(P 21) EXAMINING THE THERAPEUTIC EFFECT OF TBL1/ β-CATENIN TARGETED COMBINATION THERAPIES ON METASTATIC OSTEOSARCOMA

Objective: Osteosarcoma (OS) is the most prevalent pediatric bone cancer and treatment outcomes and survival rates have not changed in decades. Patients with metastatic or relapsed/refractory disease face five-year survival rates below 30%, with no salvage therapies available after standard of care failure. Dysregulation of the Wnt signaling pathway, particularly through TBL1-mediated nuclear translocation of β-catenin and transcription of target genes promoting metastasis, correlates with poor prognosis in OS. Tegavivint, a novel first-in-class small molecule inhibitor targeting TBL1XR1, has shown promising antitumor activity in preclinical models and is currently in clinical trial. However, resistance to Tegavivint monotherapy necessitates identification of effective combination approaches.

Methods: A high-throughput drug screen was performed on high-risk patient-derived xenograft (PDX) OS cell lines using Tegavivint to identify synergistic agents. IC50 values were determined for Tegavivint and lead candidates, Ponatinib (multi-tyrosine kinase inhibitor) and Vorinostat (histone deacetylase inhibitor), both as monotherapies and in synergy assays. Cell viability was assessed in 2D and 3D culture systems. In vivo efficacy of Tegavivint was examined using two high MYC-expressing PDX models in immunodeficient NOD scid gamma (NSG) mice.

Results: Tegavivint and the candidate drugs demonstrated IC50 values below 1.5μM, indicating high sensitivity. Combination treatments exhibited additive and synergistic effects, reducing cell viability at lower Tegavivint concentrations. In 3D spheroids, Tegavivint treatment decreased ATP levels without visible spheroid size reduction. In vivo studies revealed decreased tumor volume in both high-MYC models treated with Tegavivint monotherapy, with one study showing complete inhibition of metastasis.

Conclusion: Targeting the TBL1/β-catenin axis with Tegavivint in combination with Ponatinib or Vorinostat may offer a more effective treatment strategy for high-risk OS. These combinations show promise in overcoming drug resistance and improving outcomes for patients with limited options.