Article abstract
Nature Biotechnology 26, 91 - 100 (2008)
Published online: 6 January 2008 | doi:10.1038/nbt1366
Peptide-conjugated antisense oligonucleotides for targeted inhibition of a transcriptional regulator in vivo
Erik Henke1, Jonathan Perk1, Jelena Vider2, Paola de Candia1, Yvette Chin1, David B Solit3,4, Vladimir Ponomarev2, Luca Cartegni4, Katia Manova5, Neal Rosen3,4 & Robert Benezra1
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.
- Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, 1270 York Ave., New York, New York 10021, USA.
- Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1270 York Ave., New York, New York 10021, USA.
- Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1270 York Ave., New York, New York 10021, USA.
- Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, 1270 York Ave., New York, New York 10021, USA.
- Molecular Cytology Core Facility, Memorial Sloan-Kettering Cancer Center, 1270 York Ave., New York, New York 10021, USA.
Correspondence to: Robert Benezra1 e-mail: r-benezra@ski.mskcc.org
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