Tegavivint and the β-Catenin/ALDH Axis in Chemotherapy-Resistant and Metastatic Osteosarcoma.
Aldehyde Dehydrogenase
/ antagonists & inhibitors
Animals
Antineoplastic Agents
/ pharmacology
Apoptosis
Biomarkers, Tumor
/ metabolism
Bone Neoplasms
/ drug therapy
Cell Proliferation
Drug Resistance, Neoplasm
/ drug effects
Enzyme Inhibitors
/ pharmacology
Female
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Lung Neoplasms
/ drug therapy
Male
Mice
Mice, Inbred NOD
Mice, SCID
Osteosarcoma
/ drug therapy
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
beta Catenin
/ antagonists & inhibitors
Journal
Journal of the National Cancer Institute
ISSN: 1460-2105
Titre abrégé: J Natl Cancer Inst
Pays: United States
ID NLM: 7503089
Informations de publication
Date de publication:
01 11 2019
01 11 2019
Historique:
received:
24
05
2018
revised:
10
01
2019
accepted:
19
02
2019
pubmed:
23
2
2019
medline:
17
6
2020
entrez:
23
2
2019
Statut:
ppublish
Résumé
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.
Sections du résumé
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.
Identifiants
pubmed: 30793158
pii: 5355058
doi: 10.1093/jnci/djz026
pmc: PMC6855956
doi:
Substances chimiques
Antineoplastic Agents
0
Biomarkers, Tumor
0
CTNNB1 protein, human
0
Enzyme Inhibitors
0
beta Catenin
0
Aldehyde Dehydrogenase
EC 1.2.1.3
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1216-1227Subventions
Organisme : NIAID NIH HHS
ID : P30 AI036211
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA125123
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR024574
Pays : United States
Informations de copyright
© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.
Références
PLoS One. 2013;8(1):e55034
pubmed: 23383046
J Clin Oncol. 2015 Sep 20;33(27):3029-35
pubmed: 26304877
Biochem Biophys Res Commun. 2017 Sep 9;491(1):91-97
pubmed: 28698141
BMC Syst Biol. 2012 May 28;6:50
pubmed: 22640921
Cancer Res. 2004 Apr 15;64(8):2734-9
pubmed: 15087387
Int J Biol Sci. 2017 Apr 10;13(5):561-573
pubmed: 28539830
Biomed Res Int. 2013;2013:496193
pubmed: 23971040
Sci Rep. 2017 Jul 24;7(1):6215
pubmed: 28740094
Am J Pathol. 1999 Feb;154(2):515-23
pubmed: 10027409
J Clin Invest. 2017 Jun 30;127(7):2678-2688
pubmed: 28628032
Nat Med. 2014 Jun;20(6):670-5
pubmed: 24793237
J Biol Chem. 2010 Apr 30;285(18):13561-8
pubmed: 20177058
Oncogene. 1999 Nov 11;18(47):6615-20
pubmed: 10597266
J Cell Biochem. 2014 Apr;115(4):625-31
pubmed: 24190862
Am J Transl Res. 2016 Aug 15;8(8):3503-12
pubmed: 27648140
Cancer Res. 2015 Apr 15;75(8):1691-702
pubmed: 25660951
Oncol Rep. 2010 Aug;24(2):501-5
pubmed: 20596639
Cancer Res. 2015 Apr 1;75(7):1482-94
pubmed: 25670168
Mol Cancer Ther. 2017 Sep;16(9):1765-1778
pubmed: 28500235
Int J Cancer. 2004 Mar;109(1):106-11
pubmed: 14735475
Cancer Sci. 2015 Jun;106(6):665-71
pubmed: 25788321
Oncogene. 2015 Sep 24;34(39):5069-79
pubmed: 25579177
Neoplasia. 2012 Mar;14(3):249-58
pubmed: 22496624
Biochem Biophys Res Commun. 2013 Feb 8;431(2):274-9
pubmed: 23291185
Nat Commun. 2017 Jun 23;8:15936
pubmed: 28643781
Cell. 2006 Mar 24;124(6):1111-5
pubmed: 16564000
Proc Natl Acad Sci U S A. 2014 Dec 23;111(51):E5564-73
pubmed: 25512523
PLoS One. 2010 Feb 23;5(2):e9370
pubmed: 20186325
Oncogene. 2012 Jan 19;31(3):269-81
pubmed: 21706056
Cell. 2012 Jun 8;149(6):1192-205
pubmed: 22682243
Clin Cancer Res. 2016 Dec 15;22(24):6129-6141
pubmed: 27342399
Leukemia. 2015 Jun;29(6):1267-78
pubmed: 25482131
Diabetes. 2009 Mar;58(3):663-72
pubmed: 19073772
Cancer Res. 2012 Feb 15;72(4):1001-12
pubmed: 22147261
Sarcoma. 2013;2013:147541
pubmed: 23476112
Oncotarget. 2016 Apr 19;7(16):21114-23
pubmed: 27049730
Oncotarget. 2017 Jun 13;8(24):38541-38553
pubmed: 28404949
Mol Ther Nucleic Acids. 2017 Sep 15;8:111-122
pubmed: 28918013
Oncogene. 2015 Apr 30;34(18):2297-308
pubmed: 24954508
J Med Chem. 2015 Aug 13;58(15):5854-62
pubmed: 26182238
Cancer Lett. 2016 Jan 28;370(2):268-74
pubmed: 26571463
PLoS One. 2010 Nov 11;5(11):e13943
pubmed: 21085683
Science. 1998 Sep 4;281(5382):1509-12
pubmed: 9727977
J Biol Chem. 2005 Jun 3;280(22):21162-8
pubmed: 15802266
J Clin Invest. 2010 Aug;120(8):2979-88
pubmed: 20644255
Sci Rep. 2015 Jul 23;5:12465
pubmed: 26202299
Oncotarget. 2015 Oct 6;6(30):29469-81
pubmed: 26320182