AI Article Synopsis

  • - Neuroblastoma (NB) is a serious cancer in children linked to neural crest cells, and researchers have found specific cells within the tumor that can initiate its growth and spread in animal models.
  • - To find potential treatments, scientists screened a library of 143 protein kinase inhibitors, discovering several that effectively targeted signaling pathways crucial for the survival of the tumor-initiating cells (TICs).
  • - Among these, PLK1 inhibitors showed promising results, being toxic to TICs while sparing normal pediatric neural stem cells and significantly reducing tumor growth in animal models, suggesting they could be a valuable therapy for advanced neuroblastoma.

Article Abstract

Neuroblastoma (NB) is an often fatal pediatric tumor of neural crest origin. We previously isolated NB tumor-initiating cells (NB TIC) from bone marrow metastases that resemble cancer stem cells and form metastatic NB in immunodeficient animals with as few as ten cells. To identify signaling pathways important for the survival and self-renewal of NB TICs and potential therapeutic targets, we screened a small molecule library of 143 protein kinase inhibitors, including 33 in clinical trials. Cytostatic or cytotoxic drugs were identified that targeted PI3K (phosphoinositide 3-kinase)/Akt, PKC (protein kinase C), Aurora, ErbB2, Trk, and Polo-like kinase 1 (PLK1). Treatment with PLK1 siRNA or low nanomolar concentrations of BI 2536 or BI 6727, PLK1 inhibitors in clinical trials for adult malignancies, were cytotoxic to TICs whereas only micromolar concentrations of the inhibitors were cytotoxic for normal pediatric neural stem cells. Furthermore, BI 2536 significantly inhibited TIC tumor growth in a therapeutic xenograft model, both as a single agent and in combination with irinotecan, an active agent for relapsed NB. Our findings identify candidate kinases that regulate TIC growth and survival and suggest that PLK1 inhibitors are an attractive candidate therapy for metastatic NB.

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http://dx.doi.org/10.1158/0008-5472.CAN-10-2484DOI Listing

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