Selective targeting of neuroblastoma tumour-initiating cells by compounds identified in stem cell-based small molecule screens.
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.
Smith
Kristen M
KM
Cell Biology Program and James Burrell Laboratories, The Hospital for Sick Children, Toronto, Canada.
Datti
Alessandro
A
Fujitani
Mayumi
M
Grinshtein
Natalie
N
Zhang
Libo
L
Morozova
Olena
O
Blakely
Kim M
KM
Rotenberg
Susan A
SA
Hansford
Loen M
LM
Miller
Freda D
FD
Yeger
Herman
H
Irwin
Meredith S
MS
Moffat
Jason
J
Marra
Marco A
MA
Baruchel
Sylvain
S
Wrana
Jeffrey L
JL
Kaplan
David R
DR
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
D000903:Antibiotics, Antineoplastic; C554602:DECA-14; D054852:Small Molecule Libraries; D003868:Dequalinium; D020123:Sirolimus