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Selective targeting of neuroblastoma tumour‐initiating cells by compounds identified in stem cell‐based small molecule screens

2010; Springer Nature; Volume: 2; Issue: 9 Linguagem: Inglês

10.1002/emmm.201000093

1757-4684

Kristen M. Smith, Alessandro Datti, Mayumi Fujitani, Natalie Grinshtein, Libo Zhang, Olena Morozova, Kim M. Blakely, Susan A. Rotenberg, Loen M. Hansford, Freda D. Miller, Herman Yeger, Meredith S. Irwin, Jason Moffat, Marco A. Marra, Sylvain Baruchel, Jeffrey L. Wrana, David R. Kaplan,

Cancer, Hypoxia, and Metabolism

Neuroblastoma (NB) is the most deadly extra-cranial solid tumour in children necessitating an urgent need for effective and less toxic treatments.One reason for the lack of efficacious treatments may be the inability of existing drugs to target the tumour-initiating or cancer stem cell population responsible for sustaining tumour growth, metastases and relapse.Here, we describe a strategy to identify compounds that selectively target patient-derived cancer stem cell-like tumourinitiating cells (TICs) while sparing normal paediatric stem cells (skin-derived precursors, SKPs) and characterize two therapeutic candidates.DECA-14 and rapamycin were identified as NB TIC-selective agents.Both compounds induced TIC death at nanomolar concentrations in vitro, significantly reduced NB xenograft tumour weight in vivo, and dramatically decreased self-renewal or tumourinitiation capacity in treated tumours.These results demonstrate that differential drug sensitivities between TICs and normal paediatric stem cells can be exploited to identify novel, patient-specific and potentially less toxic therapies.