Abstract 716: ASPH_0047: a potent and selective antisense oligonucleotide-targeting transforming growth factor beta 2 (TGF-β2)

Transforming growth factor beta (TGF-β) is a key member of a large family of cytokines, including bone morphogenetic protein (BMP), nodals, activins and others, which play critical, pleiotropic roles in the pathophysiology of various human diseases, such as cancer, inflammation, autoimmune disease, and cirrhosis/fibrosis. In particular, the different TGF-β isoforms (TGF-β1, -β2, and -β3, encoded by different genes but sharing high sequence and structure homology) are overexpressed in many human tumors. Correlations between TGF-β expression, cancer stage and clinical parameters have been reported and linked to poor clinical outcome. TGF-β has been associated with a wide range of tumor-promoting processes, including tumor cell invasion and migration, angiogenesis, immunosuppression, as well as tumor stem cell maintenance and protection. Therefore, blocking the TGF-β signaling pathway via inhibition of TGF-β expression appears as an attractive therapeutic intervention in Oncology. We have previously reported the rational design and preliminary outcome of an extensive discovery program for identification of antisense oligodeoxynucleotides targeting the various TGF-β isoforms. We present here ASPH_0047, a 17-mer LNA-modified gapmer based on the sequence of the human TGF-β2 mRNA, as novel preclinical development candidate. ASPH_0047 shows potent and selective target downregulation (mRNA and protein) in various cell-based assays. Preliminary preclinical biodistribution studies in rodent point at tissue penetration in expected target organs (e.g., liver, kidney, spleen) and accumulation in tumor tissue consistent with observed target downregulation and efficacy in relevant in vivo experimental antitumor models. Key pharmacology properties and preclinical features of ASPH_0047 supporting rapid advancement to clinical development will be presented. Citation Format: Katja Wosikowski, Frank Jaschinski, Hanna Kohonen, Stephan Braun, Eugen Leo, Michel Janicot. ASPH_0047: a potent and selective antisense oligonucleotide-targeting transforming growth factor beta 2 (TGF-β2). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 716. doi:10.1158/1538-7445.AM2014-716