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PET Imaging of New Target CDK19 in Prostate Cancer - Beyond the Abstract

In collaboration with the Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, and the Tianjin Medical University Cancer Institute and Hospital, we designed and synthesized a novel PET imaging small molecule targeting CDK19 with diagnostic value for prostate cancer, and verified the specific uptake of the small molecule by prostate cancer cells or tissues in vitro and in vivo experiments. This new target for prostate cancer imaging is expected to make up for some shortcomings of PSMA imaging and become an alternative diagnostic method for NEPC and low-expression PSMA prostate cancer.

PET imaging of PSMA can indicate the initial stage and biochemical recurrence of patients.1 PSMA is not only expressed in prostate cancer (PCa) cells but also in normal tissues such as salivary glands, kidneys, ovaries, and breasts of non-prostate tumors.2,3 In addition, even in prostate cancer, the expression of PSMA in NEPC is very low, which may cause this high-risk prostate cancer to escape diagnosis.1 In our previous studies, we found a new diagnostic target CDK19, which has been reported to be specific in prostate tissue and highly correlated with the staging and biochemical recurrence of prostate cancer.4 In this paper, we also found that the expression of CDK19 was prostate tissue-specific and gradually increased from primary PCa to CRPC to NEPC. This suggests that CDK19 may be suitable for a wider range of prostate cancer patients.

In addition, up to 23% false-negatives have been reported on PSMA imaging.5 This may be due to significant inter- and intrapatient heterogeneity in PSMA expression. The heterogeneity of patients depends on their molecular heterogeneity, including TP53 mutations, PTEN metloss, or BRAF mutations.6-9 In our study, we found that CDK19 is highly expressed in metastatic CRPC and NEPC. Molecular taxonomy study showed that CDK19 expression was associated with ERG and ETV1 fusion and ETV fusion, TP53 mutation, PTEN deletion, and BRAF mutation in the TCGA cohort.10 This suggests that CDK19 may be a new diagnostic method for metastatic CRPC and NEPC. CDK19/PSMA combined PET-scan might supply a two-dimensional and novel diagnosis strategy by doctors to rule out false-negative rates or to search missed micrometastases in clinic.

Written by: Dong Dai,1,2 Jiang Yu,3 Ting Huang,3 Yansheng Li,4 Ziyang Wang,2 Shuangmeng Yang,3 Shuai Li,4 Yanli Li,3 Wenfeng Gou,3 Deguan Li,3 Wenbin Hou,3 Saijun Fan,5 Yiliang Li,6 Yu Zhao,7,8

  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.
  2. Department of Molecular Medicine, Tianjin Cancer Hospital Airport Hospital, National Clinical Research Center for Cancer, 300308, Tianjin, China.
  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.
  4. Department of PET-CT Diagnostic, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, 300020, Tianjin, China.
  5. 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.
  6. 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.
  7. 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.
  8. 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.

References:

  1. Maurer T, Eiber M, Schwaiger M, et al. Current use of PSMA-PET in prostate cancer management[J]. Nat Rev Urol, 2016, 13(4): 226-35.
  2. Farag M, Bolton D, Lawrentschuk N. Prostate-specific membrane antigen for the surgical oncologist: interpreting expression beyond the prostate[J]. ANZ J Surg, 2020, 90(5): 715-718.
  3. Jafari E, Ahmadzadehfar H, Dadgar H, et al. An overview on prostate-specific membrane antigen uptake in malignancies other than prostate cancer: A pictorial essay[J]. World J Nucl Med, 2020, 19(3): 260-265.
  4. Wen S, Wei Y, Zen C, et al. Long non-coding RNA NEAT1 promotes bone metastasis of prostate cancer through N6-methyladenosine[J]. Mol Cancer, 2020, 19(1): 171.
  5. Hofman M S, Lawrentschuk N, Francis R J, et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study[J]. Lancet, 2020, 395(10231): 1208-1216.
  6. Brennen W N, Zhu Y, Coleman I M, et al. Resistance to androgen receptor signaling inhibition does not necessitate development of neuroendocrine prostate cancer[J]. JCI Insight, 2021, 6(8).
  7. Cyrta J, Prandi D, Arora A, et al. Comparative genomics of primary prostate cancer and paired metastases: insights from 12 molecular case studies[J]. J Pathol, 2022, 257(3): 274-284.
  8. Grasso C S, Wu Y M, Robinson D R, et al. The mutational landscape of lethal castration-resistant prostate cancer[J]. Nature, 2012, 487(7406): 239-43.
  9. Yang Y, Bai Y, He Y, et al. PTEN Loss Promotes Intratumoral Androgen Synthesis and Tumor Microenvironment Remodeling via Aberrant Activation of RUNX2 in Castration-Resistant Prostate Cancer[J]. Clin Cancer Res, 2018, 24(4): 834-846.
  10. Cancer Genome Atlas Research Network. The Molecular Taxonomy of Primary Prostate Cancer[J]. Cell, 2015, 163(4): 1011-25.
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