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Anti-angiogenic therapy increases intratumoral adenovirus distribution by inducing collagen degradation

Gene Therapy volume 20, pages 318–327 (2013)Cite this article

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Abstract

Conditionally replicating adenoviruses (CRAd) are a promising class of gene therapy agents that can overcome already known glioblastoma (GBM) resistance mechanisms but have limited distribution upon direct intratumoral (i.t.) injection. Collagen bundles in the extracellular matrix (ECM) have an important role in inhibiting virus distribution. In fact, ECM pre-treatment with collagenases improves virus distributions to tumor cells. Matrix metalloproteinases (MMPs) are an endogenous class of collagenases secreted by tumor cells whose function can be altered by different drugs including anti-angiogenic agents, such as bevacizumab. In this study we hypothesized that upregulation of MMP activity during anti-angiogenic therapy can improve CRAd-S-pk7 distribution in GBM. We find that MMP-2 activity in human U251 GBM xenografts increases (*P=0.03) and collagen IV content decreases (*P=0.01) during vascular endothelial growth factor (VEGF-A) antibody neutralization. After proving that collagen IV inhibits CRAd-S-pk7 distribution in U251 xenografts (Spearman rho=−0.38; **P=0.003), we show that VEGF-blocking antibody treatment followed by CRAd-S-pk7 i.t. injection reduces U251 tumor growth more than each individual agent alone (***P<0.0001). Our data propose a novel approach to improve virus distribution in tumors by relying on the early effects of anti-angiogenic therapy.

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Acknowledgements

We thank Feifei Liu for statistically analyzing the data and Derek A Wainwright for optimizing the immunofluorescence staining protocol. A cross species reacting monoclonal antibody to VEGF-A (clone B20-4.1.1) was provided by Genentech (San Francisco, CA, USA). This work was supported by the NCI (R01CA122930, R01CA138587), the National Institute of Neurological Disorders and Stroke (U01NS069997), and the American Cancer Society (RSG-07-276-01-MGO).

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  1. The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, IL, USA

    B Thaci, I V Ulasov, A U Ahmed, S D Ferguson, Y Han & M S Lesniak

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  1. B Thaci
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Correspondence to M S Lesniak.

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Thaci, B., Ulasov, I., Ahmed, A. et al. Anti-angiogenic therapy increases intratumoral adenovirus distribution by inducing collagen degradation. Gene Ther 20, 318–327 (2013). https://doi.org/10.1038/gt.2012.42

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