| First Author | Johnson L | Year | 2013 |
| Journal | J Clin Invest | Volume | 123 |
| Issue | 9 | Pages | 3997-4009 |
| PubMed ID | 23945239 | Mgi Jnum | J:201596 |
| Mgi Id | MGI:5514447 | Doi | 10.1172/JCI67892 |
| Citation | Johnson L, et al. (2013) Anti-EGFL7 antibodies enhance stress-induced endothelial cell death and anti-VEGF efficacy. J Clin Invest 123(9):3997-4009 |
| abstractText | Many oncology drugs are administered at their maximally tolerated dose without the knowledge of their optimal efficacious dose range. In this study, we describe a multifaceted approach that integrated preclinical and clinical data to identify the optimal dose for an antiangiogenesis agent, anti-EGFL7. EGFL7 is an extracellular matrix-associated protein expressed in activated endothelium. Recombinant EGFL7 protein supported EC adhesion and protected ECs from stress-induced apoptosis. Anti-EGFL7 antibodies inhibited both of these key processes and augmented anti-VEGF-mediated vascular damage in various murine tumor models. In a genetically engineered mouse model of advanced non-small cell lung cancer, we found that anti-EGFL7 enhanced both the progression-free and overall survival benefits derived from anti-VEGF therapy in a dose-dependent manner. In addition, we identified a circulating progenitor cell type that was regulated by EGFL7 and evaluated the response of these cells to anti-EGFL7 treatment in both tumor-bearing mice and cancer patients from a phase I clinical trial. Importantly, these preclinical efficacy and clinical biomarker results enabled rational selection of the anti-EGFL7 dose currently being tested in phase II clinical trials. |
