Abstract 5923: CD133-targeted oncolytic adenovirus exhibits anti-tumor effect in colorectal cancers, and its combination with irradiation inhibits liver metastasis
Authors: Huang Jing Li , Sato-Dahlman Mizuho , Jacobsen Kari , Yamamoto Masato 
Published: August 2018

Abstract
Colorectal cancer (CRC) is the third most common cancer in the world, and about 50% of patients relapse after treatment. Cancer stem cells (CSCs) have contribution to recurrence, metastasis and chemotherapy resistant of CRC. CD133 (Prominin-1), a member of the transmembrane glycoprotein family, is a marker of CSCs in several cancers including CRC: its expression correlates with recurrence, metastases and chemotherapy resistance, as well as poor prognosis in CRC. It is therefore reasonable to develop a CSC-directed CRC therapeutic strategy by employing CD133as a target molecule. Recently, we have established a method for isolating transductionally-targeted infectivity-selective adenovirus by high-throughput screening. Using this adenovirus library screening system, we isolated the CD133-specific Oncolytic Adenovirus (OAd) and tested the oncolytic activity of CD133-targeted OAd (CD133-OAd) in both in vitro and in vivo, with and without irradiation which induces CD133 expression. The infectivity-selective OAd (ISOAd) with CD133-targeting motif (TYML motif) selectively infected CD133+ CRC cell lines and lysed them efficiently. In the context of modulation of stemness, CD133-OAd inhibited colony formation in vitro. In tumor formation assay in nude mice, treatment with CD133-OAd prior to tumor inoculation inhibited the establishment of tumor of CD133+ CRC cell lines. Intra-tumor (i.t.) administration of CD133-OAd into established subcutaneous tumor exhibited significantly stronger antitumor effect compared to OAd without targeting.
We have reported that the irradiation increases CD133 expression in CRC cells, and the replication of CD133-OAd increased significantly after irradiation. In athymic nude mice, treatment of irradiated cells with CD133-OAd abolished tumor-forming capacity, compared to cells without irradiated and cells treated with radiation alone (5% vs 94% and 5% vs 73% respectively, p&lt;0.0001). When the antitumor effect of CD133-OAd was analyzed on subcutaneously established tumors, treatment with radiation and CD133-OAd significantly reduced tumor growth compared to no treatment and treatment with radiation only (both p&lt;0.0001).
In addition to the effect on the main tumor, CD133-OAd suppressed liver metastasis of CRC. The mice injected with human CRC cells pretreated with CD133-OAd combined with irradiation had significantly lower incidence of liver metastasis compared with the untreated control group or the groups received irradiation or CD133-OAd treatment alone.
Our CD133-targeted ISOAd is effective for cytotoxic killing, reduces tumor formation, and mitigates tumor growth in radiation resistant CRC cells. This targeted OAd therapy may be applicable to address therapeutic resistance and prevent the establishment of recurrent colorectal cancer.
Citation Format: Jing Li Huang, Mizuho Sato-Dahlman, Kari Jacobsen, Masato Yamamoto. CD133-targeted oncolytic adenovirus exhibits anti-tumor effect in colorectal cancers, and its combination with irradiation inhibits liver metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5923.