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Novel strategy of liver cancer treatment with modified antisense oligonucleotides targeting human vasohibin-2
Sachiko Horie1, Yasuhiro Suzuki1,2, Tsuyoshi Yamamoto3
1Department of Vascular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Abstract:
Vasohihibin-2 (VASH2) is a homolog of vasohibin-1 (VASH1) and is overexpressed in various cancers. Vasohihibin-2 acts on both cancer cells and cancer microenvironmental cells. Previous analyses have shown that VASH2 promotes cancer progression and abrogation of VASH2 results in significant anticancer effects. We therefore propose VASH2 to be a practical molecular target for cancer treatment. Modifications of antisense oligonucleotide (ASO) such as bridged nucleic acids (BNA)-based modification increases the specificity and stability of ASO, and are now applied to the development of a number of oligonucleotide-based drugs. Here we designed human VASH2-ASOs, selected an optimal one, and developed 2',4'-BNA-based VASH2-ASO. When systemically administered, naked 2',4'-BNA-based VASH2-ASO accumulated in the liver and showed its gene-silencing activity. We then examined the effect of 2',4'-BNA-based VASH2-ASO in liver cancers. Intraperitoneal injection of naked 2',4'-BNA-based VASH2-ASO exerted a potent antitumor effect on orthotopically inoculated human hepatocellular carcinoma cells. The same manipulation also showed potent antitumor activity on the splenic inoculation of human colon cancer cells for liver metastasis. These results provide a novel strategy for the treatment of primary as well as metastatic liver cancers by using modified ASOs targeting VASH2.
Insights
Vasohihibin-2 (VASH2) is a promising cancer target. Modified antisense oligonucleotides (ASOs) targeting VASH2 demonstrate potent antitumor effects against liver cancer, offering a new treatment strategy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Vasohihibin-2 (VASH2) is overexpressed in various cancers and promotes tumor progression.
- VASH2's role in cancer necessitates exploring it as a therapeutic target.
- Antisense oligonucleotides (ASOs) modified with bridged nucleic acids (BNAs) offer enhanced stability and specificity.
Purpose of the Study:
- To design and develop a 2',4'-BNA-modified antisense oligonucleotide (ASO) targeting human VASH2.
- To evaluate the efficacy of this VASH2-ASO in preclinical models of liver cancer.
Main Methods:
- Design and optimization of human VASH2-specific ASOs with 2',4'-BNA modifications.
- Systemic administration of naked 2',4'-BNA-based VASH2-ASO in mouse models.
- Assessment of antitumor activity against orthotopic human hepatocellular carcinoma and splenic human colon cancer liver metastasis models.
Main Results:
- The developed 2',4'-BNA-based VASH2-ASO demonstrated gene-silencing activity upon systemic administration, accumulating in the liver.
- Intraperitoneal injection of the VASH2-ASO showed significant antitumor effects in hepatocellular carcinoma models.
- The VASH2-ASO also exhibited potent antitumor activity against liver metastasis models of colon cancer.
Conclusions:
- Modified antisense oligonucleotides targeting VASH2 represent a novel therapeutic strategy for primary and metastatic liver cancers.
- The 2',4'-BNA modification enhances the potential of ASOs for clinical application in cancer treatment.
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