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- W4361951121 abstract "<div>Abstract<p><b>Background:</b> In pediatric tumor xenograft models, tumor-derived insulin growth factor (IGF-2) results in intrinsic resistance to IGF-IR–targeted antibodies, maintaining continued tumor angiogenesis. We evaluated the antiangiogenic activity of a ligand-binding antibody (MEDI-573) alone or in combination with IGF-I receptor binding antibodies (MAB391, CP01-B02).</p><p><b>Methods:</b> IGF-stimulated signaling was monitored by increased Akt phosphorylation in sarcoma and human umbilical cord vascular endothelial cells (HUVEC). Angiogenesis was determined <i>in vitro</i> using capillary tube formation in HUVECs and <i>in vivo</i> using a VEGF-stimulated Matrigel assay. Tumor growth delay was examined in 4 sarcoma xenograft models.</p><p><b>Results:</b> The IGF ligand-binding antibody MEDI-573 suppressed Akt phosphorylation induced by exogenous IGF-I and IGF-2 in sarcoma cells. Receptor-binding antibodies suppressed IGF-I stimulation of Akt phosphorylation, but IGF-2 circumvented this effect and maintained HUVEC tube formation. MEDI-573 inhibited HUVEC proliferation and tube formation <i>in vitro</i>, but did not inhibit angiogenesis <i>in vivo</i>, probably because MEDI-573 binds murine IGF-I with low affinity. However, <i>in vitro</i> antiangiogenic activity of MEDI-573 was also circumvented by human recombinant IGF-I. The combination of receptor- and ligand-binding antibodies completely suppressed VEGF-stimulated proliferation of HUVECs in the presence of IGF-I and IGF-2, prevented ligand-induced phosphorylation of IGF-IR/IR receptors, and suppressed VEGF/IGF-2–driven angiogenesis <i>in vivo</i>. The combination of CP1-BO2 plus MEDI-573 was significantly superior to therapy with either antibody alone against IGF-I and IGF-2 secreting pediatric sarcoma xenograft models.</p><p><b>Conclusions:</b> These results suggest that combination of antibodies targeting IGF receptor and ligands may be an effective therapeutic strategy to block angiogenesis for IGF-driven tumors. <i>Clin Cancer Res; 19(11); 2984–94. ©2013 AACR</i>.</p></div>" @default.
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- W4361951121 date "2023-03-31" @default.
- W4361951121 modified "2023-10-16" @default.
- W4361951121 title "Data from Dual Targeting of the Type 1 Insulin-like Growth Factor Receptor and Its Ligands as an Effective Antiangiogenic Strategy" @default.
- W4361951121 doi "https://doi.org/10.1158/1078-0432.c.6522509.v1" @default.
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