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

Clinical cancer research : an official journal of the American Association for Cancer Research (2015-07-15)
Chitra Venugopal, Robin Hallett, Parvez Vora, Branavan Manoranjan, Sujeivan Mahendram, Maleeha A Qazi, Nicole McFarlane, Minomi Subapanditha, Sara M Nolte, Mohini Singh, David Bakhshinyan, Neha Garg, Thusyanth Vijayakumar, Boleslaw Lach, John P Provias, Kesava Reddy, Naresh K Murty, Bradley W Doble, Mickie Bhatia, John A Hassell, Sheila K Singh
ABSTRACT

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. 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. 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. 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.

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