Abstract 3277: Insulin-like growth factor-2 (IGF-2) circumvents the antiangiogenic activity of SCH717454, a human antibody that blocks ligand binding to the Type 1 insulin-like growth factor receptor (IGF-1R)

Abstract

Abstract Background. Deregulated insulin-like growth factor signaling through IGF-1R is common to many human cancers, including childhood solid tumors, and has become an important target for therapeutics development. We reported that there was a rapid decrease in tumor-associated VEGF in childhood sarcoma xenografts responding to an IGF-1R-targeted antibody (Kurmasheva RT Cancer Res, 2010). Subsequently the IGF-1R targeted antibody SCH717454 (SCH) was shown to reduce blood vessel formation in tumor xenografts (Wang Y Mol Cancer Ther. 2010). However, relatively few xenograft tumors respond to treatment (Kolb EA Ped Blood &Cancer, 2009). Here we examine a possible contributing factor to resistance to IGF-1R blockade. Methods. IGF-1R activity was measured by phosphorylation of IGF-1R, insulin receptor (IN-R), and Akt subsequent to addition of ligand (IGF-1, IGF-2). Effects of SCH on angiogenesis in vitro were determined by HUVEC proliferation and tube formation assays. Angiogenesis in vivo was determined using Matrigel plugs infused with PBS (control), VEGF or VEGF+IGF-2 and assay of hemoglobin and CD34 immunostaining. Results. SCH rapidly blocked IGF-1 but not IGF-2 stimulated phosphorylation of Akt in all sarcoma cell lines. Immunoprecipitation using anti-IGF-1R and anti-IN-R antibodies revealed that in the presence of SCH, IGF-2 partially signaled through IGF-1R but significantly induced phosphorylation of IN-R. SCH completely blocked VEGF-stimulated proliferation and tube formation of HUVECs indicating that IGF-1R signaling is essential to these processes. Exogenous IGF-2, but not IGF-1, circumvented SCH inhibition of VEGF- stimulated proliferation and tube formation. In mice SCH (20 mg/kg) dramatically inhibited angiogenesis in VEGF-infused Matrigel plugs, demonstrating anti-angiogenic activity. However, mice lack circulating IGF-2, and many childhood sarcomas secrete IGF-2. To test whether IGF-2 could circumvent the antiangiogenic activity of SCH in vivo, Matrigel plugs infused with VEGF or VEGF+IGF-2 were implanted. SCH suppressed angiogenesis into VEGF-infused Matrigel plugs, but had no inhibitory activity when plugs contained both VEGF+IGF-2. Similarly, in vitro co-culture of HUVECs with IGF-2-secreting tumor cells (Rh30) in transwell plates completely abrogated SCH inhibition of VEGF-stimulated HUVEC proliferation/tube formation. Conclusions. These results support the anti-angiogenic activity of SCH. Both in vitro and in vivo IGF-2 circumvented the effects of SCH and other IGF-1R-targeted antibodies examined in clinical development. Many childhood cancers secrete IGF-2, suggesting that tumor-derived IGF-2 in the microenvironment maintains angiogenesis in the presence of antibodies such as SCH. (Supported by NCI awards CA77776, CA23099 and from Schering-Plough). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3277. doi:10.1158/1538-7445.AM2011-3277