Abstract B114: Clinical-stage Wnt/β-catenin antagonist peptide ST316, suppresses colorectal cancer tumor growth by promoting BCL9 degradation

Abstract Aberrant activation of the Wnt/β-catenin signaling pathway is a critical driver of tumor progression in colorectal cancer (CRC) but has remained a challenging therapeutic target due to its essential functions in normal tissue homeostasis. General inhibition of the pathway significantly impairs intestinal regeneration and bone maintenance, leading to dose-limiting toxicities. As a key transcriptional co-activator of β-catenin, BCL9 binds to β-catenin and is essential for oncogenic β-catenin-mediated transcription in CRC, but not homeostatic β-catenin activity. Notably, BCL9 and its paralog BCL9L are frequently overexpressed in CRC and sustain aberrant pathway activation even in the absence of external Wnt stimulation. ST316 is a phase 2 clinical-stage Wnt/β-catenin antagonist designed to selectively disrupt the interaction between β-catenin and BCL9/9L. Unlike general inhibition of β-catenin, ST316 spares physiological β-catenin activity and demonstrates a favorable safety profile. Nonclinical studies demonstrate that ST316 promotes BCL9 proteasome-dependent degradation in HCT116 CRC cells that harbor a β-catenin-stabilizing mutation (S45del) and COLO320DM CRC cells that contain an APC truncation mutation (S811X) alongside BCL9 overexpression. Disruption of the β-catenin- BCL9 complex led to downregulation of key oncogenic and metastatic gene signatures in vitro. In vivo, ST316 significantly inhibited tumor growth in an HCT116 xenograft model. Histological analysis confirmed tumor-specific accumulation of ST316 and a marked decrease in nuclear-to-cytoplasmic β-catenin ratio, consistent with in vitro observations. Combination studies in the HCT116 xenograft model utilizing sub-pharmacologic ST316 with Lonsurf (20mg/kg 1x/week) or Folfiri (5 mg/kg 5-FU and 10 mg/kg irinotecan QD) indicated significantly enhanced tumor growth inhibition in the combination setting compared to either single agent, highlighting the potential of ST316 for integration into standard of care regimens. Our nonclinical data demonstrating ST316 mediated disruption of the β-catenin- BCL9 complex, subsequent BCL9 degradation and potent antitumor efficacy in CRC models support its continued development as a promising therapeutic strategy for CRC with enhanced effectiveness when combined with standard-of-care treatments. Citation Format: Lila Ghamsari, Franco Abbate, Rick Ramirez, Siok Leong, Zachary F. Mattes, Mark Koester, Erin Gallagher, Abi Vainstein-Haras, Barry J. Kappel, Jim A. Rotolo. Clinical-stage Wnt/β-catenin antagonist peptide ST316, suppresses colorectal cancer tumor growth by promoting BCL9 degradation [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 B114.