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Oncolytic adenovirus retargeted to Delta-EGFR induces selective antiglioma activity

Cancer Gene Therapy volume 16, pages 256–265 (2009)Cite this article

Abstract

The fact that glioblastomas, which are one of the most devastating cancers, frequently express the Delta-EGFR (epithelial growth factor receptor) also called mutant variant III of EGFR (EGFRvIII) suggests that this cancer cell-specific receptor might serve as an ideal target for cancer therapy. To assess its potential as such a target, we constructed an oncolytic adenovirus with Retargeted Infectivity Via EGFR (Delta-24-RIVER) on the backbone of Delta-24. This new oncolytic adenovirus targets, as Delta-24 does, the disrupted Rb pathway in cancer cells; in addition, this adenovirus has also been retargeted through the abrogation of CAR binding (Y477A mutation in adenoviral fiber protein) and insertion of an EGFRvIII-specific binding peptide in the HI loop of the fiber protein. As compared with Delta-24, Delta-24-RIVER induced EGFRvIII-selective cytotoxicity in U-87 MG isogenic cell lines and in tetracycline-inducible EGFRVIII expressing U-251 MG cells. Accordingly, by tittering the viral progeny and examining fiber protein expression in the above cells, we showed that the replication of this new construct also correlated with EGFRvIII expression. Consistently, immunohistochemistry staining of the adenoviral capsid protein hexon in the virus-treated tumors revealed that the virus replicated more efficiently in EGFRvIII-expressing U-87 MG.ΔEGFR xenografts than in the tumors grown from U-87 MG cells. Importantly, treatment with Delta-24-RIVER prolonged the survival of animals with intracranial xenografts derived from U-87 MG.ΔEGFR cells. Therefore, our results constitute the first proof of the direct targeting of a cancer-specific receptor using an oncolytic adenovirus.

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Acknowledgements

We thank Betty Notzon (Department of Scientific Publications, The University of Texas MD Anderson Cancer Center) for editorial support and Verlene Henry and Jennifer Edge (Brain Tumor Center, The University of Texas MD Anderson Cancer Center) for technical assistance in the in vivo experiments. These studies were supported by R01-CA090879 and R01 CA116621 from National Cancer Institute (to JF and VK, respectively), Marcus Foundation (to JF and CAC), Nick Eric Wichman Foundation grant (to JF and CG-M), an Institutional Research Grant to MD Anderson (to HJ), and NCI CA-16672 grant (to MD Anderson Cancer Center: DNA Analysis, Research Animal Support, and Media Preparation Facilities).

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Author notes

  1. Y Piao and H Jiang: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neuro-Oncology, Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Y Piao, H Jiang, J Xu, M M Alonso, C A Conrad, C Gomez-Manzano & J Fueyo

  2. Translational Research Laboratory, Institut Catalá d’Oncologia, Barcelona, Spain

    R Alemany

  3. Department of Experimental Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    V Krasnykh

  4. Department of Stem Cell Transplantation Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    F C Marini

  5. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    K D Aldape

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  1. Y Piao
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  2. H Jiang
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Correspondence to J Fueyo.

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Piao, Y., Jiang, H., Alemany, R. et al. Oncolytic adenovirus retargeted to Delta-EGFR induces selective antiglioma activity. Cancer Gene Ther 16, 256–265 (2009). https://doi.org/10.1038/cgt.2008.75

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