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Selinexor demonstrates anti-tumor efficacy in paired patient-derived xenograft models and hydrogel-embedded histoculture drug sensitivity test of penile cancer

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Abstract

Background

Penile cancer is a rare malignancy with a poor prognosis, even with various treatment options. Considering the little progress in the study of the pathogenesis and treatment of penile cancer because of the lack of models that mimic the biological properties of the tumor, we have developed a patient-derived xenograft (PDX) model and paired hydrogel-embedded histoculture drug sensitivity test (HDST) to screen for drugs that can inhibit tumors. The increased expression of XPO1, as a key nuclear export protein involved in the transport of various tumor suppressors and cell cycle regulatory proteins, is associated with the prognosis of a variety of tumors [World J Uroly 27(2):141–150, 2009]. Selinexor is an inhibitor of XPO1, which can treat cancers, such as multiple myeloma, gastric cancer, triple-negative breast cancer, and non-small cell carcinoma [Transl Androl Urol 6(5):785–790, 2017; OncoTargets Therapy 13:6405–6416, 2020]. However, whether XPO1 inhibition has a role in penile cancer remains unknown. Therefore, this article used the PDX and HDST models to investigate whether the inhibition of XPO1 has an effect on penile cancer and its underlying mechanism.

Methods

We used penile cancer tumor tissues to construct a PDX model of penile cancer and paired PDXE model and confirmed the consistency of PDX tumor tissues in source patients. Then, we assessed the ability of Selinexor to inhibit penile cancer tissues in vivo using a PDX model and in vitro by HDST. We also examined the potential mechanism of XPO1 action on penile cancer by IHC and TUNEL. Finally, we assessed the safety of the drug treatment by H&E and biochemical blood analysis.

Results

Result showed that the penile cancer PDX model and patient penile cancer tissues were clinically consistent in morphological characteristics and protein expression. In addition, Selinexor could inhibit tumor growth in PDX models and HDST. We found that P53, P21 expression was upregulated; Cyclin D1 expression was downregulated, and apoptosis of tumor cells was increased in the Selinexor-treated PDX model. Moreover, it had no significant effect on liver, kidney, and cardiac function.

Conclusion

The PDX model of penile cancer was a powerful tool for penile cancer research and new drug development. It showed that Selinexor can effectively inhibit penile cancer in vitro and in vivo. In addition, XPO1 may affect P53, P21, and Cyclin D1 expression to regulate the growth and apoptosis of penile carcinoma.

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Data availability

The data that support the findings of this study are available on request from the corresponding author upon reasonable request.

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Acknowledgements

We thank Nanchang Royo Biotechnology for the technical assistance and instrument support of Jiangxi Provincial Key Laboratory of Laboratory Animals.

Funding

This work was provided by the National Natural Science of China (No. 81760284 to Y. H, No. 82060465 to X.L.), the Natural Foundation of Jiangxi Province (No. 20192BCD40003 to Y. H., No. 20212ACB206023 to X. L.), and the Science Foundation of Jiangxi Provincial Education Department (No. GJJ150231 to Y. H.).

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Authors and Affiliations

  1. Center of Laboratory Animal Science, Nanchang University, Nanchang, 330031, China

    Yuanqiao He

  2. Jiangxi Province Key Laboratory of Laboratory Animal, Nanchang, 330031, China

    Yuanqiao He

  3. Nanchang Royo Biotechnology, Nanchang, 330006, China

    Yuanqiao He

  4. The First Clinical Medical College, Nanchang University, Nanchang University, Nanchang, 330031, China

    Jiaqi Mei

  5. Department of Pathology, School of Medicine, Yangpu Hospital, Tongji University, Shanghai, 200090, China

    Hua Hao

  6. Department of Pathology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China

    Fanrong Liu

  7. Center of Biobank, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China

    Yun Yi

  8. Department of Urology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China

    Chao Hu, Fangxing Zou & Xiongbing Lu

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  1. Yuanqiao He
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Contributions

XL and YH conceived of the study. YH, MJ, HH, FL, YY, CH, and FZ performed experiments and analyzed date. XL and YH wrote the manuscript.

Corresponding author

Correspondence to Xiongbing Lu.

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Conflict of interest

The authors declare no competing interests.

Ethics statement

All animal studies were approved by the Institutional Animal Care and Use Committee (IACUC) of Nanchang Royo Biotech Co., Ltd. (Permit RYE2022040301). The patient had signed the informed consent form, and the sample collection was approved by the medical ethics committee of the Second Affiliated Hospital of Nanchang University (Permit No. 2021012). Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

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He, Y., Mei, J., Hao, H. et al. Selinexor demonstrates anti-tumor efficacy in paired patient-derived xenograft models and hydrogel-embedded histoculture drug sensitivity test of penile cancer. J Cancer Res Clin Oncol 149, 6931–6941 (2023). https://doi.org/10.1007/s00432-023-04618-0

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