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Nat Rev Clin Oncol. 2015 Aug;12(8):445-64. doi: 10.1038/nrclinonc.2015.61. Epub 2015 Apr 7.

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

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Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institute of Health, 9609 Medical Center Drive MSC9739, Bethesda, MD 20852, USA.
Stanley Scott Cancer Center, Louisiana State University Health Sciences Center and Louisiana Cancer Research Consortium, USA.
Cancer Therapy and Research Center, University of Texas, USA.
Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Japan.
Norris Comprehensive Cancer Research Center, University of Southern California, USA.
National Clinical Target Validation Laboratory, Division of Cancer Treatment and Diagnosis, National Cancer Institute, USA.


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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