Taming the Notch Transcriptional Regulator for Cancer Therapy - PubMed (original) (raw)

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Taming the Notch Transcriptional Regulator for Cancer Therapy

Luca Tamagnone et al. Molecules. 2018.

Abstract

Abstract Notch signaling is a highly conserved pathway in all metazoans, which is deeply involved in the regulation of cell fate and differentiation, proliferation and migration during development. Research in the last decades has shown that the various components of the Notch signaling cascade are either upregulated or activated in human cancers. Therefore, its downregulation stands as a promising and powerful strategy for cancer therapy. Here, we discuss the recent advances in the development of small molecule inhibitors, blocking antibodies and oligonucleotides that hinder Notch activity, and their outcome in clinical trials. Although Notch was initially identified as an oncogene, later studies showed that it can also act as a tumor suppressor in certain contexts. Further complexity is added by the existence of numerous Notch family members, which exert different activities and can be differentially targeted by inhibitors, potentially accounting for contradictory data on their therapeutic efficacy. Notably, recent evidence supports the rationale for combinatorial treatments including Notch inhibitors, which appear to be more effective than single agents in fighting cancer.

Keywords: Notch transcription complex; blocking antibody; clinical trials; combination therapy; gamma secretase inhibitors.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Figure 1

Therapeutic targets in the Notch signaling pathway. The Notch pathway can be targeted by small molecule Gamma Secretase Inhibitors (GSI), antibodies (Anti-Notch, Anti-Dll4), decoys, and peptides.

Figure 2

Figure 2

GSI structures. Structures of some commonly used GSI, which are used in vitro and in clinical trials.

Figure 3

Figure 3

Functional effects of gamma secretase inhibitors. The pie chart represents the main biological activities promoted or inhibited by GSI, based on the prevalence of their report in literature (approx. 450 Pubmed-indexed research papers related to the use of GSI were individually analyzed).

Figure 4

Figure 4

Clinical trials (named by the NCT

ClinicalTrials.gov

identifier) for the treatment of the indicated tumor types based on the use of Notch inhibitors, either as a single agents (upper panel) or in combination with other drugs (lower panel).

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