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PET imaging of new target CDK19 in prostate cancer

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Prostate-specific membrane antigen (PSMA)-positron emission tomography (PET) is a superior method to predict patients’ risk of cancer progression and response to specific therapies. However, its performance is limited for neuroendocrine prostate cancer (NEPC) and PSMA-low prostate cancer cells, resulting in diagnostic blind spots. Hence, identifying novel specific targets is our aim for diagnosing those prostate cancers with low PSMA expression.

Methods

The Cancer Genome Atlas (TCGA) database and our cohorts from men with biopsy-proven high-risk metastatic prostate cancer were used to identify CDK19 and PSMA expression. PDX lines neP-09 and P-16 primary cells were used for cellular uptake and imaging mass cytometry in vitro. To evaluate in vivo CDK19-specific uptake of gallium(Ga)-68-IRM-015-DOTA, xenograft mice models and blocking assays were used. PET/CT imaging data were obtained to estimate the absorbed dose in organs.

Results

Our study group had reported the overexpression of a novel tissue-specific gene CDK19 in high-risk metastatic prostate cancer and CDK19 expression correlated with metastatic status and tumor staging, independently with PSMA and PSA levels. Following up on this new candidate for use in diagnostics, small molecules targeting CDK19 labeled with Ga-68 (68Ga-IRM-015-DOTA) were used for PET in this study. We found that the 68Ga-IRM-015-DOTA was specificity for prostate cancer cells, but the other cancer cells also took up little 68Ga-IRM-015-DOTA. Importantly, mouse imaging data showed that the NEPC and CRPC xenografts exhibited similar signal strength with 68Ga-IRM-015-DOTA, but 68Ga-PSMA-11 only stained the CRPC xenografts. Furthermore, target specificity was elucidated by a blocking experiment on a CDK19-bearing tumor xenograft. These data concluded that 68Ga-CDK19 PET/CT was an effective technology to detect lesions with or without PSMA in vitro, in vivo, and in the PDX model.

Conclusion

Thus, we have generated a novel PET small molecule with predictive value for prostate cancer. The findings indicate that 68Ga-CDK19 may merit further evaluation as a predictive biomarker for PET scans in prospective cohorts and may facilitate the identification of molecular types of prostate cancer independent of PSMA.

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Data availability

All data that support the findings of this study are available from the corresponding authors upon reasonable request.

Abbreviations

AUC:

Area under the curve

CRPC:

Castration-resistant prostate cancer

CT:

Computed tomography

mPCa:

Metastatic prostate cancer

NEPC:

Neuroendocrine prostate cancer

PCR:

Polymerase chain reaction

PET:

Positron emission tomography

qPCR:

Quantitative real-time PCR

RT:

Radiotherapy

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Acknowledgements

We thank the patients and their families for their altruism in participating in research studies. We thank Dr. Yuanjie Niu for reagents, plasmids, and suggestions about PDXs.

Funding

This work was supported in part by grants from the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2021-RC310-010 to Y.Z.), the CAMS Innovation Fund for Medical Sciences (2021-I2M-1-060 to Y.Z.).

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Author notes

  1. Dong Dai, Jiang Yu, and Ting Huang contributed equally.

Authors and Affiliations

  1. Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for China, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 300000, Tianjin, China

    Dong Dai & Yu Zhao

  2. Department of Molecular Medicine, Tianjin Cancer Hospital Airport Hospital, National Clinical Research Center for Cancer, 300308, Tianjin, China

    Dong Dai & Ziyang Wang

  3. Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 300192, Tianjin, China

    Jiang Yu, Ting Huang, Shuangmeng Yang, Yanli Li, Wenfeng Gou, Deguan Li, Wenbin Hou, Saijun Fan, Yiliang Li & Yu Zhao

  4. Department of PET-CT Diagnostic, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, 300020, Tianjin, China

    Yansheng Li & Shuai Li

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  1. Dong Dai
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Contributions

DD, TH, YL, SY, YL (Yanli), SW, DL, WH, and WG performed the experiments. JY, SL, and YL performed the synthesis of molecules. DD and ZW performed the PET imaging. YL, JY, and YZ prepared all the figures and wrote the manuscript. DD collected the patients’ samples. YZ, SF, and YL supervised the project. YZ, SF, and YL provided fund for the whole project. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Saijun Fan, Yiliang Li or Yu Zhao.

Ethics declarations

Ethics declarations

All experimental protocols were approved by the Ethics Committee of Tianjin Medical University and performed in accordance with the relevant guidelines and regulations (Ethical approval number: KY2019K036). Written informed consents were obtained from all patients. All animal experiments were approved by the Institutional Animal Care and Use Committee of Tianjin Medical University (Tianjin, China).

Competing interests

DD, JY, TH, YL, WZ, SY, YL (Yanli), WG, DL, WH, YL, and YZ disclosed no relevant relationships. L: Activities related to the present article: grants pending from Hospital; other relationships: disclosed no relevant relationships.

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Dai, D., Yu, J., Huang, T. et al. PET imaging of new target CDK19 in prostate cancer. Eur J Nucl Med Mol Imaging 50, 3452–3464 (2023). https://doi.org/10.1007/s00259-023-06277-2

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