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

B. C. Ahn, J. A. Ronald, Y. I. Kim, R. Katzenberg, A. Singh, R. Paulmurugan, S. Ray, L. V. Hofmann, S. S. Gambhir

Research output: Contribution to journalArticle

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 (P0.30) 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 (P0.01), a strong trend towards reduced liver expression compared with Ad-pCMV-FL (P0.07), and importantly, similar FL levels within tumor compared with Ad-pCMV-FL (P0.32). 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.

Original languageEnglish (US)
Pages (from-to)606-612
Number of pages7
JournalGene Therapy
Volume18
Issue number6
DOIs
StatePublished - Jun 1 2011

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Keywords

  • Survivin
  • adenoviral vector
  • hepatocellular carcinoma
  • two-step transcriptional amplification

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Ahn, B. C., Ronald, J. A., Kim, Y. I., Katzenberg, R., Singh, A., Paulmurugan, R., Ray, S., Hofmann, L. V., & Gambhir, S. S. (2011). Potent, tumor-specific gene expression in an orthotopic hepatoma rat model using a Survivin-targeted, amplifiable adenoviral vector. Gene Therapy, 18(6), 606-612. https://doi.org/10.1038/gt.2011.5