以JCVLP攜帶PSA為promoter的自殺基因可以有效抑制mCRPC  

沈正煌¹張德卿² 方瓊瑤³ 王梅林⁴ 林勉君¹ 周志傑²    

1嘉義基督教醫院泌尿外科; 2國立中正大學分子生物研究所3嘉義基督教醫院醫學研究部4中山醫學大學醫學系微生物及免疫學科 

mCRPC could be effective suppressed by using

JC polyomavirus-like particles packaged with a PSA promoter

driven-suicide gene

Cheng-Huang Shen^1, Deching Chang² Chiung-Yao Fang³Meilin Wang⁴  Mien-Chun Lin¹ Chih-Chieh Chou²  

1Department of Urology, Dimension Medical Foundation Chiayi Christian 2 Institute of Molecular Biology, National Chung Cheng University, Chiayi, Taiwan3 Department of Medical Research, Dimension Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan 4Department of Microbiology and Immunology School of Medicine, Chung-Shan.Taichung, Taiwan

Purpose:

Prostate cancer is the second most common cancer in men globally. Prostate cancer patients at advanced stages are usually treated with androgen deprivation therapy (ADT). However, with disease progression, it often becomes the incurable castration-resistant prostate cancer (CRPC). JC polyomavirus (JCPyV) is a human DNA virus. Its virus-like particles (VLPs) exhibit similar tropism to native virions and they are capable of delivering exogenous genes to the target cells for expression. JCPyV has been detected in prostate cells; therefore, prostate cancer cells may be

susceptible to JCPyV infection and JCPyV VLPs may be used as a vector for gene therapy against prostate cancer.

Materials and Methods:

We conducted 3 different mouse models to confirm the effectiveness of JC VLP as a vector to carry pPSAtk (PSAtk-VLPs) for transcriptional targeting in prostate cancer cells.

1.     JC polyomavirus can deliver exogenous genes to prostate cancer cells for expression. JCPyV VLPs packaging pPSAtk (PSAtk-VLPs) possess the ability to transcriptionally target and selectively induce cytotoxicity in prostate cancer cells in vitro and in vivo, as pPSAtk can only express the thymidine kinase gene, a suicide gene, in androgen receptor-positive cells.

2.     PSAtk-VLPs effectively inhibited the growth of prostate cancer cells that had metastasized to the bone in the metastatic animal model and showed a higher effectiveness than hormone therapy in this animal model study

3.     To confirm the efficacy of suppression of orthotopic PCa growth and metastasis by PSAtk-VLPs. We established an iRFP stable expression CRPC. Systemic PSAtk-VLPs administration with GCV and subsequent FMT scanning facilitated real-time observation of the suppressed growth in mouse iRFP CRPC orthotopic tumors.

Results:

1 .PSAtk-VLPs could only kill AR-positive CRPC 22Rv1 cells in vitro and inhibit the growth of tumor nodules in the xenograft mouse model.

2. PSAtk-VLPs effectively inhibited the growth of prostate cancer cells that had metastasized to the bone in the metastatic animal model. In addition, PSAtk-VLPs showed a higher effectiveness than hormone therapy in this animal model study

3.Systemic PSAtk-VLPs administration with GCV and subsequent FMT scanning facilitated real-time observation of the suppressed growth in mouse iRFP CRPC orthotopic tumors, which further revealed a notable metastasis rate reduction. Systemic PSAtk-VLPs and GCV administration effectively inhibited orthotopic prostate cancer growth and metastasis.

Conclusion:

Conclusively, systemically administered JCPyV VLPs carrying a tissue-specific promoter, JCPyV VLPs can protect genes within the bloodstream to be specifically expressed in specific organs and these results suggest that PSAtk-VLPs may serve as a treatment option for mCRPC therapy in the future.