Tegavivint and the β-Catenin/ALDH Axis in Chemotherapy-Resistant and Metastatic Osteosarcoma

Abstract

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/transducin 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 three-dimensional pulmonary metastasis assay 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 Reverse transcription polymerase chain reaction or immunoblot analysis. Bone integrity was determined via microCT. All statistical tests were two-sided. Results Tegavivint exhibited antiproliferative 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% confidence interval [CI] = 0.68 to 1.22 vs Tegavivint group, mean = 0.011, 95% CI = 0.0012 to 0.056, P < .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 < .001). ALDH1high PDX-derived lung OS cells, which demonstrated enhanced metastatic potential compared with 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 Tegavivint is a promising therapeutic agent for advanced stages of OS via its targeting of the β-catenin/ALDH1 axis.

Development and characterization of the novel human osteosarcoma cell line COS-33 with sustained activation of the mTOR pathway

“…Our newly established COS-33 line can provide a complementary or new tool to screen new drugs and to perform a relatively rapid in vitro test on efficacy of combination therapy with rapamycin and other therapeutic agents. For example, we and others have shown that Wnttargeted monotherapies (PRI-724 or tegavivint) can reduce OS growth in vitro or in vivo [31,32]. A combination therapy with inhibitors of both mTOR and Wnt pathways warrants further study, as together they play a key role in cancer metastasis formation and chemoresistance.…”

Long noncoding RNA lncARSR confers resistance to Adriamycin and promotes osteosarcoma progression

“…We investigated the phosphorylation of the frequently hyperactivated kinases in osteosarcoma, including PI3K/ AKT 20 , MAPK/ERK 21 , β-Catenin 22 , and NFκB 23 . The results in Fig.…”

Wnt/β-catenin–activated Ewing sarcoma cells promote the angiogenic switch

“…We propose that, given its role as an upstream regulator of such a critical and broad proangiogenic program, the Wnt/β-catenin axis deserves exploration as a target for adjuvant antiangiogenic therapeutics. Intriguingly, Tegavivint, a new β-catenin inhibitor, was recently reported to inhibit metastasis of osteosarcoma in preclinical models (41). We propose that further study of Wnt/β-catenin inhibition is warranted in the context of Ewing sarcoma, in particular for patients who are at high risk of relapse and metastatic progression.…”