Abstract
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.
MeSH terms
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Angiogenesis Inhibitors / pharmacology*
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Animals
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Antibodies / pharmacology*
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Antibodies, Monoclonal, Humanized / pharmacology
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Apoptosis*
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Bevacizumab
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Calcium-Binding Proteins
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / pathology
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Clinical Trials, Phase I as Topic
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EGF Family of Proteins
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Endothelial Growth Factors / immunology*
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Human Umbilical Vein Endothelial Cells / drug effects*
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Human Umbilical Vein Endothelial Cells / physiology
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Humans
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Insulinoma / blood supply
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Insulinoma / drug therapy
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Insulinoma / metabolism
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Lung Neoplasms / drug therapy
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Lung Neoplasms / pathology
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Mice
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Mice, Nude
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Mice, Transgenic
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Neoplastic Cells, Circulating / drug effects
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Neoplastic Cells, Circulating / metabolism
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Neoplastic Stem Cells / drug effects
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Neoplastic Stem Cells / metabolism
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Pancreatic Neoplasms / blood supply
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Pancreatic Neoplasms / drug therapy
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Pancreatic Neoplasms / metabolism
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Tumor Burden / drug effects
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Tumor Cells, Cultured
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Vascular Endothelial Growth Factor A / antagonists & inhibitors*
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Vascular Endothelial Growth Factor A / physiology
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Xenograft Model Antitumor Assays
Substances
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Angiogenesis Inhibitors
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Antibodies
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Antibodies, Monoclonal, Humanized
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Calcium-Binding Proteins
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EGF Family of Proteins
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EGFL7 protein, human
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Endothelial Growth Factors
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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Bevacizumab