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Cancer targeted gene therapy of BikDD inhibits orthotopic lung cancer growth and improves long-term survival

Oncogene volume 28, pages 3286–3295 (2009)Cite this article

Abstract

Lung cancer is a leading cause of cancer death due to the high incidence of metastasis; therefore, novel and effective treatments are urgently needed. A current strategy is cancer-specific targeted gene therapy. Although many identified that cancer-specific promoters are highly specific, they tend to have low activity compared with the ubiquitous cytomegalovirus (CMV) promoter, limiting their application. We developed a targeted gene therapy expression system for lung cancer that is highly specific with strong activity. Our expression vector uses the survivin promoter, highly expressed in many cancers but not normal adult tissues. We enhanced the survivin promoter activity comparable to the CMV promoter in lung cancer cell lines using an established platform technology, whereas the survivin promoter remained weak in normal cells. In mouse models, the transgene was specifically expressed in the lung tumor tissue, compared with the CMV promoter that was expressed in both normal and tumor tissues. In addition, the therapeutic gene BikDD, a mutant form of pro-apoptotic Bcl2 interacting killer, induced cell killing in vitro, and inhibited cell growth and prolonged mouse survival in vivo. Importantly, there was virtually no toxicity when BikDD was expressed with our expression system. Thus, the current report provides a therapeutic efficacy and safe strategy worthy of development in clinical trials treating lung cancer.

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Acknowledgements

This work was supported by Grants from NRPGM in DOH97-TD-G-111-041 and MDACC SPORE grants in pancreatic (P20 CA101936) and breast (1P50 CA116199) cancer (to M-C Hung) and DOH97-TD-111-TM003 (to L-Y Li). YP Sher was also supported by a postdoctoral fellowship award from the National Health Research Institutes, Taiwan (PD9602). In memory of Mr Nan-Tu Huang, the late Chairman of Wei-Chuan Group in Taiwan for his courageous battle in lung cancer.

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Authors and Affiliations

  1. Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University & Hospital, Taichung, Taiwan

    Y-P Sher, T-F Tzeng, S-F Kan, L-Y Li & M-C Hung

  2. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J Hsu, X Xie, Z Han & M-C Hung

  3. Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan

    W-C Lin

  4. Asia University, Taichung, Taiwan

    L-Y Li & M-C Hung

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  1. Y-P Sher
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  2. T-F Tzeng
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  3. S-F Kan
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  4. J Hsu
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  7. W-C Lin
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  8. L-Y Li
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  9. M-C Hung
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Corresponding authors

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

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Sher, YP., Tzeng, TF., Kan, SF. et al. Cancer targeted gene therapy of BikDD inhibits orthotopic lung cancer growth and improves long-term survival. Oncogene 28, 3286–3295 (2009). https://doi.org/10.1038/onc.2009.187

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