A novel hTERT promoter-driven E1A therapeutic for ovarian cancer.
Currently, an effective gene therapy strategy, which not only retains cancer-specific expression but also limits toxicity, has yet to be developed for ovarian cancer. Mounting reports over the years have shown that human telomerase activity is significantly elevated in cancer cells compared with normal cells. In this study, we evaluated the human telomerase reverse transcriptase (hTERT; T) promoter and showed that it can direct target gene expression preferentially in ovarian cancer cells. However, its promoter (T) activity is much lower than that of cytomegalovirus (CMV), a commonly used nonspecific promoter. To overcome this problem, we have integrated the T promoter into our recently developed VP16-Gal4-WPRE integrated systemic amplifier (VISA) system and dramatically enhanced transgene expression. In addition, to further develop this cancer-specific promoter gene expression system into an applicable therapeutic vector, we expressed E1A (an adenoviral type 5 transcription factor that possesses anticancer properties) through this novel VISA platform. We showed that the T-VISA system specifically targeted the expression of E1A to ovarian cancer cells at a level greater than or comparable with the commonly used CMV promoter, yet remained nearly silent in normal cells, thus making this a suitable gene therapy construct. By using this cancer-specific promoter that limits target gene expression in normal cells/tissues, potential toxicity induced by the CMV promoter would be prevented. More importantly, we showed significant antitumor activity with much less toxicity in animal models through i.v. delivery of T-VISA-E1A:liposomal nanoparticles, suggesting a promising role of T-VISA-E1A for ovarian cancer treatment under a gene therapy setting.
Xie
Xiaoming
X
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, Houston, Texas 77030, USA.
Hsu
Jennifer L
JL
Choi
Min-Gew
MG
Xia
Weiya
W
Yamaguchi
Hirohito
H
Chen
Chun-Te
CT
Trinh
Bon Q
BQ
Lu
Zhen
Z
Ueno
Naoto T
NT
Wolf
Judith K
JK
Bast
Robert C
RC
Hung
Mien-Chie
MC
D017500:Adenovirus E1A Proteins / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D010051:Ovarian Neoplasms / Q000628:therapy*; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
D017500:Adenovirus E1A Proteins; C509186:TERT protein, human; D019098:Telomerase