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

Erik Henke, Jonathan Perk, Jelena Vider, Paola De Candia, Yvette Chin, David B. Solit, Vladimir Ponomarev, Luca Cartegni, Katia Manova, Neal Rosen, Robert Benezra

Research output: Contribution to journalArticlepeer-review

98 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)91-100
Number of pages10
JournalNature biotechnology
Issue number1
StatePublished - Jan 2008
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology
  • Molecular Medicine
  • Biomedical Engineering


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