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.

• Authors: Motonari Nomura, Nino Rainusso, Yi-Chien Lee, Brian Dawson, Cristian Coarfa, Ruolan Han, Jeffrey L Larson, Ryan Shuck, Lyazat Kurenbekova, Jason T Yustein
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 111 Issue 11 Pg. 1216-1227 (11 01 2019) ISSN: 1460-2105 [Electronic] United States
• PMID: 30793158 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• CTNNB1 protein, human
• Enzyme Inhibitors
• beta Catenin
• Aldehyde Dehydrogenase

Topics

• Aldehyde Dehydrogenase (antagonists & inhibitors)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Biomarkers, Tumor (metabolism)
• Bone Neoplasms (drug therapy, metabolism, pathology)
• Cell Proliferation
• Drug Resistance, Neoplasm (drug effects)
• Enzyme Inhibitors (pharmacology)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lung Neoplasms (drug therapy, metabolism, secondary)
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Osteosarcoma (drug therapy, metabolism, pathology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays
• beta Catenin (antagonists & inhibitors, metabolism)