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Targeting αV-integrins decreased metastasis and increased survival in a nude rat breast cancer brain metastasis model

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Abstract

Brain metastases commonly occur in patients with breast, lung and melanoma systemic cancers. The anti-αV integrin monoclonal antibody intetumumab binds cell surface proteins important for adhesion, invasion and angiogenesis in the metastatic cascade. The objective of this study was to investigate the anti-metastatic effect of intetumumab in a hematogenous breast cancer brain metastasis model. Female nude rats received intra-carotid infusion of human brain-seeking metastatic breast cancer cells (231BR-HER2) and were randomly assigned into four groups: (1) control; (2) intetumumab mixed with cells in vitro 5 min before infusion without further treatment; (3) intetumumab intravenously 4 h before and weekly after cell infusion; (4) intetumumab intravenously weekly starting 7 days after cell infusion. Brain metastases were detected by magnetic resonance imaging (MRI) and immunohistochemistry. Comparisons were made using the Kruskal–Wallis test and Dunnett’s test. Survival times were estimated using Kaplan–Meier analysis. All control rats with brain tissue available for histology (9 of 11 rats) developed multiple brain metastases (median = 14). Intetumumab treatment either in vitro prior to cell infusion or intravenous before or after cell infusion prevented metastasis formation on MRI and decreased the number of metastases on histology (median = 2, p = 0.0055), including 30 % of animals without detectable tumors at the end of the study. The overall survival was improved by intetumumab compared to controls (median 77+ vs. 52 days, p = 0.0277). Our results suggest that breast cancer patients at risk of metastases might benefit from early intetumumab treatment.

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Abbreviations

INT:

Intetumumab

ECM:

Extracellular matrix

VEGF:

Vascular endothelial growth factor

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Acknowledgments

The authors thank Sheila Taylor, Ryan Kartheiser, Murat Oztaskin and Seth Lewin for their technical assistance. This study was supported by a sponsored research agreement from Ortho Biotech Oncology R&D, DOD center of excellence grant (Pat Steeg PI), and NIH grants: NS053468, CA137488, and NS44687 to EAN.

Conflict of Interest

This study was financially sponsored in part by Ortho Biotech Oncology R&D., the manufacturer of the intetumumab antibody. DJM is an employee and stockholder of Ortho Biotech Oncology R&D. The other authors currently have no financial interest and affiliation in this agent, its developer Ortho Biotech Oncology R&D, or its parent company Johnson & Johnson.

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Author notes

  1. Dale F. Kraemer

    Present address: Center for Health Equity and Quality Research and Department of Neurology, University of Florida at Jacksonville, Jacksonville, FL, 32209, USA

Authors and Affiliations

  1. Department of Neurology, Oregon Health and Sciences University, 3181 Sam Jackson Park Road L603, Portland, OR, 97239, USA

    Y. Jeffrey Wu, Leslie L. Muldoon, Seymur Gahramanov & Edward A. Neuwelt

  2. Department of Cell & Developmental Biology, Oregon Health & Sciences University, Portland, OR, 97239, USA

    Leslie L. Muldoon

  3. Department of Neurosurgery, Oregon Health & Sciences University, Portland, OR, 97239, USA

    Edward A. Neuwelt

  4. Department of Pharmacy Practice, Oregon State University, Portland, OR, 97239, USA

    Dale F. Kraemer

  5. Ortho Biotech Oncology R&D, Radnor, PA, 19087, USA

    Deborah J. Marshall

  6. Department of Veterans Affairs Medical Center, Portland, OR, 97239, USA

    Edward A. Neuwelt

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  1. Y. Jeffrey Wu
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Corresponding author

Correspondence to Edward A. Neuwelt.

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Wu, Y.J., Muldoon, L.L., Gahramanov, S. et al. Targeting αV-integrins decreased metastasis and increased survival in a nude rat breast cancer brain metastasis model. J Neurooncol 110, 27–36 (2012). https://doi.org/10.1007/s11060-012-0942-0

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  • DOI: https://doi.org/10.1007/s11060-012-0942-0

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