Imaging assisted evaluation of antitumor efficacy of a new histone deacetylase inhibitor in the castration-resistant prostate cancer

Abstract

Purpose

Castration-resistant prostate cancer (CRPC) is the most common cause of death in men. The effectiveness of HDAC inhibitors has been demonstrated by preclinical models, but not in clinical studies, probably due to the ineffectively accumulation of HDACI in prostate cancer cells. The purpose of this work was to evaluate effects of a novel HDACI (CN133) on CRPC xenograft model and 22Rv1 cells, and develops methods, PET/CT imaging, to detect the therapeutic effects of CN133 on this cancer.

Methods

We designed and performed study to compare the effects of CN133 with SAHA on the 22Rv1 xenograft model and 22Rv1 cells. Using PET/CT imaging with [11C] Martinostat and [18F] FDG, we imaged mice bearing 22Rv1 xenografts before and after 21-day treatment with placebo and CN133 (1 mg/kg), and uptake on pre-treatment and post-treatment imaging was measured. The anti-tumor mechanisms of CN133 were investigated by qPCR, western blot, and ChIP-qPCR.

Results

Our data showed that the CN133 treatment led to a 50% reduction of tumor volume compared to the placebo that was more efficacious than SAHA treatment in this preclinical model. [11C] Martinostat PET imaging could identify early lesions of prostate cancer and can also be used to monitor the therapeutic effect of CN133 in CRPC. Using pharmacological approaches, we demonstrated that effects of CN133 showed almost 100-fold efficacy than SAHA treatment in the experiment of cell proliferation, invasion, and migration. The anti-tumor mechanisms of CN133 were due to the inhibition of AR signaling pathway activity by decreased HDAC 2 and 3 protein expressions.

Conclusion

Taken together, these studies provide not only a novel epigenetic approach for prostate cancer therapy but also offering a potential tool, [11C] Martinostat PET/CT imaging, to detect the early phase of prostate cancer and monitor therapeutic effect of CN133. These results will likely lead to human trials in the future.

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Data availability

Data transparency.

Abbreviations

CRPC:

castration-resistance prostate cancer

HDAC:

histone deacetylase

HDACIs:

histone deacetylase inhibitors

SAHA:

suberoylanilide hydroxamic acid

AR:

androgen receptor

ChIP:

chromatin immunoprecipitation

PET:

positron emission tomography

[18F]FDG:

18F-fluorodeoxyglucose

PSA:

prostate specific antigen

KLK2:

recombinant Kallikrein 2

TMPRSS2:

transmembrane protease serine 2

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Acknowledgments

This work was supported by a pilot funding from the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital (C.W.), and a short-term visiting program of Sichuan University (Z.C.). The authors are grateful to the Athinoula A. Martinos Center Radiopharmacy Lab staff for the assistant in radiochemistry. The authors thank Drs. Jianzhong Ai, Kunjie Wang and Liang Zhou for their helpful discussion during the paper preparation and revision.

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Authors

Contributions

C.W. and Z.C. conceived the experiment. C.W., Y.Y., Z.C., X.W., H.W., X.Y., J.Y., T.L., D.R., R.K., C.R. performed research. C. W., X.Y., P.B., T. L., G.Y. analyzed data. C.W., Z.C., X.Y. wrote the paper. C.W., H.C., S.F., R.S., Q.C., H.L., B.X. contributed to writing and revising the manuscript. All authors read, revised if needed and approved the manuscript.

Corresponding authors

Correspondence to Hong Li or Changning Wang.

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Competing interests

Dr. Changing Wang is a co-inventor of CN133 and [11C] Martinostat used in the paper. The other authors declare that they have no conflict of interest.

Ethical approval

The animal study was reviewed and approved by IACUC committee at Massachusetts General Hospital.

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Chen, Z., Wang, X., Yang, X. et al. Imaging assisted evaluation of antitumor efficacy of a new histone deacetylase inhibitor in the castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging 48, 53–66 (2021). https://doi.org/10.1007/s00259-020-04896-7

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Keywords

  • PET
  • HDAC
  • Epigenetics
  • CRPC