Abstract C133: Distinct aspects of β-catenin biology drive multiple biologically rational FOG-001 combinations for MSS colorectal cancer

Abstract Genetic and epigenetic alterations in the Wnt signaling pathway are common with ∼15% of all cancers carrying Wnt pathway activating mutations (WPAMs). These alterations lead to the constitutive activation of the driver oncogene β-catenin and its nuclear translocation by neutralizing the β-catenin degradation complex normally active in wild-type cells. Activated nuclear β-catenin forms a complex with TCF/LEF (T-cell factor/lymphoid enhancer binding factor) and drives the transcription of genes essential for cancer cell proliferation and survival. We have discovered and developed conformationally stabilized α-helical peptides (Helicons) that bind directly to β-catenin with picomolar affinity and high selectivity and block its interaction with TCF transcription factors. FOG-001 is a Helicon™ peptide that competitively inhibits the interaction between β-catenin and TCF transcription factors in the Wnt-signaling pathway and has entered Phase 1/2 clinical trials (NCT05919264). Clinical data to date suggests safety, β-catenin target engagement and efficacy in patients. In order to provide additional preclinical data to aid the advancement of FOG-001 in patients with MSS CRC, we have explored the use of FOG-001 in combination with multiple approved and novel experimental agents based on multiple aspects of β-catenin biology either previously published or observed from paired baseline and on-treatment tumor biopsies from CRC patients in our ongoing clinical trial. We have are executing rationally designed combination studies to assess both tolerability and efficacy. Biologically distinct molecular hypotheses drove the selection of combination studies using FOG-001 together with a chemotherapeutic agent (5-FU), immune checkpoint inhibitor (anti-PD1), anti-VEGF and RAS pathway inhibitors. In all cases FOG-001 was well tolerated in combination with these agents. FOG-001 down-regulates both the tumor stemness phenotype and DNA repair machinery in patients and preclinical models. Consistent with these effects, combination of FOG-001 5-FU leads to strong additive anti-tumor activity in CRC PDX models. Combination of FOG-001 with anti-PD1 enhanced immune checkpoint therapy activity in the MC38 CRC allograft model only when used in the context of activated β-catenin. This data is consistent with the finding that FOG-001 induces upregulation of the tumor inflammation signature that includes IFN-g, PD-L1/2 and CXCL9. Finally, FOG-001 leads to upregulation of RAS pathway signaling in paired patient tumor biopsies and preclinical models. This finding is consistent with data shared by multiple independent groups showing compensatory crosstalk of these two pathways in the presence of single agents including Porcupine inhibitors. RAS pathway inhibition in combination with FOG-001 resulted in improved tumor growth inhibition when compared to single agent activities in CRC PDX models. Several of these combination approaches are now being tested in ongoing clinical studies of FOG-001. Citation Format: Brandon Nicolay, Pratik Chopade, Xinwei Han, Ziyang Yu, Kelsey Barrasso, Mandana Abbassi, Amber Wells, YaGuang Si, Erica Visness, Jack Russella Pollard, Brian White, John McGee, Greg Verdine, Keith Orford, Marie Nguyen, Mathai Mammen, Jonathan Hurov. Distinct aspects of β-catenin biology drive multiple biologically rational FOG-001 combinations for MSS colorectal cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C133.