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Cancer gene therapy with iCaspase-9 transcriptionally targeted to tumor endothelial cells

Cancer Gene Therapy volume 15, pages 667–675 (2008)Cite this article

Abstract

Antiangiogenic therapies have shown varying results partly because each tumor type secretes a distinct panel of angiogenic factors to sustain its own microvascular network. In addition, recent evidence demonstrated that tumors develop resistance to antiangiogenic therapy by turning on alternate angiogenic pathways when one pathway is therapeutically inhibited. Here, we test the hypothesis that expression of a caspase-based artificial death switch in tumor-associated endothelial cells will disrupt tumor blood vessels and slow down tumor progression irrespective of tumor type. Adenoviral vectors expressing inducible Caspase-9 (iCaspase-9) under transcriptional regulation with the endothelial cell-specific vascular endothelial growth factor receptor-2 (VEGFR2) promoter (Ad-hVEGFR2-iCaspase-9) induced apoptosis of proliferating human dermal microvascular endothelial cells (HDMECs), but not human tumor cells (UM-SCC-17B, head and neck squamous cell carcinoma; HepG2, hepatocellular carcinoma; PC-3, prostate adenocarcinoma; SLK, Kaposi's sarcoma; MCF-7, breast adenocarcinoma). Notably, apoptosis was dependent upon activation of iCaspase-9 with the dimerizer drug AP20187. Local delivery of Ad-hVEGFR2-iCaspase-9 followed by intraperitoneal injection of AP20187 ablated tumor microvessels and inhibited xenografted tumor growth in all tumor models evaluated here. We conclude that a cancer gene therapy strategy based on a transcriptionally targeted viral vector expressing an inducible caspase allows for selective and controlled ablation of microvessels of histopathologically diverse tumor types.

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Acknowledgements

We thank David Spencer for providing us with the iCaspase-9 construct and for critically reading this article and providing thoughtful suggestions to this study. We thank Ruben Hernandez-Alcoceba for help in designing the adenovirus vectors, and John Westman and Chris Strayhorn for help with the histology. We also thank Ariad Pharmaceuticals (www.ariad.com/regulationkits) for the dimerizing agent AP20187. This research was supported by Grants R01-DE14601, R01-DE15948, R01-DE16586 from the NIH/NIDCR (JEN), and a grant from the American Dental Association Health Foundation (JEN).

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Authors and Affiliations

  1. Department of Restorative Sciences, Angiogenesis Research Laboratory, University of Michigan School of Dentistry, Ann Arbor, MI, USA

    W Song, Z Dong, T Jin, M G Mantellini & J E Nör

  2. Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA

    G Núñez

  3. Department of Biomedical Engineering, College of Engineering, University of Michigan, Ann Arbor, MI, USA

    J E Nör

  4. Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA

    G Núñez & J E Nör

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  1. W Song
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  2. Z Dong
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  3. T Jin
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  4. M G Mantellini
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  5. G Núñez
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  6. J E Nör
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Correspondence to J E Nör.

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Song, W., Dong, Z., Jin, T. et al. Cancer gene therapy with iCaspase-9 transcriptionally targeted to tumor endothelial cells. Cancer Gene Ther 15, 667–675 (2008). https://doi.org/10.1038/cgt.2008.38

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