Wnt/β-catenin signaling is a therapeutic target in anaplastic thyroid carcinoma.
Journal
Endocrine
ISSN: 1559-0100
Titre abrégé: Endocrine
Pays: United States
ID NLM: 9434444
Informations de publication
Date de publication:
28 May 2024
28 May 2024
Historique:
received:
23
03
2024
accepted:
17
05
2024
medline:
29
5
2024
pubmed:
29
5
2024
entrez:
28
5
2024
Statut:
aheadofprint
Résumé
Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy that has consistently shown Wnt/β-catenin (canonical) signaling activation in various study populations. There are currently no targetable treatments for BRAF-wildtype ATC and a lack of effective treatment for BRAF In this Institutional Review Board-approved study, we utilize a cohort of 32 ATCs and 20 non-neoplastic multinodular goiters (MNG). We also use 4 ATC spheroid cell lines (THJ-16T, THJ-21T, THJ-29T, and THJ-11T) and two primary patient-derived ATC organoid cultures (VWL-T5 and VWL-T60). Finally, we use a murine xenograft mouse model of ATC for in vivo treatment studies. Using a large patient cohort, we demonstrate that this near-universal Wnt signaling activation is associated with ligand expression- rather than being mutationally-driven. We show that pyrvinium pamoate, a potent Wnt inhibitor, exhibits in vitro efficacy against both ATC cell lines and primary patient-derived ATC organoids VWL-T5 (p < 0.05) and VWL-T60 (p < 0.01) Finally, using a murine xenograft model of ATC, we show that pyrvinium significantly delays the growth of ATC tumors in THJ-16T (p < 0.005) and THJ-21T (p < 0.001). We tested Wnt inhibitor treatment, both in vitro and in vivo, as a potential novel therapy for this highly lethal disease. Future large-scale studies utilizing multiple Wnt inhibitors will lay the foundation for the development of these novel therapies for patients with ATC.
Sections du résumé
BACKGROUND
BACKGROUND
Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy that has consistently shown Wnt/β-catenin (canonical) signaling activation in various study populations. There are currently no targetable treatments for BRAF-wildtype ATC and a lack of effective treatment for BRAF
METHODS
METHODS
In this Institutional Review Board-approved study, we utilize a cohort of 32 ATCs and 20 non-neoplastic multinodular goiters (MNG). We also use 4 ATC spheroid cell lines (THJ-16T, THJ-21T, THJ-29T, and THJ-11T) and two primary patient-derived ATC organoid cultures (VWL-T5 and VWL-T60). Finally, we use a murine xenograft mouse model of ATC for in vivo treatment studies.
RESULTS
RESULTS
Using a large patient cohort, we demonstrate that this near-universal Wnt signaling activation is associated with ligand expression- rather than being mutationally-driven. We show that pyrvinium pamoate, a potent Wnt inhibitor, exhibits in vitro efficacy against both ATC cell lines and primary patient-derived ATC organoids VWL-T5 (p < 0.05) and VWL-T60 (p < 0.01) Finally, using a murine xenograft model of ATC, we show that pyrvinium significantly delays the growth of ATC tumors in THJ-16T (p < 0.005) and THJ-21T (p < 0.001).
CONCLUSIONS
CONCLUSIONS
We tested Wnt inhibitor treatment, both in vitro and in vivo, as a potential novel therapy for this highly lethal disease. Future large-scale studies utilizing multiple Wnt inhibitors will lay the foundation for the development of these novel therapies for patients with ATC.
Identifiants
pubmed: 38806891
doi: 10.1007/s12020-024-03887-0
pii: 10.1007/s12020-024-03887-0
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIH HHS
ID : T32GM007628-42
Pays : United States
Organisme : NIH HHS
ID : T32GM007347
Pays : United States
Organisme : NIH HHS
ID : T32GM007347
Pays : United States
Organisme : NIH HHS
ID : R35GM122516
Pays : United States
Organisme : NCI NIH HHS
ID : 5F31C261060-02
Pays : United States
Organisme : NCI NIH HHS
ID : 1F30CA281125- 01
Pays : United States
Organisme : VCORCDP
ID : K12CA090625
Organisme : ATA
ID : 2019-0000000090
Organisme : ACS
ID : 133934-CSDG-19-216-01-TBG
Informations de copyright
© 2024. The Author(s).
