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Therapeutic Targeting of Cancer Stem-Like Cells (CSC) – The Current State of the Art

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Cancer stem-like cells (CSC) represent a subpopulation of tumor cells with elevated tumor-initiating potential. CSCs are also resistant to conventional and targeted therapeutics as well as radiation and have enhanced metastasis-forming potential. They may also have a role in tumor relapse, and have been found ...

Cancer stem-like cells (CSC) represent a subpopulation of tumor cells with elevated tumor-initiating potential. CSCs are also resistant to conventional and targeted therapeutics as well as radiation and have enhanced metastasis-forming potential. They may also have a role in tumor relapse, and have been found to be enriched in minimal residual disease of several malignancies. Given these properties, it is not surprising that CSCs have become a target of great interest in drug discovery. Recent research has demonstrated that CSCs can be regenerated in vivo after their selective ablation. In spite of this limitation, the therapeutic targeting of CSCs, particularly in combination with other approaches that act on the bulk of differentiated tumor cells, is expected to represent a significant step forward in cancer therapy.

CSCs can exhibit different fates that include quiescence, self-renewal and clonal expansion/differentiation. Cell fate determination from CSCs implies a fine-tuned regulation of their energy balance and metabolic status. CSCs can shift their metabolic substrate utilization, between glycolysis and mitochondrial oxidative metabolism, during specification and/or differentiation. Moreover, by analogy with normal stem cells, CSC are described to reside in a permissive tumor microenvironment (the so-called “stem cell niche”). This niche allows for the induction and/or the maintenance of a stem-like state, by facilitating cell death evasion, protecting them from the immune system, and promoting their metastatic potential. Physico-chemical and cellular properties of this specific microenvironmental niche also entail a metabolic reprogramming in CSCs.

Several different approaches are being pursued in order to target CSCs: i) Antibodies and antibody-drug conjugates targeting circulating proteins or surface receptors such as progastrin and leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5); ii) small molecules targeting surface biomarkers or signaling pathways that induce/maintain phenotypic features of CSCs such as Wnt/Notch/Hedgehog; iii) small molecules targeting the metabolic pathways involved in the induction/maintenance of the CSC phenotype such as stearoyl-CoA desaturase-1 (SCD1) or (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase) HMG-CoA reductase. For each of these approaches there are a plethora of compounds that are being investigated at the exploratory research level or are at different stages of preclinical or clinical development. Targeting those pathways that are also critical for normal stem cells might be challenging or even prohibitive. Therefore, choosing the good target(s) is critical to avoiding an unacceptable side-effect profile.

We are interested in articles that reflect the current state of the art in CSC targeting. Both articles that address innovative approaches, as well as articles that set the point on the status of compounds in active development are welcome. Optimally, the collection should reflect the entire spectrum of activities that are ongoing in this field so to have an integrated view of the therapeutic targeting of CSCs.


Topic Editor Alexandre Prieur is employed by the company Accompagnement Pharma. All other topic editors declare no competing interests with regards to the Research Topic subject. 


Keywords: CSC, antibodies, antibody-drug conjugates, small molecules, transcription factors


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