Abstract LB-317: Potent in vivo pharmacology of AZD9150, a next-generation, constrained ethyl-modified antisense oligonucleotide targeting STAT3 in multiple preclinical cancer models.

Abstract

Abstract Next generation sequencing technologies have greatly expanded our understanding of cancer genomes, epigenomes and transcriptomes. This knowledge, however, has not yet been effectively translated into improved cancer therapeutics, partly due to the inability of available therapeutic modalities to target the most promising cancer driver pathways. In contrast to other therapeutic approaches, the druggable universe is not limited with antisense technology as inhibitors can be rationally designed based on sequence information alone. Recent human clinical data has demonstrated potent activity of systemically-administered, unformulated, antisense oligonucleotides (ASOs) when targeted to liver expressed genes. However, robust activity in extra-heptatic tissues and tumors has been limited with existing ASO chemistries. Here we evaluate the activity of high affinity next generation (constrained ethyl) ASOs in extrahepatic tissues and tumors of multiple preclinical cancer models including spontaneous tumors, human tumor xenografts and several primary patient-derived xenograft models. As a test case we employed next generation ASOs to inhibit the difficult to drug transcription factor STAT3. ASOs targeting mouse STAT3 sequences and the human-specific STAT3 ASO (AZD9150) demonstrate potent and selective inhibition of target RNA and protein levels in tumors and tumor-associated stromal cells of a broad range of cancer models, resulting in strong antitumor activity in several models. These findings suggest that next generation ASO technology is now poised to become a key therapeutic modality to bridge the pharmacogenomic divide in cancer drug discovery. The STAT3 ASO inhibitor, AZD9150 is currently in human clinical studies including patients with lymphomas. Citation Format: Youngsoo Kim, Jeff Hsu, Tianyuan Zhou, Nancy Zhang, Richard Woessner, Murali VP Nadella, Deborah Lawson, Corinne Reimer, Guobin He, Joanna Schmidt, Xiaokun Xiao, Sarah Greenlee, Gourab Bhattacharjee, Gene Hung, Brett P. Monia, A. Robert MacLeod. Potent in vivo pharmacology of AZD9150, a next-generation, constrained ethyl-modified antisense oligonucleotide targeting STAT3 in multiple preclinical cancer models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-317. doi:10.1158/1538-7445.AM2013-LB-317