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

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. 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. 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). Tegavivint is a promising therapeutic agent for advanced stages of OS via its targeting of the β-catenin/ALDH1 axis.

Nomura M ，Rainusso N ，Lee YC ，Dawson B ，Coarfa C ，Han R ，Larson JL ，Shuck R ，Kurenbekova L ，Yustein JT ... -  《-》

SPARCL1 suppresses osteosarcoma metastasis and recruits macrophages by activation of canonical WNT/β-catenin signaling through stabilization of the WNT-receptor complex.

Zhao SJ ，Jiang YQ ，Xu NW ，Li Q ，Zhang Q ，Wang SY ，Li J ，Wang YH ，Zhang YL ，Jiang SH ，Wang YJ ，Huang YJ ，Zhang XX ，Tian GA ，Zhang CC ，Lv YY ，Dai M ，Liu F ，Zhang R ，Zhou D ，Zhang ZG ... -  《-》

Inhibition of oleandrin on the proliferation show and invasion of osteosarcoma cells in vitro by suppressing Wnt/β-catenin signaling pathway.

Ma Y ，Zhu B ，Liu X ，Yu H ，Yong L ，Liu X ，Shao J ，Liu Z ... -  《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》

High Expression of XRCC6 Promotes Human Osteosarcoma Cell Proliferation through the β-Catenin/Wnt Signaling Pathway and Is Associated with Poor Prognosis.

Zhu B ，Cheng D ，Li S ，Zhou S ，Yang Q ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

Notch pathway inhibition using DAPT, a γ-secretase inhibitor (GSI), enhances the antitumor effect of cisplatin in resistant osteosarcoma.

Overcoming platinum drug resistance represents a major clinical challenge in osteosarcoma (OS) treatment. The high rates and patterns of therapeutic failure seen in patients are consistent with a steady accumulation of drug-resistant cancer stem cells (CSCs). Notch signaling is implicated in regulating CSCs and tumor resistance to platinum. Thus, we attempt to investigate whether inhibiting of Notch pathway could sensitize cisplatin (CDDP) to CDDP-resistant OS cells and the underlying molecular mechanisms. OS cell lines resistant to CDDP were treated with DAPT, CDDP or combination, we present evidences that DAPT enhances the cytotoxic effect of CDDP in resistant OS by inhibiting proliferation, resulting in G0/G1 cell-cycle arrest, inducing apoptosis, and reducing motility. In addition, DAPT targeting depletes OS stem cells (OSCs), thus increasing tumor sensitivity to platinum, which indicating that a dual combination targeting both OSCs and the bulk of tumor cells are needed for tumor eradication. We also found that the combination of CDDP and DAPT exhibit additive suppression on phosphorylated AKT and ERK, contributing to the anti-cancer effects. In animal model, this combination therapy inhibits the growth and metastasis of CDDP resistant tumor xenografts in nude mice to a greater extent than treatment with either reagent alone. Based on these results, we conclude that CDDP plus DAPT was able to sensitize CDDP-resistant human OS cells to CDDP by downregulation of Notch signaling. CDDP and DAPT combination treatment may be effective and promising for advanced OS.

Dai G ，Deng S ，Guo W ，Yu L ，Yang J ，Zhou S ，Gao T ... -  《-》