Therapeutic promise and challenges of targeting DLL4/NOTCH1

DLL4-mediated NOTCH1 signaling represents an essential pathway for vascular development and has emerged as an attractive target for angiogenesis-based cancer therapies. However, newly reported toxicity findings raise safety concerns of chronic pathway blockade. Lessons learned from the development of γ-secretase inhibitors (GSIs) might offer insights into how to safely harness this important signaling pathway.