Therapeutic promise and challenges of targeting DLL4/NOTCH1

In metazoans, the evolutionarily conserved NOTCH pathway functions as an essential mechanism to regulate numerous cell fate/lineage decisions during embryogenesis, postnatal development, and in the maintenance of adult tissue homeostasis. NOTCH receptors are normally constrained in a dormant state. Ligand binding exposes the ADAM protease cleavage site that is normally buried within the negative regulatory region (NRR)[1]. Subsequent intramembrane cleavage catalyzed by γ-secretase, a multisubunit protein complex, permits the release of the intracellular portion (NICD) from the cell membrane and its entry into the nucleus where it forms a transcriptional activation complex. In mammals, the NOTCH signaling apparatus consists of four single-pass transmembrane receptors (NOTCH1-4) and at least five membrane-anchored ligands (Jagged1, 2 and Delta-like or DLL1, 3 and 4). Despite the apparent redundancy of multiple NOTCH ligands and receptors expressed in the vascular system, recent studies have revealed that the DLL4-NOTCH 1 interaction appears to be the dominant functioning component in the vascular system. DLL4 was initially identified as an endothelium-specific NOTCH ligand [2-5]. Haploinsufficiency of Dll4 in mice results in early embryonic lethality due to severe vascular defects including impaired arteriogenesis, disrupted vascular hierarchy, and enhanced vascular density with reduced vessel caliber [2,6,7]. This uniquely non-redundant role of DLL4 goes beyond early embryonic development. Studies utilizing a DLL4-selective antagonistic antibody demonstrate that DLL4 is also essential for early postnatal vascular development, angiogenesis during pathological wound healing (unpublished observations) and tumor angiogenesis [8]. Compared to DLL4, NOTCH1 is more broadly expressed and targeted disruption of Notch1 results in vascular defects similar to what has been observed with Dll4 deficiency [9,10]. Moreover, results from recent work using paralogue-specific antibodie