Tegavivint and the beta-catenin/ALDH Axis in Chemotherapy-Resistant and Metastatic Osteosarcoma
Menée in vitro, ex-vivo et à l'aide de xénogreffes d'ostéosarcome métastatique chimiorésistant sur des modèles murins, cette étude analyse l'efficacité antitumorale du tégavivint, un nouvel inhibiteur de la bêta-caténine et de l'aldéhyde déshydrogénase ALDH1
Background : The Wnt/
β-catenin pathway is closely associated with osteosarcoma (OS) development and metastatic progression. We investigated the antitumor activity of Tegavivint, a novel β-catenin/transducing β-like protein 1 (TBL1) inhibitor, against OS employing in vitro, ex vivo and in vivo cell line and patient-derived xenograft (PDX) models that recapitulate high risk disease. Methods
:
The antitumor efficacy of Tegavivint was evaluated in vitro using established OS and PDX-derived cell lines. Use of an ex vivo 3D pulmonary metastasis assay (PuMA) assessed targeting of β-catenin activity during micro- and macrometastatic development. The in vivo activity of Tegavivint was evaluated using chemoresistant and metastatic OS PDX models. Gene and protein expression were quantified by quantitative RT-PCR (qPCR) or western blot analysis. Bone integrity was determined via microCT. All statistical tests were two-sided. Results
:
Tegavivint exhibited anti-proliferative activity against OS cells in vitro and actively reduced micro- and macrometastatic development ex vivo. Multiple OS PDX tumors (n
= 3), including paired patient primary and lung metastatic tumors with inherent chemoresistance, were suppressed by Tegavivint in vivo. We identified that metastatic lung OS cell lines (n = 2) exhibited increased stem cell signatures, including enhanced concomitant aldehyde dehydrogenase (ALDH1) and
β-catenin expression and downstream activity, which were suppressed by Tegavivint (ALDH1: control group, mean relative mRNA expression =1.00, 95% CI
= 0.68 to 1.22 vs Tegavivint group mean=0.011 ,95%CI=0.0012 to 0.056, p < 0.001;
β-catenin: control group, mean relative mRNA expression =1.00, 95% CI
= 0.71 to 1.36 vs Tegavivint group mean=0.45, 95%CI=0.36 to 0.52, p < 0.001). ALDH1high PDX-derived lung OS cells, which demonstrated enhanced metastatic potential compared to ALDHlow cells in vivo, were sensitive to Tegavivint. Toxicity studies revealed decreased bone density in male Tegavivint-treated mice (n = 4 mice per group). Conclusions : Thus, Tegavivint is a promising therapeutic agent for advanced stages of OS via its targeting of the
β-catenin/ALDH1 axis.