Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update

Preclinical models provide evidence of cancer stem cells (CSCs) contributing to cancer proliferation, relapse and metastasis; this theory is being examined and validated in the clinical setting, currently in advanced malignanciesOver the past few years, new investigational agents have been developed to block the Notch, Hedgehog (HH) or Wnt signalling pathways for targeting CSCsTo date, robust antitumour activity has not been observed by targeting CSCs using Notch, HH or Wnt inhibitors, either as single agents or in combination with standard chemotherapy, in clinical trialsCombination approaches to overcome the crosstalk among Notch, HH and Wnt pathways, as well as other signalling pathways, has been examined mostly in preclinical models, with promising resultsThe success of the combination therapy in clinical trials might depend on CSC–tumour microenvironment interactions, perhaps in the context of the genotypes and phenotypes of the bulk tumour, CSCs, and the tumour microenvironmentA number of clinical trials have incorporated surrogate CSC assays to measure the effects of an investigational agent on CSCs, but further technological improvements in assays are needed