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

    Author(s)
    Henke, Erik
    Perk, Jonathan
    Vider, Jelena
    de Candia, Paola
    Chin, Yvette
    Solit, David B
    Ponomarev, Vladimir
    Cartegni, Luca
    Manova, Katia
    Rosen, Neal
    Benezra, Robert
    Griffith University Author(s)
    Vider, Jelena
    Year published
    2008
    Metadata
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    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 ...
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    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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    Journal Title
    Nature Biotechnology
    Volume
    26
    Issue
    1
    DOI
    https://doi.org/10.1038/nbt1366
    Subject
    Molecular targets
    Publication URI
    http://hdl.handle.net/10072/44693
    Collection
    • Journal articles

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