Anti-VEGFR2 and anti-IGF-1R-Adnectins inhibit Ewing%26apos;s sarcoma A673-xenograft growth and normalize tumor vascular architecture

作者：Ackermann Maximilian; Morse Brent A; Delventhal Vera; Carvajal Irvith M; Konerding Moritz A^*

来源：Angiogenesis, 2012, 15(4): 685-695.

DOI：10.1007/s10456-012-9294-9

• Adnectin
• Antiangiogenesis
• Tumor microvasculature
• Corrosion casting
• Ewing%26apos
• s sarcoma
• Xenograft
• Intussusceptive angiogenesis

Increasing experimental evidence suggests that IGF-1 may modulate tumor angiogenesis via activation of the expression of VEGF in Ewing sarcomas and rhabdomyosarcomas. This study investigates the effects of the PEGylated Adnectins (TM) CT-322, a VEGFR2-inhibitor and AT580Peg40, an IGF-1R inhibitor, as monotherapy and in combination in a murine A673 xenograft tumor model. The combination of Adnectins CT-322 and AT580Peg40 revealed a 83 % reduction in tumor growth, a nearly 5 times lower vessel density, less necrotic areas and less appearance of intussusceptive angiogenesis. Monotherapy with IGF-1R or CT-322 revealed equally a significant inhibition of tumor and vessel growth. Combinatory inhibition of IGF-1R and VEGFR2 shows a downregulation of IGF-binding protein 2 and a compensatory upregulation of VEGF levels. Immunohistological analysis showed remodeling vascular effects of CT-322-treatment or combination therapy. The vascular architecture in Adnectin-treated tumors was characterized by a strong normalization of vasculature. 3D-evaluation in microvascular corrosion casts showed significantly higher intervascular and interbranching distances in Adnectin-treated tumors. CT-322-treatment and combinatory inhibition reveal a significant reduction of intussusceptive angiogenesis. These pronounced effects on tumor vasculature suggest potential therapeutic benefit of combinatorial IGF1- and VEGF- pathways inhibition in Ewing%26apos;s sarcoma.

• 出版日期2012-12