Références
R. Liu et al. A novel prognostic model for papillary thyroid cancer based on epithelial-mesenchymal transition-related genes. Cancer Med. 11, 4703–4720 (2022)
doi: 10.1002/cam4.4836
pubmed: 35608185
pmcid: 9741981
V. Subbiah, C. Baik, J.M. Kirkwood, Clinical development of BRAF plus MEK inhibitor combinations. Trends Cancer 6, 797–810 (2020)
doi: 10.1016/j.trecan.2020.05.009
pubmed: 32540454
V. Subbiah et al. Dabrafenib and Trametinib treatment in patients with locally advanced or metastatic BRAF V600–mutant anaplastic thyroid cancer. J. Clin. Oncol. 36, 7–13 (2018)
doi: 10.1200/JCO.2017.73.6785
pubmed: 29072975
G. Nagaiah, A. Hossain, C.J. Mooney, J. Parmentier, S.C. Remick, Anaplastic thyroid cancer: a review of epidemiology, pathogenesis, and treatment. J. Oncol. 2011, 1–13 (2011)
doi: 10.1155/2011/542358
G. Garcia-Rostan et al. β-Catenin dysregulation in thyroid neoplasms. Am. J. Pathol. 158, 987–996 (2001)
doi: 10.1016/S0002-9440(10)64045-X
pubmed: 11238046
pmcid: 1850336
G. Garcia-Rostan et al. Frequent mutation and nuclear localization of beta-catenin in anaplastic thyroid carcinoma. Cancer Res. 59, 1811–1815 (1999)
pubmed: 10213482
T. Kurihara et al. Immunohistochemical and sequencing analyses of the wnt signaling components in Japanese anaplastic thyroid cancers. Thyroid 14, 1020–1029 (2004)
doi: 10.1089/thy.2004.14.1020
pubmed: 15650354
G.J. Xu et al. Molecular signature incorporating the immune microenvironment enhances thyroid cancer outcome prediction. Cell Genomics 3, 100409 (2023)
doi: 10.1016/j.xgen.2023.100409
pubmed: 37868034
pmcid: 10589635
C.A. Thorne et al. Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α. Nat. Chem. Biol. 6, 829–836 (2010)
doi: 10.1038/nchembio.453
pubmed: 20890287
pmcid: 3681608
M.A. Lee et al. Novel three-dimensional cultures provide insights into thyroid cancer behavior. Endocr. Relat. Cancer 27, 111–121 (2020)
doi: 10.1530/ERC-19-0374
pubmed: 31804972
pmcid: 7295136
K. Bergdorf et al. High-throughput drug screening of fine-needle aspiration-derived cancer organoids. STAR Protoc 1, 100212 (2020)
doi: 10.1016/j.xpro.2020.100212
pubmed: 33377106
pmcid: 7757655
C.J. Phifer et al. Obtaining patient-derived cancer organoid cultures via fine-needle aspiration. STAR Protoc 2, 100220 (2021)
doi: 10.1016/j.xpro.2020.100220
pubmed: 33377121
A.E. Vilgelm et al. Fine-needle aspiration-based patient-derived cancer organoids. iScience 23, 101408 (2020)
doi: 10.1016/j.isci.2020.101408
pubmed: 32771978
pmcid: 7415927
G. Vlachogiannis et al. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science 359, 920–926 (2018)
doi: 10.1126/science.aao2774
pubmed: 29472484
pmcid: 6112415
M.I. Love, W. Huber, S. Anders, Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15, 550 (2014)
doi: 10.1186/s13059-014-0550-8
pubmed: 25516281
pmcid: 4302049
A. Liberzon et al. The molecular signatures database hallmark gene set collection. Cell Syst. 1, 417–425 (2015)
doi: 10.1016/j.cels.2015.12.004
pubmed: 26771021
pmcid: 4707969
H. Wickham Ggplot2: Elegant Graphics for Data Analysis. (Springer International Publishing: Imprint: Springer, Cham, 2016). https://doi.org/10.1007/978-3-319-24277-4 .