Abstract 1153: Targeting CA125 transcription for ovarian cancer treatment

Abstract

CA125 coded by MUC16 gene is highly expressed in most ovarian cancer cells and serves as a tumor marker to monitor disease progression or response to treatment of ovarian cancer patients. However, targeting CA125 for ovarian cancer treatment has never been successful. We performed multiple steps of high-fidelity PCR and obtained a 4.2kb DNA fragment upstream of the human MUC16 gene, which included a region upstream from the transcription start site (TSS) and a region downstream from the TSS that contains both the 59 untranslated region and the first 136bp of the open reading frame. Reporter assays showed that this DNA fragment possesses strong transactivation activity in CA125-high cancer cells, but not in CA125-low cells, indicating that the DNA fragment we cloned contains the transactivation region that controls specific expression of MUC16 gene in ovarian cancer cells. We further refined the promoter and found a 1040bp fragment with similar transcriptional activity and specificity. We used this refined MUC16 promoter to replace the E1A promoter in the adenovirus type 5 genome DNA to control expression of E1A, an essential gene for adenovirus replication, and successfully generated a conditionally replication-competent adenovirus that can replicate in and lyse CA125-high-expressing cancer cells, including CAOV3, Kuramochi, MADH2774, OVCAR3, OVCAR4, and TOV112D cells, but not in CA125-low or -negative cancer cell lines, such as A2780, OVCAR5, PEO4, or SKOV3 cells. In vivo studies showed that intraperitoneal virus injection prolonged survival of NSG mice inoculated intraperitoneally with MADH2774 cells. Preliminary experiment showed that a mouse ovarian cancer cell line, ID8, infected with the virus might elicit a protective immune response to rechallenge of parental cancer cells. Our data indicate that targeting MUC16 transactivation for ovarian cancer treatment by conditionally replicative adenovirus development is feasible and practical. Citation Format: Er Yue, Guangchao Yang, Yuanfei Yao, Guangyu Wang, Yanqiao Zhang, Edward W. Wang. Targeting CA125 transcription for ovarian cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1153.