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

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Abstract

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™ 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’s sarcoma.

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Abbreviations

VEGF:

Vascular endothelial growth factor

IGFBP:

Insulin-like growth factor binding protein

MVD:

Microvessel density

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Acknowledgments

This work was supported by Adnexus, A Bristol-Myers Squibb R&D Company, Waltham, MA. The authors thank Kerstin Bahr for her skillful technical assistance.

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Authors and Affiliations

  1. Institute of Functional and Clinical Anatomy, University Medical Center of the Johannes Gutenberg-University Mainz, 55099, Mainz, Germany

    Maximilian Ackermann, Vera Delventhal & Moritz A. Konerding

  2. Adnexus, A Bristol-Myers Squibb R&D Company, Waltham, MA, USA

    Brent A. Morse & Irvith M. Carvajal

Authors
  1. Maximilian Ackermann
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  2. Brent A. Morse
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  3. Vera Delventhal
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  4. Irvith M. Carvajal
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  5. Moritz A. Konerding
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Correspondence to Moritz A. Konerding.

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Ackermann, M., Morse, B.A., Delventhal, V. et al. Anti-VEGFR2 and anti-IGF-1R-Adnectins inhibit Ewing’s sarcoma A673-xenograft growth and normalize tumor vascular architecture. Angiogenesis 15, 685–695 (2012). https://doi.org/10.1007/s10456-012-9294-9

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  • DOI: https://doi.org/10.1007/s10456-012-9294-9

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