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Translational Therapeutics

Dual-modified antisense oligonucleotides targeting oncogenic protocadherin to treat gastric cancer

British Journal of Cancer volume 131, pages 1555–1566 (2024)Cite this article

Subjects

Abstract

Background

The objective of this study was to develop an innovative treatment strategy utilizing antisense oligonucleotides (ASOs) that target the gene encoding protocadherin alpha 11 (PCDHA11) and to elucidate the role of PCDHA11 in gastric cancer cells.

Methods

We designed and screened 54 amido-bridged nucleic acid (AmNA)-modified ASOs, selecting them based on PCDHA11-knockdown efficacy, in vitro and in vivo activity, and off-target effects. We assessed the impact of AmNA-modified anti-PCDHA11 ASOs on cellular functions and signaling pathways, and investigated the effects of Pcdha11 deficiency in mice.

Results

AmNA-modified anti-PCDHA11 ASOs significantly reduced the proliferation of gastric cancer cells and other solid tumors, whereas overexpression of PCDHA11 enhanced cell proliferation. The selected ASOs inhibited cellular functions related to the metastatic potential of gastric cancer cells, including migration, invasiveness, spheroid formation, and cancer stemness. Our findings revealed that AmNA-modified anti-PCDHA11 ASOs disrupted the AKT/mTOR, Wnt/β-catenin, and JAK/STAT signaling pathways. In mouse models of peritoneal metastasis (gastric and pancreatic cancer), systemic metastasis, and established subcutaneous tumors, administration of AmNA-modified anti-PCDHA11 ASOs inhibited tumor growth. ASO treatment induced reversible, dose- and sequence-dependent liver damage. Pcdha11-deficient mice demonstrated normal reproductive, organ, and motor functions.

Conclusions

AmNA-modified anti-PCDHA11 ASOs offer a promising therapeutic strategy for the treatment of gastric cancer and other solid malignancies.

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Fig. 1: Clinical relevance of PCDHA11 expression.
Fig. 2: Effects of candidate ASOs, hPCDHA11-2382 and -3716, on knockdown of PCDHA11 mRNA expression, cellular functions of cancer cells and in vivo tumor growth.
Fig. 3: Design and influence of hPCDHA11-2255, -3319 and -3969 on PCDHA11 mRNA and protein expression, in vitro and in vivo cancer cell growth.
Fig. 4: Specificity and influence of AmNA-modified anti-PCDHA11 ASOs on caspase activity, apoptosis, cancer stemness, and functions associated with metastatic potential.
Fig. 5: Toxicities of hPCDHA11-2255, -3319 and -3969.
Fig. 6: Effect of AmNA-modified anti-PCDHA11 ASOs on signal transduction pathways.
Fig. 7: Characterization of Pcdha11-deficient mice.

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Data availability

Data sources and handling of the publicly available datasets used in this study are described in the Materials and Methods. The other data generated in this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Edanz Group (www.edanzediting.com/ac) and Springer Nature Author Services for editing a draft of this paper.

Funding

This work was supported by the Japan Agency for Medical Research and Development (AMED; JP20lm02030005, JP21ak0101154, JP22ak0101154 and JP23ak0101154) and a Grant-in-Aid for Scientific Research (20K21629).

Author information

Authors and Affiliations

  1. Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Mitsuro Kanda, Dai Shimizu, Takahiro Shinozuka, Masahiro Sasahara, Shunsuke Nakamura & Yasuhiro Kodera

  2. National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan

    Yuuya Kasahara

  3. Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Yohei Iguchi & Masahisa Katsuno

  4. Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Masahisa Katsuno

  5. Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan

    Satoshi Obika

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Contributions

Study concept and design: M.K. (Mitsuro Kanda), Y.K. (Yuuya Kasahara) and S.O. Acquisition of the data: Y.K. (Yuuya Kasahara), S.N., T.S., M.S., Y.I. and M.K. (Masahisa Katsuno). Statistical analysis: D.S. Management of data acquisition: M.K. (Mitsuro Kanda) and Y.K. (Yuuya Kasahara). Analysis of the present data: S.N., T.S., M.S. D.S. and Y.I. Critical interpretation of the present data: M.K. (Mitsuro Kanda) and Y.K. (Yuuya Kasahara). Drafting of the paper: M.K. (Mitsuro Kanda). Critical revision of the paper for important intellectual content: Y.K. (Yuuya Kasahara), S.N., T.S., M.S., D.S., Y.I. and M.K. (Masahisa Katsuno), S.O. and Y.K. (Yasuhiro Kodera). Obtained funding: M.K. (Mitsuro Kanda), Y.K. (Yuuya Kasahara) and S.O. Technical or material support: Y.K. (Yuuya Kasahara) and S.O. Study supervision: Y.K. (Yasuhiro Kodera).

Corresponding author

Correspondence to Mitsuro Kanda.

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The authors declare no competing interests.

Ethics approval and consent to participate

The Institutional Review Board of Nagoya University, Japan, approved this study, and written informed consent was obtained from all patients (approval number 2014-0043). The Animal Research Committee of Nagoya University approved experiments using animals, performed according to ARRIVE guidelines (approval number M230102-002).

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Kanda, M., Kasahara, Y., Shimizu, D. et al. Dual-modified antisense oligonucleotides targeting oncogenic protocadherin to treat gastric cancer. Br J Cancer 131, 1555–1566 (2024). https://doi.org/10.1038/s41416-024-02859-5

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