Abstract B069: Pharmacodynamic evidence of Wnt/β-catenin inhibition by tegavivint, a TBL1-directed transcriptional modulator, in advanced hepatocellular carcinoma: a phase 1 study
TL;DR
An integrated analysis of preclinical and clinical pharmacodynamic data characterizing tegavivint activity establishes TBL1 as a clinically actionable regulator of oncogenic transcription and demonstrates that tegavivint achieves pharmacodynamic modulation of the Wnt pathway through a differentiated downstream mechanism.
Abstract
Wnt/β-catenin pathway activation is a hallmark of many cancers, with Wnt pathway mutations present in ∼40% of advanced HCC (aHCC). TBL1 functions as a central scaffold and chromatin-state regulator within the TCF/β-catenin transcriptional machinery and controls degradation of nuclear b-catenin and is required for assembly of the active transcriptional complex, promoting oncogenic Wnt signaling. Tegavivint is a first-in-class small-molecule inhibitor of TBL1, discovered in a chemical genomics screen as an inhibitor of β-catenin transcriptional activity. Binding of TBL1 by tegavivint disrupts theTBL1/β-catenin complex, resulting in selective degradation of nuclear β-catenin while preserving cytoplasmic and membrane-bound β-catenin functions associated with normal tissue homeostasis. This mechanism inhibits Wnt-driven oncogenicity while avoiding toxicities observed with upstream Wnt inhibitors, representing a novel downstream approach to targeting the Wnt pathway. Tegavivint has been evaluated in a phase 1/2 dose escalation study in advanced hepatocellular carcinoma (NCT05797805) in which the drug was well tolerated and demonstrated clinical responses in a heavily pre-treated population harboring Wnt-pathway mutations. Here, we present an integrated analysis of preclinical and clinical pharmacodynamic (PD) data characterizing tegavivint activity. Tumor mutational status was correlated with clinical status and patient outcomes. Clinical benefit was observed only in patients with mutations in the Wnt pathway genes, CTNNB1, AXIN1, APC, and CREBBP. Transcriptional signatures of tegavivint were analyzed by RNA-seq, demonstrating downregulation of Wnt/β-catenin target genes and induction of apoptotic pathways, consistent with transcriptional reprogramming via TBL1-mediated inhibition of β-catenin activity. Clinical pharmacodynamic effects were evaluated by IHC of paired tumor biopsies, which revealed reductions in active β-catenin following treatment, supporting on-target activity. Serum biomarker analysis showed modulation of Wnt-regulated proteins, including decreases in DKK1, FGF-2, MMP-1, PDGF-AA, and VEGF-A. These PD changes mirror those observed in desmoid tumor patients treated with tegavivint (NCT03459469), indicating mechanism-based biomarker changes across tumor types. The concordance of transcriptional, tissue-based, and circulating biomarkers provides compelling evidence of on-target inhibition of the TBL1/β-catenin transcriptional complex. Collectively, these findings establish TBL1 as a clinically actionable regulator of oncogenic transcription and demonstrate that tegavivint achieves pharmacodynamic modulation of the Wnt pathway through a differentiated downstream mechanism. This approach represents a novel strategy for targeting Wnt-driven cancers. Aundrietta D. Duncan, Elena Ramirez, Julissa Simmons, Mahtab Youseffi, David D. Stenehjem, Stephen K. Horrigan. Pharmacodynamic evidence of Wnt/β-catenin inhibition by tegavivint, a TBL1-directed transcriptional modulator, in advanced hepatocellular carcinoma: a phase 1 study [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B069.