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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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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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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DOI: https://doi.org/10.1038/nbt1366
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