Advances in the management of anaplastic thyroid carcinoma: transforming a life-threatening condition into a potentially treatable disease

Califano, Inés; Smulever, Anabella; Jerkovich, Fernando; Pitoia, Fabian

doi:10.1007/s11154-023-09833-1

Cited by 15 publications

(11 citation statements)

References 132 publications

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“…In particular, over the last few years, the advancement of knowledge on ATC genomic alterations has led to the clinical trials of a number of molecular targeted drugs [51]. Among these, small molecule inhibitors targeting BRAF (dabrafenib) and MEK (trametinib) exhibited outstanding responses in ATC patients carrying the BRAF V600E mutation [3,[52][53][54][55][56]. However, effective therapies for patients harboring the wild type BRAF are still lacking.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Therapeutic Effects of Harmine on Anaplastic Thyroid Cancer Cells

Baldini,

Cardarelli,

Campese

et al. 2024

IJMS

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Anaplastic thyroid carcinoma (ATC) is an extremely difficult disease to tackle, with an overall patient survival of only a few months. The currently used therapeutic drugs, such as kinase inhibitors or immune checkpoint inhibitors, can prolong patient survival but fail to eradicate the tumor. In addition, the onset of drug resistance and adverse side-effects over time drastically reduce the chances of treatment. We recently showed that Twist1, a transcription factor involved in the epithelial mesenchymal transition (EMT), was strongly upregulated in ATC, and we wondered whether it might represent a therapeutic target in ATC patients. To investigate this hypothesis, the effects of harmine, a β-carboline alkaloid shown to induce degradation of the Twist1 protein and to possess antitumoral activity in different cancer types, were evaluated on two ATC-derived cell lines, BHT-101 and CAL-62. The results obtained demonstrated that, in both cell lines, harmine reduced the level of Twist1 protein and reverted the EMT, as suggested by the augmentation of E-cadherin and decrease in fibronectin expression. The drug also inhibited cell proliferation and migration in a dose-dependent manner and significantly reduced the anchorage-independent growth of both ATC cell lines. Harmine was also capable of inducing apoptosis in BHT-101 cells, but not in CAL-62 ones. Finally, the activation of PI3K/Akt signaling, but not that of the MAPK, was drastically reduced in treated cells. Overall, these in vitro data suggest that harmine could represent a new therapeutic option for ATC treatment.

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Section: Discussionmentioning

confidence: 99%

Evaluation of the Therapeutic Effects of Harmine on Anaplastic Thyroid Cancer Cells

Baldini,

Cardarelli,

Campese

et al. 2024

IJMS

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“…On the other hand, little is known about neoadjuvant treatment in ALK-positive ATC. Recently, it was shown that the neoadjuvant use of dabrafenib and trametinib followed by surgery achieved 24-month OS rates of 80% [ 70 ].…”

Section: Discussionmentioning

confidence: 99%

Antineoplastic Effect of ALK Inhibitor Crizotinib in Primary Human Anaplastic Thyroid Cancer Cells with STRN–ALK Fusion In Vitro

Ferrari,

Ragusa,

Elia

et al. 2024

IJMS

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Anaplastic thyroid cancer (ATC) is one of the deadliest human cancers and represents <2% of thyroid carcinomas. A therapeutic target for ATC is represented by anaplastic lymphoma kinase (ALK) rearrangements, involved in tumor growth. Crizotinib is an oral small-molecule tyrosine kinase inhibitor of the ALK, MET, and ROS1 kinases, approved in ALK-positive non-small cell lung cancer. Until now, the effect of crizotinib in “primary human ATC cells” (pATCs) with transforming striatin (STRN)–ALK fusion has not been reported in the literature. In this study, we aimed to obtain pATCs with STRN–ALK in vitro and evaluate the in vitro antineoplastic action of crizotinib. Thyroid surgical samples were obtained from 12 ATC patients and 6 controls (who had undergone parathyroidectomy). A total of 10/12 pATC cultures were obtained, 2 of which with transforming STRN–ALK fusion (17%). Crizotinib inhibited proliferation, migration, and invasion and increased apoptosis in 3/10 pATC cultures (2 of which with/1 without STRN–ALK), particularly in those with STRN–ALK. Moreover, crizotinib significantly inhibited the proliferation of AF cells (a continuous cell line obtained from primary ATC cells). In conclusion, the antineoplastic activity of crizotinib has been shown in human pATCs (with STRN–ALK) in preclinical studies in vitro, opening the way to future clinical evaluation in these patients.

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“…The treatment of advanced thyroid carcinomas as PDTC and ATC with BRAF inhibitor dabrafenib and MEK inhibitor trametinib have shown significant redifferentiation and response rates in BRAF-mutated tumors [70][71][72] . In this study, we examined the effect of isolated dabrafenib and trametinib inhibitors, as well as their combination with PI3K inhibition, on thyroid cancer organoids.…”

Section: Dabrafenib and Trametinib Effect On Redifferentiation Is Pot...mentioning

confidence: 99%

Dual targeting of MAPK and PI3K pathways unlocks redifferentiation ofBraf-mutated thyroid cancer organoids

Lasolle

Schiavo

Tourneur

et al. 2023

Preprint

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Thyroid cancer is the most common endocrine malignancy and several genetic events have been described to promote the development of thyroid carcinogenesis. Besides the effects of specific mutations on thyroid cancer development, the molecular mechanisms controlling tumorigenesis, tumor behavior, and drug resistance are still largely unknown. Cancer organoids have been proposed as a powerful tool to study aspects related to tumor development and progression and appear promising to test individual response to therapies. Here, using mESC-derived thyroid organoids, we developed a BrafV637E-inducible model able of recapitulating the features of papillary thyroid cancer in vitro. Overexpression of BrafV637E rapidly leads to MAPK activation, cell dedifferentiation, and disruption of follicular organization. BrafV637E-expressing organoids show a transcriptomic signature for p53, focal adhesion, ECM-receptor interactions, EMT, and inflammatory signaling pathways. Finally, PTC-like thyroid organoids were used for drug screening assays. The combination of MAPK and PI3K inhibitors reversed Braf oncogene-promoted cell dedifferentiation while restoring thyroid follicle organization and function in vitro. Our results demonstrate that pluripotent stem cells-derived thyroid cancer organoids can mimic tumor development and features while providing an efficient tool for testing novel targeted therapies.

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Advances in the management of anaplastic thyroid carcinoma: transforming a life-threatening condition into a potentially treatable disease

Cited by 15 publications

References 132 publications

Evaluation of the Therapeutic Effects of Harmine on Anaplastic Thyroid Cancer Cells

Evaluation of the Therapeutic Effects of Harmine on Anaplastic Thyroid Cancer Cells

Antineoplastic Effect of ALK Inhibitor Crizotinib in Primary Human Anaplastic Thyroid Cancer Cells with STRN–ALK Fusion In Vitro

Dual targeting of MAPK and PI3K pathways unlocks redifferentiation ofBraf-mutated thyroid cancer organoids

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