Format

Send to

Choose Destination
Clin Cancer Res. 2015 Dec 1;21(23):5324-37. doi: 10.1158/1078-0432.CCR-14-3147. Epub 2015 Jul 7.

Pyrvinium Targets CD133 in Human Glioblastoma Brain Tumor-Initiating Cells.

Author information

1
McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada.
2
McMaster Centre for Functional Genomics, McMaster University, Hamilton, Ontario, Canada.
3
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.
4
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.
5
Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
6
Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
7
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.
8
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.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

PMID:
26152745
DOI:
10.1158/1078-0432.CCR-14-3147
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center