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

Journal of the National Cancer Institute
Motonari NomuraJason T Yustein

Abstract

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...Continue Reading

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Citations

Jun 17, 2020·JCI Insight·Allegra G HawkinsElizabeth R Lawlor
Aug 6, 2020·Cancers·Andrea NapolitanoBruno Vincenzi
Sep 26, 2020·International Journal of Molecular Sciences·Soo-Im ChoiIn-Gyu Kim
Dec 8, 2019·Cancer Metastasis Reviews·Amy L WalzJames I Geller
Oct 7, 2020·Cancer·Bernd KasperAlessandro Gronchi
Oct 13, 2020·Journal of Cellular Physiology·Shenglong Li, Xiaohong Wang
Oct 22, 2020·International Journal of Molecular Sciences·Malvina KoniMaria Felice Brizzi
Jan 6, 2021·Cancers·Zachary D Prudowsky, Jason T Yustein
Mar 7, 2021·Journal of Cellular and Molecular Medicine·Chaonan Sun, Shenglong Li
Mar 16, 2021·Current Oncology Reports·Ravin RatanAndrew J Bishop
Apr 14, 2021·Journal of Medicinal Chemistry·Marta SerafiniArmando A Genazzani
May 24, 2021·Cell & Bioscience·Xiaobin YuJianming Xu
Jun 21, 2021·Biochemical and Biophysical Research Communications·Yihua ShiLin Cai
Jul 3, 2021·Journal of Clinical Medicine·Sofía T MenéndezRené Rodríguez
Aug 5, 2021·Journal of Bone Oncology·Jiazheng ZhaoHelin Feng
Oct 16, 2021·Nature Reviews. Disease Primers·Filippo SpreaficoKathy Pritchard-Jones

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