Targeting Cancer Stemness in the Clinic: From Hype to Hope Caner Saygin, Daniela Matei, Ravindra Majeti, Ofer Reizes, Justin D. Lathia  Cell Stem Cell  Volume 24, Issue 1, Pages 25-40 (January 2019) DOI: 10.1016/j.stem.2018.11.017 Copyright © 2018 Elsevier Inc. Terms and Conditions

Figure 1 Cancer Stem Cell-Directed Therapies Selected anti-cancer stem cell (CSC) drugs, which are currently under clinical investigation, with reported results are illustrated. Their mechanisms of actions include targeting shared developmental pathways, CSC-associated surface markers, upregulated apoptotic pathways, tumor microenvironment, and upregulated drug efflux pumps. APC, adenomatous polyposis coli; β-cat, β-catenin; Bcl-2, B cell lymphoma 2; CAR, chimeric antigen receptor; ECM, extracellular matrix; EpCAM, epithelial cell adhesion molecule; FAK, focal adhesion kinase; Fz, frizzled; HGF, hepatocyte growth factor; Hh, hedgehog; LRP, low-density-lipoprotein-related protein; MDR, multi-drug resistance; NICD, intracellular domain of Notch protein; SMO, smoothened; TGFß, transforming growth factor; TGFßR, transforming growth factor receptor. Cell Stem Cell 2019 24, 25-40DOI: (10.1016/j.stem.2018.11.017) Copyright © 2018 Elsevier Inc. Terms and Conditions

Figure 2 Novel Approaches to Target CSCs Expressing Specific Surface Markers Certain CSC surface markers can be targeted with newer approaches in drug development. These include antibody-drug conjugates, whereby the antibody specific for CSC marker is conjugated to a cytotoxic drug, which induces cell death via DNA damage and/or microtubule disruption. Chimeric antigen receptor T (CAR-T) cells are genetically engineered T cells transfected with a CAR, which recognize CSC-specific antigens and contain intracellular costimulatory protein domain (e.g., CD28) that provide the second signal for T cell activation. Bispecific antibodies can recognize CSC antigens and CD3 and thus bring CSCs in the vicinity of T cells to facilitate cytotoxicity. Certain bispecific antibodies harbor Fc regions that can bind to accessory cells, leading to tumor cell phagocytosis or antibody-dependent cellular cytotoxicity (ADCC). DC, dendritic cell; NK, natural killer cell. Cell Stem Cell 2019 24, 25-40DOI: (10.1016/j.stem.2018.11.017) Copyright © 2018 Elsevier Inc. Terms and Conditions

Figure 3 Potential Clinical Trial Designs of CSC-Directed Therapies The optimal timing for use of a CSC-specific therapy is soon after diagnosis, before or concurrently with neoadjuvant chemoradiotherapy, if the latter is indicated. Concurrent administration of CSC-directed therapy and adjuvant chemoradiotherapy is also feasible, provided that the combination is not antagonistic or associated with significant toxicity. Finally, anti-CSC therapy can be employed as a maintenance regimen to prevent recurrence, and potentially, prolong survival. There is still an unmet need for robust assays to measure CSC content and function during treatment and follow-up. Currently used tools that might be useful include assessment of CSC frequency, stemness markers, gene signatures, and xenotransplantation assays. CAR-T, chimeric antigen receptor T cell. Cell Stem Cell 2019 24, 25-40DOI: (10.1016/j.stem.2018.11.017) Copyright © 2018 Elsevier Inc. Terms and Conditions