Laboratory of Cancer Cell Biology, Candiolo Cancer Institute-FPO, IRCCS, Str. Prov. 142, 10060 Candiolo, TO, Italy.
Department of Oncology, University of Torino, c/o IRCCS, S.P. 142, 10060 Candiolo, TO, Italy.
Molecules. 2018 Feb 15;23(2):431. doi: 10.3390/molecules23020431.
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.
Notch 信号通路是所有后生动物中高度保守的通路，它在发育过程中细胞命运和分化、增殖和迁移的调控中起着重要作用。过去几十年的研究表明， Notch 信号级联的各种成分在人类癌症中要么上调，要么被激活。因此，下调 Notch 的表达被认为是一种有前途和强大的癌症治疗策略。在这里，我们讨论了小分子抑制剂、阻断抗体和寡核苷酸的最新进展，这些抑制剂和寡核苷酸可以阻止 Notch 的活性，并讨论了它们在临床试验中的结果。虽然 Notch 最初被鉴定为致癌基因，但后来的研究表明，在某些情况下它也可以作为肿瘤抑制基因发挥作用。 Notch 家族成员的存在增加了更多的复杂性，它们发挥不同的活性，并且可以被抑制剂不同地靶向，这可能导致它们在治疗效果上的数据相互矛盾。值得注意的是，最近的证据支持联合治疗的合理性，包括 Notch 抑制剂，它们在对抗癌症方面似乎比单一药物更有效。
