Combination of Dll4/Notch and Ephrin-B2/EphB4 targeted therapy is highly effective in disrupting tumor angiogenesis

<p>Abstract</p> <p>Background</p> <p>Dll4/Notch and Ephrin-B2/EphB4 pathways play critical roles in tumor vessel development and maturation. This study evaluates the efficacy of the inhibition of both signaling pathways, alone and in combination, in reducing the growth of an autochthonous mouse tumor and assesses potential adverse effects.</p> <p>Methods</p> <p>We used the transgenic RIP1-Tag2 tumor model to study the effects of 1) inhibition of Dll4/Notch by either <it>Dll4 </it>allelic deletion or use of a soluble extracellular Dll4 (sDll4), 2) inhibition of Ephrin-B2/EphB4 signaling by a soluble extracellular EphB4 fused to albumin (sEphB4-Alb), and 3) inhibition of both pathways by sEphB4-Alb combined with either <it>Dll4 </it>allelic deletion or sDll4. To investigate adverse effects, we used inducible endothelial-specific <it>Dll4 </it>knock-out mice, treated with sEphB4-Alb, and carried out histopathological analysis.</p> <p>Results</p> <p><it>Dll4 </it>allele deletion or soluble Dll4 treatment resulted in increased tumor vessel density, reduced mural cell recruitment and vessel perfusion which resulted in reduced tumor size. The soluble EphB4 instead reduced vessel density and vessel perfusion, leading to reduction of tumor size. Greater efficacy was observed when sEphB4-Alb was combined with either <it>Dll4 </it>allele deletion or sDll4 in regards to tumor size, vessel perfusion and mural cell recruitment. Induced endothelial specific <it>Dll4 </it>loss-of-function caused hepatic vascular alterations, which were prevented by concomitant sEphB4-Alb treatment.</p> <p>Conclusion</p> <p>Combination targeting of Dll4/Notch and Ephrin-B2/EphB4 has potential for clinical investigation, providing cumulative efficacy and increased safety over Dll4/Notch inhibition alone.</p

The EphB4 Receptor Tyrosine Kinase Promotes Lung Cancer Growth: A Potential Novel Therapeutic Target

Despite progress in locoregional and systemic therapies, patient survival from lung cancer remains a challenge. Receptor tyrosine kinases are frequently implicated in lung cancer pathogenesis, and some tyrosine kinase inhibition strategies have been effective clinically. The EphB4 receptor tyrosine kinase has recently emerged as a potential target in several other cancers. We sought to systematically study the role of EphB4 in lung cancer. Here, we demonstrate that EphB4 is overexpressed 3-fold in lung tumors compared to paired normal tissues and frequently exhibits gene copy number increases in lung cancer. We also show that overexpression of EphB4 promotes cellular proliferation, colony formation, and motility, while EphB4 inhibition reduces cellular viability in vitro, halts the growth of established tumors in mouse xenograft models when used as a single-target strategy, and causes near-complete regression of established tumors when used in combination with paclitaxel. Taken together, these data suggest an important role for EphB4 as a potential novel therapeutic target in lung cancer. Clinical trials investigating the efficacy of anti-EphB4 therapies as well as combination therapy involving EphB4 inhibition may be warranted.</p

Low-Dosage Inhibition of DII4 Signaling Promotes Wound Healing by Inducing Functional Neo-Angiogenesis

Recent findings regarding Dll4 function in physiological and pathological conditions indicate that this Notch ligand may constitute an important therapeutic target. Dll4 appears to be a major anti-angiogenic agent, occupying a central role in various angiogenic pathways. The first trials of anti-Dll4 therapy in mice demonstrated a paradoxical effect, as it reduced tumor perfusion and growth despite leading to an increase in vascular density. This is seen as the result of insufficient maturation of the newly formed vasculature causing a circulatory defect and increased tumor hypoxia. As Dll4 function is known to be closely dependent on expression levels, we envisioned that the therapeutic anti-Dll4 dosage could be modulated to result in the increase of adequately functional blood vessels. This would be useful in conditions where vascular function is a limiting factor for recovery, like wound healing and tissue hypoxia, especially in diabetic patients. Our experimental results in mice confirmed this possibility, revealing that low dosage inhibition of Dll4/Notch signaling causes improved vascular function and accelerated wound healing

Two-particle correlations in azimuthal angle and pseudorapidity in inelastic p + p interactions at the CERN Super Proton Synchrotron

Results on two-particle ΔηΔϕ correlations in inelastic p + p interactions at 20, 31, 40, 80, and 158 GeV/c are presented. The measurements were performed using the large acceptance NA61/SHINE hadron spectrometer at the CERN Super Proton Synchrotron. The data show structures which can be attributed mainly to effects of resonance decays, momentum conservation, and quantum statistics. The results are compared with the Epos and UrQMD models.ISSN:1434-6044ISSN:1434-605

Soluble EphB4 Inhibition of PDGF-Induced RPE Migration In Vitro

EphB4 receptor and its ligand, EphrinB2, have been shown to be important regulators of cell adhesion and migration. Although the critical role of this system has been explored in neurobiology and vascular biology, little is known about its role in epithelial biology and especially in the retinal pigment epithelium (RPE). Here the authors show a novel mechanism by which soluble EphB4 modulates the migration of RPE cells mediated by platelet-derived growth factor. These results are relevant to human disorders involving RPE migration, such as proliferative vitreoretinopathy