Rational targeting of Notch signaling in cancer.

Accumulating preclinical and clinical evidence supports a pro-oncogenic function for Notch signaling in several solid tumors, particularly but not exclusively in breast cancer. Notch inhibitory agents, such as gamma-secretase inhibitors, are being investigated as candidate cancer therapeutic agents. Interest in therapeutic modulation of the Notch pathway has been increased by recent reports, indicating that its role is important in controlling the fate of putative 'breast cancer stem cells'. However, as is the case for most targeted therapies, successful targeting of Notch signaling in cancer will require a considerable refinement of our understanding of the regulation of this pathway and its effects in both normal and cancer cells. Notch signaling has bidirectional 'cross talk' interaction with multiple other pathways that include candidate therapeutic targets. Understanding these interactions will greatly increase our ability to design rational combination regimens. To determine which patients are most likely to benefit from treatment with Notch inhibitors, it will be necessary to develop molecular tests to accurately measure pathway activity in specific tumors. Finally, mechanism-based toxicities will have to be addressed by a careful choice of therapeutic agents, combinations and regimens. This article summarizes the current state of the field, and briefly describes opportunities and challenges for Notch-targeted therapies in oncology.