Abstract 4533: Serum protein changes in patients with desmoid tumors responsive to the TBL1 inhibitor, tegavivint

Abstract

Abstract Background: A Phase 1/2 clinical trial (NCT03459469) of the small molecule tegavivint in patients with desmoid tumors (DTs), demonstrated drug safety and tolerability with evidence of clinical activity. Transducin Beta-Like Protein 1 (TBL1) is a necessary co-activator for beta-catenin’s oncogenic activity. Wnt-activation promotes formation of a TBL1: beta-catenin complex that protects β-catenin from degradation in the nucleus and promotes Wnt-target gene activation. Tegavivint binds TBL1 preventing the interaction with beta-catenin, which results in nuclear beta-catenin degradation and inhibition of downstream transcription. For patients whose desmoid tumors responded to tegavivint we assayed changes in serum-based proteins, selected based on their cancer-related function and dysregulation by aberrant Wnt/beta-catenin signaling, to potentially identify suitable biomarkers that may be useful in future studies. Methods: Whole blood and tumor tissue was collected from desmoid patients before and after administration of tegavivint at dose levels ranging from 1 to 5 mg/kg administered via a 4-hour intravenous (IV) infusion on days 1, 8, and 15 of a 28-day cycle. Collection timepoints were pre-dose and up 1 week (wk.) following the start of the infusion. Secreted protein levels were profiled in the serum using Luminex multiplex technology. Changes in protein levels were compared to the tegavivint pharmacokinetic (PK) profiles. Tissue samples were analyzed for gene expression changes. Results: Preliminary analyses demonstrated that the majority of tegavivint treated patients with an objective response to tegavivint showed a consistent and expected pattern in serum levels of known Wnt/beta-catenin regulated proteins. Decreases in levels of DKK1, FGF-2, MMP-1, PDGF-AA and VEGF-A and an increase in CCL5 levels were observed. In treated patient serum, protein level changes were detected as early as 2 hours (h) following the start of infusion and continued to progress in the predicted direction at 24 h. At the 5 mg/kg dose, all selected biomarkers remained decreased (or in the case of CCL5, increased) during the dosing interval, with a tegavivint half-life of 48.6 h and Cmin (trough value) 1 wk. post treatment above in vitro IC50 values. Gene expression changes were found in tumor tissue in comparing pre- to post-tegavivint treatment. Conclusion: A panel of beta-catenin regulated proteins and transcripts were identified as candidate pharmacodynamic biomarkers in patients whose desmoid tumor responded to tegavivint. Alterations in these serum proteins continued throughout the dosing interval and, for several proteins, a potential dose response correlation was observed. Further characterization of the relationship between tegavivint plasma levels, serum biomarkers, transcriptional changes and clinical responses in additional patients and time points will be presented. Citation Format: Stephen Horrigan, Kimberly R. Holloway, David Stenehjem, Casey Cunningham. Serum protein changes in patients with desmoid tumors responsive to the TBL1 inhibitor, tegavivint. [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 4533.