RNA-seq study of a helicon peptide targeting ß-Catenin/TCF transcription factor [in vivo]

Genetic and epigenetic alterations in the Wnt signaling pathway leading to constitutive activation of the driver oncogene ß-catenin occur in at least 20% of all human cancers. Pharmacologic suppression of aberrant ß-catenin transcriptional activity through direct targeting of its downstream effectors has proven elusive despite decades of effort. We developed conformationally hyperstabilized a-helical peptides – which we refer to as Helicons – that directly bind ß-catenin with sub-nanomolar affinity and exhibit good cytosolic exposure. COLO320DM is a human colorectal cancer line with an activated Wnt/ ß-catenin pathway driven by an APC mutation. Here, we characterize the global effects of Helicon treatment on COLO320DM xenograft tumor by whole-transcriptome RNA sequencing. Forty-eight hours after a single dose of Helicon 4 at 30 mg/kg, treatment significantly down-regulates many Wnt/ß-catenin and MYC-related gene sets in tumors, consistent with the mechanism of action of the Helicon as a ß-catenin/TCF interaction inhibitor Overall design: COLO320DM xenograft tumor model was prepared by Avastus Preclinical Services. Mice were randomized and adminstrated when the average tumor size is about 300mm3