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Updated: Jul 8, 2026
Sequence-specific and Selective Recognition of Double-stranded RNAs over Single-stranded RNAs by Chemically Modified Peptide Nucleic Acids
Published on: September 21, 2017
Peptide-conjugated antisense oligonucleotides for targeted inhibition of a transcriptional regulator in vivo
Erik Henke1, Jonathan Perk, Jelena Vider
1Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, 1270 York Ave., New York, New York 10021, USA.
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.
Insights
Researchers developed a novel antitumor agent targeting Id1 and Id3, crucial for cancer growth and spread. This agent effectively reduced Id1 in tumor cells, inhibiting tumor growth and metastasis, especially when combined with an Hsp90 inhibitor.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Transcription factors are challenging cancer targets due to nuclear localization and complex interactions.
- Id1 and Id3 are key regulators of tumor invasiveness, metastasis, and angiogenesis, making them attractive therapeutic targets.
- Developing effective inhibitors for nuclear transcription factors remains a significant challenge in cancer therapy.
Purpose of the Study:
- To develop and evaluate a novel antitumor agent targeting the Id1 transcriptional regulator.
- To assess the efficacy of targeted delivery of an antisense molecule to tumor endothelial cells.
- To investigate the combination therapy of the Id1-targeting agent with an Hsp90 inhibitor for aggressive breast tumors.
Main Methods:
- Development of an antisense molecule fused to a tumor neovessel-homing peptide for targeted delivery.
- In vivo assessment of the agent's ability to downregulate Id1 protein levels in tumor endothelium.
- Evaluation of tumor growth, metastasis, hemorrhage, and hypoxia in preclinical tumor models.
- Combination therapy studies with the Hsp90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin.
Main Results:
- The novel agent effectively downregulated Id1 protein in tumor endothelial cells in vivo.
- Systemic delivery of the agent led to enhanced tumor hemorrhage and hypoxia.
- Significant inhibition of primary tumor growth and metastasis was observed in two different tumor models.
- Combination therapy with an Hsp90 inhibitor resulted in near-complete suppression of aggressive breast tumor growth.
Conclusions:
- Targeted delivery of antisense molecules offers a viable strategy for inhibiting nuclear transcription factors like Id1.
- The developed antitumor agent demonstrates significant potential in controlling tumor progression and metastasis.
- Combination therapy holds promise for achieving robust therapeutic responses in aggressive cancers.
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