title: Selective targeting of neuroblastoma tumour-initiating cells by compounds identified in stem cell-based small molecule screens.
abstract: 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 tumour-initiating 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 tumour-initiation 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.
authors: Cell Biology Program and James Burrell Laboratories, The Hospital for Sick Children, Toronto, Canada.
authors: Kristen M
authors: KM
authors: Smith
authors: Alessandro
authors: A
authors: Datti
authors: Mayumi
authors: M
authors: Fujitani
authors: Natalie
authors: N
authors: Grinshtein
authors: Libo
authors: L
authors: Zhang
authors: Olena
authors: O
authors: Morozova
authors: Kim M
authors: KM
authors: Blakely
authors: Susan A
authors: SA
authors: Rotenberg
authors: Loen M
authors: LM
authors: Hansford
authors: Freda D
authors: FD
authors: Miller
authors: Herman
authors: H
authors: Yeger
authors: Meredith S
authors: MS
authors: Irwin
authors: Jason
authors: J
authors: Moffat
authors: Marco A
authors: MA
authors: Marra
authors: Sylvain
authors: S
authors: Baruchel
authors: Jeffrey L
authors: JL
authors: Wrana
authors: David R
authors: DR
authors: Kaplan
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D017209:Apoptosis; D003868:Dequalinium / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D004579:Electron Transport; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics; D020123:Sirolimus / Q000627:therapeutic use*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; C554602:DECA-14; D054852:Small Molecule Libraries; D003868:Dequalinium; D020123:Sirolimus