Abstract 934: Identification of a GPC3 specific RNA aptamer and its use in cell specific targeted killing of GPC3 expressing tumors

Abstract

Abstract Aptamers are short oligonucleotides that recognize specific molecular targets due to their folded three-dimensional structures. Aptamers are generated against a target molecule using a process called SELEX. This method allows the in vitro evolution of nucleic acid molecules with highly specific binding to target molecules. Here we describe a nuclease stable, fully modified 2'OMethyl aptamer that recognizes Glypican-3 (GPC3) with high affinity and specificity. GPC3 is a heparan sulfate proteoglycan and cell surface oncofetal protein which is highly expressed on a variety of liver cancers, but not in healthy adult tissues. A conjugate comprising a GPC3 aptamer and Drug Maytansinoid (DM1), a membrane-permeable inhibitor of tubulin which can prevent cell division, is used to specifically target GPC3 expressing cells in vitro and in vivo. The aptamer-drug conjugate (GRX54) is capable of selectively killing a variety of GPC3 expressing liver cells in vitro and has significantly less toxicity in cells not expressing GPC3. The anti-tumor effect of GRX54 was tested in several tumor xenograft mouse models: Hep3B xenograft, Balb/c nude mice and NCI-H446 xenograft, Balb/c nude mice. GRX54 was administered at different doses via intraperitoneal injection (IP). For each group, mice were administered with vehicle or GRX54 once a day (QD) for 3, 5 or 7 days. Tumor weight and growth were measured. An anti-cancer drug Sorafenib Tosylate (30mg/kg, oral administration, once a day - Hep3B xenograft mouse model) or irinotecan (40mg/kg, i.p. twice a day for 4 days - NCI-H446 xenograft mouse model) were used as positive controls. GRX54 decreases Hep3B tumor volume in a Balb/c nude mouse xenograft model by ~30-45% depending on treatment schedule and NCI-H446 tumor volume by ~45-90% depending on treatment schedule. Together, our data show that GRX54 is a novel GPC3-targeting molecule capable of reducing tumor size with IP injection. Citation Format: Kristin M. Thompson, Christina McGuire, Jin Yuan, Aaron Ball, Justin Sonberg, Yuxun Wang, Shuhao Zhu. Identification of a GPC3 specific RNA aptamer and its use in cell specific targeted killing of GPC3 expressing tumors [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 934.