Abstract 3739: Efficacy of CD46-mediated Ad5/35 chimeric adenoviral gene therapy in colorectal cancers

Abstract

Abstract CD46 is a complement inhibitor membrane cofactor protein and also acts as a receptor for certain pathogenic microbes, including group B denovirus (Ad). Whereas many Ads infect cells through coxsackie-adenovirus receptor (CAR), CAR expression is downregulated in many cancers preventing effective therapeutics of Ad-based therapies. There have been increasing numbers of studies in cancer gene therapy by modification of Ad fiber knobs to utilize more ubiquitously expressed CD46. However, very limited information is available on expression status of CD46 in many cancers. Our tissue microarray data demonstrated that CD46 was generally overexpressed to cancers from prostate and colon. To seek the evidence whether colorectal cancers (CRC) are good target for Ad-mediated gene therapy, chimeric Ad5 vectors that are capable of targeting CD46 were employed. CD46-ovrexpressed cells showed significantly higher response not only to Ad5/35-GFP but to Ad5/35-TK/GCV suicide therapy. While CRC cells express variable levels of CD46, CD46 expression was positively correlated with Ad5/35-mediated GFP fluorescence and cell killing, demonstrating that HCT-116, DLD-1, and Caco-2 cells are highly responsive. Furthermore, injection of Ad5/35-TK/GCV caused significantlyhigher anti-cancer effects in nude mice bearing CD46-overexpressed cancer cells compared to mice with mock cells. Using 80 selected CRC, immunohistochemical studies showed that there is inverted correlation between CD46 expression and clinico-pathological parameters in terms of differentiation, invasion, metastasis, T stage, and survival, suggesting that adenoviral gene therapy may not be as effective to the patients with highly advanced colorectal cancers. Taken altogether, our study demonstrated that CD46 is generally overexpressed in CRC in which group B-based adenoviral gene therapy seems to be suitable approach but careful consideration needs to be given to select cancer types and cancer status for effective cancer gene therapies. Citation Format: Young Seok Cho, Hung Manh Do, Sang-Jin Lee, Silvio Hemmi, Young-Eun Joo, Chaeyong Jung. Efficacy of CD46-mediated Ad5/35 chimeric adenoviral gene therapy in colorectal cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3739.