Approaches to CRCSC targeting

Principles of stem cell biology and cancer: future applications and therapeutics. Edited by T. Regad, T. J. Sayers and R. C. Rees. John Wiley & Sons (2015)

Part II. Cancer stem cells

Various approaches to CRC therapy are currently approved or under evaluation in the clinic (Joudeh et al., 2013). There is an urgent unmet need to target the CRCSC subpopulation within CRC that is the cause of tumour progression, therapy resistance, recurrence and metastasis. Currently, there is no US Food and Drug Administration (FDA)-approved agent for the targeting of CRCSCs. Targeting CRCSC markers is one approach; for example, a small-molecule inhibitor of Bmi1 prevents CRCSC-mediated long-term tumour growth and self-renewal (Kreso et al., 2014). CRCSCs have also been targeted with a neutralizing antibody against interleukin 4 (IL-4), a cytokine that protects CRCSCs from cell death (Todaro et al., 2007).

Targeting of stem cell signalling pathways, such as Wnt, Notch and Hh, using small molecules and monoclonal antibodies is currently being investigated for clinical use (Joudeh et al., 2013). For example, the Wnt pathway can be blocked by use of Cox-2 inhibitors or monoclonal antibodies targeting c-Met/HGF interaction (de Sousa et al., 2011a), and Hh signalling can be inhibited with the plant alkaloid cyclopamine (Varnat et al., 2009). Notch signalling can be targeted with β-secretase inhibitors (Sikandar et al., 2010) or antibodies against the Notch pathway component delta-like ligand 4 (DLL4).

Anti-DLL4 antibodies reduce CRCSC frequency in patient-derived tumour xenografts (Hoey et al., 2009).

CRCSCs are a rare population within CRC; as a result, targeting of CRCSCs alone would lead to a delayed but long-term antitumour effect. Considering that non-stem cells within the tumour can also give rise to CRCSCs via dedifferentiation, it is important to target both non-CRCSCs and CRCSCs. One approach is to combine CRCSC-specific agents with chemotherapy that targets bulk tumour cells, in order to achieve a potent and long-term antitumour effect. For example, the chemotherapeutic agent oxaliplatin was combined with CD133+ CRCSC-targeting anti-IL-4 antibody (Todaro et al., 2007) and an anti-DLL4 antibody targeting CRCSCs was combined with the chemotherapeutic agent irinotecan (Hoey et al., 2009). Another approach is to modulate the signalling pathways that drive or inhibit both CRCSCs and bulk tumour cells. For example, both CRCSCs and bulk tumour cells can be targeted via the p53 pathway (Prabhu et al., 2012), the PI3K-Akt pathway (He et al., 2007; Vermeulen et al., 2008) or NF-?B signalling (Myant et al., 2013), which regulate diverse cellular functions, such as cell-cycle arrest, senescence, apoptosis, stem cell self-renewal and differentiation.

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