Abstract 6167: Targeting TBL1 with tegavivint promotes anti-tumor and immunomodulatory responses in preclinical models of hepatocellular carcinoma
Authors: Holloway Kimberly R. , Drake Thomas , Bird Thomas , Horrigan Stephen 
Published: April 2023

Background: Hepatocellular cancer (HCC) is the 3rd leading cause of death worldwide with approximately 30% of patients possessing a beta-catenin activating mutation. Despite recent progress in combination with VEGF inhibition, resistance to immune checkpoint inhibitors (ICI) still occurs in a majority of HCC patients. Recent studies suggest that activated beta-catenin regulates both tumor metabolism and immune microenvironment in CTNNB1-mutated HCCs. Transducin beta-like protein 1 (TBL1) is necessary for canonical Wnt -regulated gene transcription by binding nuclear beta-catenin, which prevents its nuclear degradation and promotes recruitment to Wnt-target gene promoters. The TBL1 inhibitor, tegavivint, disrupts the TBL1-beta-catenin complex and inhibits beta catenin signaling. This study measures TBL1 levels and determines tegavivint response within preclinical models of HCC.

Methods: Tegavivint cytotoxicity (GI50) was determined in an HCC cell line panel. Tegavivint activity was measured in a syngeneic mouse model of HCC. Tumors were collected for FACS analysis of cell subpopulations of interest from the vehicle and tegavivint group at study termination. Efficacy and tolerability were measured and evaluated by tumor growth curve and body weight change in treatment groups. Liver and tumor tissue were collected at study termination. TBL1 levels were measured in HCC cells and mouse tumors via western blot and immunohistochemical (IHC) staining.

Results: Tegavivint sensitivity was measured in a of HCC cell line panel resulting in GI50 values ranging from 0.03 μM - 0.20 μM. Correlation between cell sensitivity and activating beta-catenin mutational status was identified and further characterized by measurement of active beta-catenin and TBL1 expression in cell lysates. In an HCC syngeneic mouse model with reported elevated levels of beta-catenin, tegavivint significantly inhibited tumor growth in comparison to vehicle control and demonstrated a significant change in PD-1+ CD3+ and PD-1+ CD4+ subpopulations. TBL1 and active beta-catenin levels were also characterized in tumor mouse tissue relative to tegavivint response.

Conclusion: Tegavivint monotherapy demonstrated antitumor activity in a range of HCC preclinical models. In vitro studies show correlation between tegavivint potency and beta-catenin mutation. In a syngeneic HCC mouse model with elevated beta-catenin, tegavivint reduces tumor growth and induces an activated T-cell subpopulation. We are currently characterizing potential biomarkers of TBL1/beta-catenin activity to identify HCC patient populations that will be most responsive to tegavivint in a clinical setting.

Citation Format: Kimberly R. Holloway, Thomas Drake, Thomas Bird, Stephen Horrigan. Targeting TBL1 with tegavivint promotes anti-tumor and immunomodulatory responses in preclinical models of hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6167.