Development of notch pathway inhibitors for cancer therapy

Abstract

Notch signaling is an evolutionarily conserved cell-signaling pathway involved in cell fate during development, stem cell renewal and differentiation in postnatal tissues. Roles for Notch in carcinogenesis, in the biology of cancer stem cells and tumor angiogenesis have been reported. These features identify Notch as a potential therapeutic target in oncology. A series of pre-clinical studies using primarily small molecule inhibitors of γ-secretase have demonstrated anti-tumor effects. Phase I trials have identified a reasonable safety profile for these agents, especially with intermittent administration. Mechanism-based combinations specific for individual indications are being investigated. Several other classes of Notch inhibitors are being developed. In this review, we describe the basics of Notch signaling, the role of Notch in normal and cancer stem cells; finally we describe opportunity and challenges in the development of Notch inhibitors as novel targeted agents for cancer patients.