Targeted BikDD expression kills androgen-dependent and castration-resistant prostate cancer cells.
Targeted gene therapy is a promising approach for treating prostate cancer after the discovery of prostate cancer-specific promoters such as prostate-specific antigen, rat probasin, and human glandular kallikrein. However, these promoters are androgen dependent, and after castration or androgen ablation therapy, they become much less active or sometimes inactive. Importantly, the disease will inevitably progress from androgen-dependent (ADPC) to castration-resistant prostate cancer (CRPC), at which treatments fail and high mortality ensues. Therefore, it is critical to develop a targeted gene therapy strategy that is effective in both ADPC and CRPC to eradicate recurrent prostate tumors. The human telomerase reverse transcriptase-VP16-Gal4-WPRE integrated systemic amplifier composite (T-VISA) vector we previously developed, which targets transgene expression in ovarian and breast cancer, is also active in prostate cancer. To further improve its effectiveness based on androgen response in ADPC progression, the ARR2 element (two copies of androgen response region from rat probasin promoter) was incorporated into T-VISA to produce AT-VISA. Under androgen analog (R1881) stimulation, the activity of AT-VISA was increased to a level greater than or comparable to the cytomegalovirus promoter in ADPC and CRPC cells, respectively. Importantly, AT-VISA demonstrated little or no expression in normal cells. Systemic administration of AT-VISA-BikDD encapsulated in liposomes repressed prostate tumor growth and prolonged mouse survival in orthotopic animal models as well as in the transgenic adenocarcinoma mouse prostate model, indicating that AT-VISA-BikDD has therapeutic potential to treat ADPC and CRPC safely and effectively in preclinical setting.
Authors' Affiliations: Department of Breast Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; mhung@mdanderson.org xiexm@sysucc.org.cn.
Xiaoming
X
Xie
Authors' Affiliations: Department of Breast Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China.
Yanan
Y
Kong
Authors' Affiliations: Department of Breast Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China.
Hailin
H
Tang
Authors' Affiliations: Department of Breast Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China.
Lu
L
Yang
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University; and Department of Biotechnology, Asia University, Taichung, Taiwan.
Jennifer L
JL
Hsu
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University; and Department of Biotechnology, Asia University, Taichung, Taiwan mhung@mdanderson.org xiexm@sysucc.org.cn.
Mien-Chie
MC
Hung
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics*; D058990:Molecular Targeted Therapy; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000628:therapy; D011471:Prostatic Neoplasms / Q000235:genetics / Q000628:therapy*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics / Q000628:therapy; D011897:Random Allocation; D014162:Transfection; D019076:Transgenes; D023041:Xenograft Model Antitumor Assays
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C096820:BIK protein, human; C111741:Bik protein, mouse; D008565:Membrane Proteins; D024101:Mitochondrial Proteins