Targeting Therapies for Cancer Stem Cells

Cancer stem cells (CSCs) represent a small subpopulation of the bulk of a tumor. The CSCs possess the characteristics of self-renewal, clonal repopulation and resistance to conventional therapies, and thereby contribute to cancer metastasis and relapse. Moreover, CSCs establish homeostasis under stress via autophagy, endoplasmic reticulum (ER)-stress-mediated unfolded protein response (UPR) pathways, and mitophagy. Recent evidence indicate that besides many protein molecules, the noncoding RNAs (ncRNAs) also play a significant role in CSC growth and maintenance, as well as in cancer metastasis and therapeutic resistance. Therefore, targeting the CSCs has evolved as an important strategy for cancer therapy. Recent advancements in cancer immunotherapy has shown excellent application of its potential in targeting CSCs. Various immunotherapy approaches like immune checkpoint inhibitors, dendritic cell (DC)-based vaccines, adoptive T-cell therapy, oncolytic viruses, and combination therapies are currently used to target the CSCs. Also, recent multi-omic technologies can divulge exclusive CSC-associated cell surface markers, which can be used in detection or therapeutics of CSCs for various cancers. Additionally, detection of CSC-specific neoantigens can help in the design of new immunotherapeutics for cancers. Available literature suggests that many types of cancers have CSCs located in anatomically distinct niches within the tumor microenvironment (TME), which help in CSC’s survival and maintenance. Unique pro-survival and anti-survival intercellular and intracellular cross talk also exists among the CSCs, its niche and/or TME. Modulating unique CSC-niche/TME interaction(s) can reduce the maintenance potential of CSCs, and thereby prevent tumor development and progression or cancer metastasis. Many important cell signaling pathways play a key role in the maintenance and regulation of CSCs. Several new potential therapeutic molecules that could specifically target the CSCs or their signaling pathways to overcome cancer metastasis, treatmentresistance or relapse, are being developed. Furthermore, the emerging clinical studies strongly support the use of drugs as a monotherapy or in combination with other available standard therapies. This chapter highlights the roles of various critical CSC markers and pathways in or around the CSCs, and the several CSC-targeting approaches or therapies that are used or being developed to treat cancer for a cure.