Targeting key stemness-related pathways in human cancers

It is increasingly apparent that cancer stem cells (CSCs) play a substantial role in the response of human cancers to therapy. Indeed, the failure of mainstream chemotherapies to reduce the CSC burden may explain the high rates of tumor recurrence and metastasis. The development of new, anti-CSC agents is thus of great importance to reduce cancer-related mortality. One strategy to target CSCs focuses on their dependence on cell-signaling pathways, which differ from the majority of the tumor cells; these pathways include the embryonic Notch, Winglessrelated (Wnt), and Hedgehog (Hh) pathways. Recently, there has been a surge in the development and clinical evaluation of targeted anti-Notch, anti-Wnt, and anti-Hh agents. Herein, we discuss the signaling paradigm for each of these pathways, identify druggable targets, and discuss selected pre-clinical and clinical findings with agents targeting each pathway. A number of natural molecules have shown some efficacy in inhibiting these stemness pathways. Importantly, we consider other disease- specific targeted agents to discuss roadblocks to the success of these antistemness agents - including financial considerations, the development of resistance, and on-target adverse effects. Novel clinical trial elements are required to adequately assess the success of these agents; however, the future for anti-CSC therapy is promising.