Targeting CA-125 Transcription by Development of a Conditionally Replicative Adenovirus for Ovarian Cancer Treatment

• Main Authors: Er Yue, Guangchao Yang, Yuanfei Yao, Guangyu Wang, Atish Mohanty, Fang Fan, Ling Zhao, Yanqiao Zhang, Tamara Mirzapoiazova, Tonya C. Walser, Lorna Rodriguez-Rodriguez, Yuman Fong, Ravi Salgia, Edward Wenge Wang
• Format: Article
• Language: English
• Published: MDPI AG 2021-08-01
• Series: Cancers
• Subjects: conditionally replicative oncolytic adenovirus; ovarian cancer; CA-125; <i>MUC16</i>; transcription; targeted therapy
• Online Access: https://www.mdpi.com/2072-6694/13/17/4265

CA-125, encoded by the <i>MUC16</i> gene, is highly expressed in most ovarian cancer cells and thus serves as a tumor marker for monitoring disease progression or treatment response in ovarian cancer patients. However, targeting <i>MUC16</i>/CA-125 for ovarian cancer treatment has not been successful to date. In the current study, we performed multiple steps of high-fidelity PCR and obtained a 5 kb DNA fragment upstream of the human <i>MUC16</i> gene. Reporter assays indicate that this DNA fragment possesses transactivation activity in CA-125-high cancer cells, but not in CA-125-low cancer cells, indicating that the DNA fragment contains the transactivation region that controls specific expression of the <i>MUC16</i> gene in ovarian cancer cells. We further refined the promoter and found a 1040 bp fragment with similar transcriptional activity and specificity. We used this refined <i>MUC16</i> promoter to replace the E1A promoter in the adenovirus type 5 genome DNA, where E1A is an essential gene for adenovirus replication. We then generated a conditionally replicative oncolytic adenovirus (CRAd) that replicates in and lyses CA-125-high cancer cells, but not CA-125-low or -negative cancer cells. In vivo studies showed that intraperitoneal virus injection prolonged the survival of NSG mice inoculated intraperitoneally (ip) with selected ovarian cancer cell lines. Furthermore, the CRAd replicates in and lyses primary ovarian cancer cells, but not normal cells, collected from ovarian cancer patients. Collectively, these data indicate that targeting <i>MUC16</i> transactivation utilizing CRAd is a feasible approach for ovarian cancer treatment that warrants further investigation.