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Targeted hepatocellular carcinoma proapoptotic BikDD gene therapy

Oncogene volume 30, pages 1773–1783 (2011)Cite this article

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Abstract

Hepatocellular carcinoma (HCC), the third leading cause of cancer death in the world, is the most general type of primary liver cancer. Although current treatment modalities, such as liver transplantation, resection, percutaneous ablation, transarterial embolization, chemotherapy and radiotherapy are potentially curative, these methods are not universally applicable to all of HCC patients, especially for those with poor prognosis in which no effective remedy is available. Therefore, development of novel therapeutic approach for the treatment of HCC is urgently needed. In the current study, we developed a promising HCC-targeted gene therapy vector driven by liver cancer-specific α-fetoprotein promoter/enhancer coupled to an established platform technology. The activity of this expression vector is comparable with or even higher than that of strong cytomegalovirus (CMV) promoter and exhibits strong promoter activity in liver cancer cells/tumors, but has nearly no or very low activity in normal cells/organs in vitro and in orthotopic animal models in vivo. Its cancer specificity exceeds that of the CMV promoter, which expresses non-specifically in both normal and tumor cells. In addition, targeted expression of a therapeutic BikDD, a mutant of proapoptotic gene Bik effectively and preferentially killed liver cancer cells, but not normal cells and significantly repressed growth of HCC tumors, and prolonged survival in multiple xenograft and syngeneic orthotopic mouse models of HCC through intravenous systemic gene delivery. Importantly, systemic administration of BikDD by our expression vector exerted no systemically acute toxicity compared with CMV-BikDD in mice. Taken together, this study elucidates a relatively safe and highly effective and specific systemic gene therapy strategy for liver cancer, and is worthy of further development for future clinical trials.

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Acknowledgements

This work was supported by grants from DOH97-TD-I-111-TM003, DOH98-TD-I-111-TM002, NHRI-EX98-9603BC (to L-YL), DOH98-TD-G-111-030 (to M-CH), NSC96-3111-B-039, NSC97-3111-B-039 and DOH99-TD-C-111-005 (to M-CH and L-YL).

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Author notes

  1. L-Y Li and H-Y Dai: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan

    L-Y Li, H-Y Dai, F-L Yeh, S-F Kan, Y-H Chen, Y-P Sher & M-C Hung

  2. Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan

    L-Y Li & M-C Hung

  3. Department of Biotechnology, Asia University, Taichung, Taiwan

    L-Y Li

  4. Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    J Lang, J L Hsu & M-C Hung

  5. Department of Surgery, China Medical University Hospital, Taichung, Taiwan

    L-B Jeng

  6. Department of Medicine, China Medical University, Taichung, Taiwan

    L-B Jeng

  7. Department of Pharmacology, China Medical University, Taichung, Taiwan

    W-C Lin

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  1. L-Y Li
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Correspondence to L-Y Li or M-C Hung.

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Competing interests

The corresponding author, Dr Mien-Chie Hung, is an inventor on patents covering BikDD as a therapeutic agent filed with the University of Texas MD Anderson Cancer. The other authors declare no conflict of interest.

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Supplementary Information accompanies the paper on the Oncogene website

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Li, LY., Dai, HY., Yeh, FL. et al. Targeted hepatocellular carcinoma proapoptotic BikDD gene therapy. Oncogene 30, 1773–1783 (2011). https://doi.org/10.1038/onc.2010.558

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