Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide, with the incidence increasing significantly in the West. The prognosis for HCC is poor, and the limited success of the standard of care drug sorafenib along with recent Phase III failures of other treatments underscores the need for novel HCC therapeutics. Intrahepatic cholangiocarcinoma (IHCC), the second most frequent primary liver tumor, is also associated with poor prognosis. Colorectal cancer (CRC) is the fourth most common cause of cancer deaths throughout the world. Despite the recent advances in treatment strategies, post-operative prognosis of CRC patients with liver, lymph node, or distant organ metastasis remains poor, underscoring the need for novel therapeutics. The Wnt signaling pathway is commonly activated in all three of these diseases, and this is thought to be a causal event in their tumorigenesis. In this application we continue the development of a lipid nanoparticle (LNP) platform, using an RNAi- based payload that targets a key component of the Wnt signaling pathway, beta-catenin (CTNNB1). Beta- catenin, which is well-validated as an oncology target with high clinical mutation occurrence and experimental evidence, is considered undruggable via conventional approaches. However, by enabling pharmacological intervention at the mRNA level as opposed to the protein level, our RNAi approach inhibits synthesis of beta- catenin protein and causes tumor growth inhibition in preclinical models. Building upon the successful development of our LNP-encapsulated Dicer Substrate siRNA (siRNA) targeting the MYC oncogene, we sought to improve LNP formulations and demonstrate effectiveness with a second payload, delivering CTNNB1 to tumors. Our in-house experience with developing and cGMP manufacturing LNP-formulated therapeutics, as well as the similarities to approved liposomal oncology products, led us to generate and characterize LNPs with unique chemical compositions carrying novel CTNNB1 DsiRNA payloads. Here we demonstrate dramatic improvement in efficacy and other properties of tumor-centric LNPs. Through this work, a formulated LNP-CTNNB1 DsiRNA candidate that is suitable for preclinical development and IND submission has been identified. In this application we seek to perform IND enabling studies, process development, and GMP manufacture of this candidate, as well as perform translational research to guide the clinical research strategy. The ultimate goal is to develop a Lipid Nanoparticle formulation that can be used to deliver a broad range of siRNA payloads, with a tolerability profile to enable treatment of patients with a spectrum of disease states and prior therapeutic histories.
| Ganesh, Shanthi; Shui, Xue; Craig, Kevin P et al. (2018) ?-Catenin mRNA Silencing and MEK Inhibition Display Synergistic Efficacy in Preclinical Tumor Models. Mol Cancer Ther 17:544-553 |
| Tao, Junyan; Zhang, Rong; Singh, Sucha et al. (2017) Targeting ?-catenin in hepatocellular cancers induced by coexpression of mutant ?-catenin and K-Ras in mice. Hepatology 65:1581-1599 |
| Ganesh, Shanthi; Koser, Martin L; Cyr, Wendy A et al. (2016) Direct Pharmacological Inhibition of ?-Catenin by RNA Interference in Tumors of Diverse Origin. Mol Cancer Ther 15:2143-54 |
