Self Renewal / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D010455:Peptides / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D011774:Pyrvinium Compounds / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D000970:Antineoplastic Agents; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; D011774:Pyrvinium Compounds; C024631:pyrvinium