Delta-like ligand 4 (Dll4), a ligand for Notch, is expressed on a

Delta-like ligand 4 (Dll4), a ligand for Notch, is expressed on arterial endothelial cells surfaces and upregulated in multiple malignancies. Together, Dll4 and Notch have been implicated in anti-angiogenic resistance, specifically with VEGFA targeted therapies (29,30). Dll4 and Notch are upregulated by VEGFA, and under physiologic check details conditions act as

a negative feedback mechanism for vessel Inhibitors,research,lifescience,medical sprouting and angiogenesis (30). Paradoxically, inhibition of Dll4 in tumor models results hypervascularity with abnormal vessels, reduced perfusion and improved tumor growth inhibition (31,32). Interestingly, upregulation of Dll4 induced bevacizumab resistance, and was in turn overcome by Notch inhibition with dibenzazepine, a γ-secretase inhibitor (33) (which in inhibits Notch singaling). In vivo inhibition of Dll4 in pancreatic

and ovarian tumor xenografts results in potent growth inhibition (34,35). Hu et al. also demonstrated that tissue Dll4 levels were predictive of clinical outcomes and response to anti-VEGF treatment Inhibitors,research,lifescience,medical in patients with ovarian cancer. Furthermore, Dll4 downregulation with siRNA in combination with anti-VEGF therapy resulted in greater tumor growth inhibition than with each agent alone (35). Multiple phase Inhibitors,research,lifescience,medical I and II studies are ongoing evaluating novel Dll4 inhibitors. Demcizumab (OMP-21M18), a monoclonal antibody targeting Dll4, is now being evaluated in phase II clinical trials. The phase I results have not yet been reported, but phase II studies in combination Inhibitors,research,lifescience,medical with chemotherapies are currently enrolling for pancreatic cancer, metastatic colorectal cancer, and NSCLC patients

(NCT01189942, NCT01189929, NCT01189968). Promising preclinical results showing promotion of hypervascularity with mural cell coverage have been demonstrated for MEDI0639, consistent with Dll4-Notch disruption (36). Phase I studies in patients with advanced solid malignancies are Inhibitors,research,lifescience,medical ongoing as well for MEDI0639 and REGN-421. The efficacy of γ-secretase inhibition is also being tested, given promising phase I results with R04929097 and MK-0752 (37,38). The Angiopoietin (Ang)-Tie axis plays an integral role in tumor blood vessel development as well. Both Ang1 and Ang2 are upregulated in numerous malignancies including non-small cell lung, gastric, and colorectal carcinomas (39). However, each ligand has differential effects on the Tie2 signaling, which is typically localized to activated tumor endothelium. Ang1 Linifanib (ABT-869) binds Tie2 resulting in decreased vascular permeability and promotion of vessel maturation and stabilization. Ang2, on the other hand, antagonizes Ang1 and induces neovascularization by destabilizing endothelial cell-pericyte junctions and promotes endothelial cell survival, migration, and proliferation (40). Accordingly, it is well established that higher ratios of Ang2 to Ang1 levels predict worse clinical outcomes (41-43).

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