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

Genetic and epigenetic alterations in the Wnt signaling pathway leading to constitutive activation of the driver oncogene β-catenin occur in at least 20% of all human cancers. Pharmacologic suppression of aberrant β-catenin transcriptional activity through direct targeting of its downstream effectors has proven elusive despite decades of effort. We developed conformationally hyperstabilized α-helical peptides – which we refer to as Helicons – that directly bind β-catenin with sub-nanomolar affinity and exhibit good cytosolic exposure. COLO320DM is a human colorectal cancer line with an activated Wnt/ β-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/β-catenin and MYC-related gene sets in tumors, consistent with the mechanism of action of the Helicon as a β-catenin/TCF interaction inhibitor