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

Key Points

  • 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 malignancies

  • Over the past few years, new investigational agents have been developed to block the Notch, Hedgehog (HH) or Wnt signalling pathways for targeting CSCs

  • To 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 trials

  • Combination 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 results

  • The 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 microenvironment

  • A 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

Abstract

During the past decade, cancer stem cells (CSCs) have been increasingly identified in many malignancies. Although the origin and plasticity of these cells remain controversial, tumour heterogeneity and the presence of small populations of cells with stem-like characteristics is established in most malignancies. CSCs display many features of embryonic or tissue stem cells, and typically demonstrate persistent activation of one or more highly conserved signal transduction pathways involved in development and tissue homeostasis, including the Notch, Hedgehog (HH), and Wnt pathways. CSCs generally have slow growth rates and are resistant to chemotherapy and/or radiotherapy. Thus, new treatment strategies targeting these pathways to control stem-cell replication, survival and differentiation are under development. Herein, we provide an update on the latest advances in the clinical development of such approaches, and discuss strategies for overcoming CSC-associated primary or acquired resistance to cancer treatment. Given the crosstalk between the different embryonic developmental signalling pathways, as well as other pathways, designing clinical trials that target CSCs with rational combinations of agents to inhibit possible compensatory escape mechanisms could be of particular importance. We also share our views on the future directions for targeting CSCs to advance the clinical development of these classes of agents.

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Figure 1: The canonical Notch signalling pathway and relevant pharmacological inhibitors under development in cancer.
Figure 2: The canonical HH-signalling pathway and pharmacological inhibitors targeting this pathway that are under ongoing development as anticancer therapies.
Figure 3: The canonical Wnt signalling pathway and pharmacological inhibitors under investigation in cancer.

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Acknowledgements

We gratefully acknowledge Dr Richard Swerdlow of PSI INTERNATIONAL, Inc., Rockville, MD, USA, for his assistance in organizing the references and formatting the manuscript, and Melissa Maher at Technical Resources International, Inc., Bethesda, MD, USA, for drafting the Figures.

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All authors contributed substantially to researching the data for the article, discussions of content, writing the article, and review/editing of the manuscript before submission.

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Correspondence to Naoko Takebe or S. Percy Ivy.

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L.M. has participated in collaborative research on Notch inhibitors with CytoMX and Merck Oncology. M.K. is an equity holder in Prism Pharma. The other authors declare no competing interests.

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Takebe, N., Miele, L., Harris, P. et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol 12, 445–464 (2015). https://doi.org/10.1038/nrclinonc.2015.61

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