Targeting cancer stem cells in drug discovery: Current state and future perspectives.

In recent decades, cancer stem cells (CSCs) have been increasingly identified in many malignancies. CSC-related signaling pathways and their functions provide new strategies for treating cancer. The aberrant activation of related signaling pathways (e.g., Wnt, Notch, and Hedgehog pathways) has been linked to multiple types of malignant tumors, which makes these pathways attractive targets for cancer therapy. CSCs display many characteristic features, such as self-renewal, differentiation, high tumorigenicity, and drug resistance. Therefore, there is an urgent need to develop new therapeutic strategies to target these pathways to control stem cell replication, survival, and differentiation. Notable crosstalk occurs among different signaling pathways and potentially leads to compensatory escape. Therefore, multitarget inhibitors will be one of the main methods to overcome the drug resistance of CSCs. Many small molecule inhibitors of components of signaling pathways in CSCs have entered clinical trials, and some inhibitors, such as vismodegib, sonidegib, and glasdegib, have been approved. Tumor cells are susceptible to sonidegib and vismodegib resistance due to mutations in the Smo protein. The signal transducers and activators of transcription 3 (STAT3) inhibitor BBI608 is being evaluated in a phase III trial for a variety of cancers. Structural derivatives of BBI608 are the main focus of STAT3 inhibitor development, which is another strategy for CSC therapy. In addition to the potential pharmacological inhibitors targeting CSC-related signaling pathways, other methods of targeting CSCs are available, such as nano-drug delivery systems, mitochondrion targeting, autophagy, hyperthermia, immunotherapy, and CSC microenvironment targeting. In addition, we summarize the latest advances in the clinical development of agents targeting CSC-related signaling pathways and other methods of targeting CSCs.