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

EMBO Mol Med. 2010 Sep;2(9):371-84. doi: 10.1002/emmm.201000093.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / therapeutic use*
  • Apoptosis
  • Dequalinium / analogs & derivatives*
  • Dequalinium / chemistry
  • Dequalinium / therapeutic use
  • Electron Transport
  • Gene Expression Profiling
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neuroblastoma / drug therapy*
  • Neuroblastoma / genetics
  • Sirolimus / therapeutic use*
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / therapeutic use
  • Xenograft Model Antitumor Assays

Substances

  • Antibiotics, Antineoplastic
  • DECA-14
  • Small Molecule Libraries
  • Dequalinium
  • Sirolimus