成像辅助评估一种新型组蛋白去乙酰化酶抑制剂在去势抵抗性前列腺癌中的抗肿瘤疗效

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

作者信息

Chen Zude, Wang Xiashuang, Yang Xiaoshuang, Xu Yulong, Yang Yu, Wang Hao, Li Tao, Bai Ping, Yuan Gengyang, Chen Huabiao, Yang Jing, Fiedler Stephanie A, Striar Robin, Bernales Daniela R, Koegel Robert E, Cao Qi, Ran Chongzhao, Xiang Bo, Li Hong, Wang Changning

机构信息

Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Guoxue Xiang 37, Chengdu, 610041, China.

Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.

出版信息

Eur J Nucl Med Mol Imaging. 2021 Jan;48(1):53-66. doi: 10.1007/s00259-020-04896-7. Epub 2020 Jun 26.

DOI:10.1007/s00259-020-04896-7

PMID:32592040

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 [C] Martinostat and [F] 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. [C] 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, [C] 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.

摘要

目的

去势抵抗性前列腺癌（CRPC）是男性最常见的死亡原因。HDAC抑制剂的有效性已在临床前模型中得到证实，但在临床研究中尚未得到证实，这可能是由于HDACI在前列腺癌细胞中积累无效。这项工作的目的是评估新型HDACI（CN133）对CRPC异种移植模型和22Rv1细胞的影响，并开发PET/CT成像方法来检测CN133对这种癌症的治疗效果。

方法

我们设计并进行了研究，以比较CN133与SAHA对22Rv1异种移植模型和22Rv1细胞的影响。使用[C]Martinostat和[F]FDG进行PET/CT成像，我们对接受安慰剂和CN133（1mg/kg）21天治疗前后的22Rv1异种移植小鼠进行成像，并测量治疗前和治疗后成像的摄取量。通过qPCR、western blot和ChIP-qPCR研究CN133的抗肿瘤机制。

结果

我们的数据显示，与安慰剂相比，CN133治疗使肿瘤体积减少了50%，在这个临床前模型中比SAHA治疗更有效。[C]Martinostat PET成像可以识别前列腺癌的早期病变，也可用于监测CN133在CRPC中的治疗效果。使用药理学方法，我们证明在细胞增殖、侵袭和迁移实验中，CN133的效果比SAHA治疗高出近100倍。CN133的抗肿瘤机制是由于HDAC 2和3蛋白表达降低，从而抑制了AR信号通路活性。