Abstract
Abstract VLA-2 is the alpha2beta1 integrin which mediates interactions of cells with collagens, laminin and other extracellular matrix components. In tumor cells, VLA-2 plays a role in neovascularization, tumor-stroma interactions and metastasis. The objective of this study was to understand the role of VLA-2 in extravasation and metastasis of prostate cancer cells. VLA-2 may play a role by mediating extravasation through the basement membrane or in supporting metastasis growth in the stroma through interactions with the extracellular matrix. We assessed whether GBR 500, a monoclonal IgG4 antibody directed against the alpha2 subunit of the alpha2beta1 integrin heterodimer could prevent extravasation and metastasis formation. GBR 500 is currently undergoing clinical phase I studies. The antibody binds to human but not to mouse VLA-2. In an orthotopic mouse Xenograft model using a DU145-luc cell line we explored the importance of VLA-2 for tumor growth by inhibition of VLA-2 with a combination of GBR 500, specific for human VLA-2 and HA1–29, specific for mouse VLA-2. Bevacizumab was used as positive control. In vitro, GBR 500 inhibits the binding of PC3 prostate cancer cells to collagen with an EC50 of 0.035 μg/ml. To study the impact of VLA-2 on extravasation in a PC3-luc metastasis model we blocked VLA-2 with GBR 500 before injection of tumor cells and by pre-dosing mice with a 50 mg/kg dose i.v. This group of mice was compared with two groups of mice which where treated i.p with GBR 500 twice a week at 1mg/kg and 5 mg/kg. The positive control was bevacizumab at 5mg/kg. Results: Bi-weekly treatment with GBR 500 5 mg/kg successfully slowed tumor growth and was as effective as bevacizumab 5 mg/kg treatment. Pre-incubation and pre-dosing with VLA-2 did not affect the extravasation and metastases formation. Conclusion: : Inhibition of tumor growth was exhibited by VLA-2 in a prostate cancer PC3-luc metastasis model. This inhibition has no apparent effect on the extravasation of PC3 cells indicating that the antibody acts in the tissue by preventing establishment of metastases. The potency of GBR 500 in this model is comparable to bevacizumab. 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 LB-294. doi:10.1158/1538-7445.AM2011-LB-294
Published Version
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