Abstract 3533: Systemic delivery of CTNNB1 Dicer-substrate siRNAs (DsiRNAs) leads to efficient oncogene silencing in diverse tumor types of extra hepatic origin
Authors: Ganesh Shanthi , Ying Bo , Koser Martin , Cyr Wendy , Chopda Girish , Dudek Hank , Lai Cheng , Wang Weimin , Brown Bob , Abrams Marc T. 
Published: August 2015

The β-catenin/Wnt pathway is consistently activated in human tumors, including &gt;50% of hepatocellular carcinomas (HCC) and &gt;80% of colorectal cancers (CRC). This is often caused directly by tumorigenic mutations in the CTNNB1 gene, which encodes β-catenin protein. Preclinical evidence in genetic cancer models strongly suggests that inhibiting β-catenin function would yield therapeutic benefit to many cancer patients. Since β-catenin is very challenging to target via conventional modalities, no efficacious therapy targeting β-catenin has emerged despite decades of research. RNA interference (RNAi) technology has enabled the inhibition of previously undruggable targets at the mRNA level and has advanced to late-stage clinical development for several indications. However, the clinical application of RNAi has proven to be most successful for targeting mRNAs in the normal liver, and challenges remain with developing formulations that efficiently deliver to extra-hepatic tumors. Here we describe the development and characterization of a platform to treat tumors of diverse primary tissue origin and metastatic location with CTNNB1-targeting DsiRNA. Tumor types tested included xenograft tumors of colorectal origin (CRC), experimental melanoma lung metastases, and difficult-to-transfect leukemia cells which have infiltrated the spleen. In addition to strong silencing of CTNNB1 mRNA, &gt;75% inhibition of tumor growth was observed for a CRC xenograft model. This was achieved by formulating the DisRNA payload in a lipid nanoparticle (LNP) platform termed EnCore (because of its specific Envelope and Core lipid components). EnCore activity against multiple tumors was further improved by optimizing critical cationic lipid and PEG-lipid components. Importantly, studies in knockout mice demonstrate that in vivo tumor activity is independent of Apolipoprotein E, which has been widely described as an essential endogenous ligand for internalization of LNPs into hepatocytes. This strongly suggests that Encore-mediated delivery to tumors in vivo is independent of the ApoE/LDLR system. DCR-MYC, an EnCore-delivered DsiRNA targeting MYC mRNA, is currently in Phase I clinical trials. Further evaluation of LNP-delivered DsiRNAs in PK/PD and efficacy models, including PDX and GEMM will guide a clinical development strategy for CTNNB1 DsiRNA.

Citation Format: Shanthi Ganesh, Bo Ying, Martin Koser, Wendy Cyr, Girish Chopda, Hank Dudek, Cheng Lai, Weimin Wang, Bob Brown, Marc T. Abrams. Systemic delivery of CTNNB1 Dicer-substrate siRNAs (DsiRNAs) leads to efficient oncogene silencing in diverse tumor types of extra hepatic origin. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3533. doi:10.1158/1538-7445.AM2015-3533