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Peptide-conjugated antisense oligonucleotides for targeted inhibition of a transcriptional regulator in vivo

Nature Biotechnology volume 26, pages 91–100 (2008)Cite this article

Abstract

Transcription factors are important targets for the treatment of a variety of malignancies but are extremely difficult to inhibit, as they are located in the cell's nucleus and act mainly by protein-DNA and protein-protein interactions. The transcriptional regulators Id1 and Id3 are attractive targets for cancer therapy as they are required for tumor invasiveness, metastasis and angiogenesis. We report here the development of an antitumor agent that downregulates Id1 effectively in tumor endothelial cells in vivo. Efficient delivery and substantial reduction of Id1 protein levels in the tumor endothelium were effected by fusing an antisense molecule to a peptide known to home specifically to tumor neovessels. In two different tumor models, systemic delivery of this drug led to enhanced hemorrhage, hypoxia and inhibition of primary tumor growth and metastasis, similar to what is observed in Id1 knockout mice. Combination with the Hsp90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin yielded virtually complete growth suppression of aggressive breast tumors.

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Figure 1: Characterization of Id1-antisense oligonucleotides and Id1-PCAOs.
Figure 2: In vitro homing and activity of Id1-PCAOs.
Figure 3: The uptake of Id1-PCAOs is nucleolin dependent and can be stimulated by VEGF-A.
Figure 4: In vivo tumor homing and activity of Id1-PCAOs.
Figure 5: Combination therapy with 17-AAG affects tumor growth and vascular integrity.
Figure 6: Id1-PCAO inhibits primary tumor growth and metastatic spread of Lewis lung carcinoma allografts.

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Acknowledgements

The authors thank Simona Curelariu for help with animal models and Ninche Alston for help with in vivo imaging. This work was supported by the Deutsche Forschungsgemeinschaft (fellowship to E.H.), the National Institutes of Health (R.B.), William H. Goodwin and Alice Goodwin and the Commonwealth Cancer Foundation for Research and the Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center (R.B.), the Breast Cancer Research Foundation (R.B.) and the Mary Kay Ash Foundation (R.B.).

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Authors and Affiliations

  1. Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, 1270 York Ave., New York, 10021, New York, USA

    Erik Henke, Jonathan Perk, Paola de Candia, Yvette Chin & Robert Benezra

  2. Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1270 York Ave., New York, 10021, New York, USA

    Jelena Vider & Vladimir Ponomarev

  3. Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1270 York Ave., New York, 10021, New York, USA

    David B Solit & Neal Rosen

  4. Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, 1270 York Ave., New York, 10021, New York, USA

    David B Solit, Luca Cartegni & Neal Rosen

  5. Molecular Cytology Core Facility, Memorial Sloan-Kettering Cancer Center, 1270 York Ave., New York, 10021, New York, USA

    Katia Manova

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  1. Erik Henke
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All authors contributed significantly to the experimental design and/or execution of the experiments described.

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Correspondence to Robert Benezra.

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Henke, E., Perk, J., Vider, J. et al. Peptide-conjugated antisense oligonucleotides for targeted inhibition of a transcriptional regulator in vivo. Nat Biotechnol 26, 91–100 (2008). https://doi.org/10.1038/nbt1366

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