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Potent, tumor-specific gene expression in an orthotopic hepatoma rat model using a Survivin-targeted, amplifiable adenoviral vector

Gene Therapy volume 18, pages 606–612 (2011)Cite this article

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Abstract

Ideal cancer gene therapies should have high tumor specificity and efficacy, and allow systemic administration to target metastases. We recently developed a bi-directional, two-step transcriptional amplification (TSTA) system driven by the tumor-specific Survivin promoter (pSurv) to amplify the correlated expression of both the reporter gene firefly luciferase (FL) and therapeutic gene tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Here, we compare the specificity and potency of an adenovirus carrying this system (Ad-pSurv-TSTA-TRAIL-FL) to a nonspecific vector (Ad-pCMV-FL) in an orthotopic hepatocellular carcinoma (HCC) rat model after systemic administration. At 24 h after injection of Ad-pCMV-FL, bioluminescence imaging revealed a trend (P=0.30) towards greater FL expression in liver versus tumor. In striking contrast, Ad-pSurv-TSTA-TRAIL-FL showed increased FL activity within the tumor compared with the liver (P<0.01), a strong trend towards reduced liver expression compared with Ad-pCMV-FL (P=0.07), and importantly, similar FL levels within tumor compared with Ad-pCMV-FL (P=0.32). Hence, this vector shows potent, tumor-specific transgene expression even after extensive liver transduction and may be of significant value in avoiding hepatotoxicity in HCC patients. Future studies will explore the benefits of tumor-specific TRAIL expression in this model, the potential to target metastases and the extension of this vector for the treatment of other Survivin-positive tumors is warranted.

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Acknowledgements

We would like to acknowledge grant support from NCI ICMIC P50CA114747 (SSG) and NCI RO1 CA082214 (SSG). We would also like to thank Tim Doyle (Stanford Center for Innovation in In Vivo Imaging, Stanford University) for help with small animal imaging. JAR is supported by the Canadian Institutes of Health Research Postdoctoral Fellowship. B-CA received financial support from the Nuclear Infra Construction of Nuclear R&D program, Korean ministry of Science and Technology.

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Author notes

  1. B-C Ahn and J A Ronald: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA, USA

    B-C Ahn, J A Ronald, R Paulmurugan, S Ray, L V Hofmann & S S Gambhir

  2. Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA

    B-C Ahn, J A Ronald, R Katzenberg, R Paulmurugan, L V Hofmann & S S Gambhir

  3. Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu, South Korea

    B-C Ahn

  4. Department of Interventional Radiology, Stanford University School of Medicine, Stanford, CA, USA

    Y I Kim & L V Hofmann

  5. Department of Radiology, Seoul National University Hospital, Seoul, South Korea

    Y I Kim

  6. Department of Radiology, University of Cambridge School of Clinical Medicine, Cambridge, UK

    A Singh

  7. Department of Bioengineering, Stanford University School of Medicine, Stanford, CA, USA

    S S Gambhir

  8. Nuclear Medicine, Stanford University School of Medicine, Stanford, CA, USA

    S S Gambhir

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  1. B-C Ahn
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Correspondence to S S Gambhir.

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Ahn, BC., Ronald, J., Kim, Y. et al. Potent, tumor-specific gene expression in an orthotopic hepatoma rat model using a Survivin-targeted, amplifiable adenoviral vector. Gene Ther 18, 606–612 (2011). https://doi.org/10.1038/gt.2011.5

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