Dataset Information

Induction of thyroid gene expression and radioiodine uptake in thyroid cancer cells by targeting major signaling pathways.

ABSTRACT: Radioiodine ablation is commonly used to treat thyroid cancer, but a major challenge is often the loss of radioiodine avidity of the cancer caused by aberrant silencing of iodide-handling genes.This study was conducted to test the therapeutic potential of targeting the aberrantly activated MAPK and PI3K/Akt/mTOR pathways and histone deacetylase to restore radioiodine avidity in thyroid cancer cells.We tested the effects of specific inhibitors targeting these pathways/molecules that had established clinical applicability, including the MAPK kinase inhibitor RDEA119, mTOR inhibitor temsirolimus, Akt inhibitor perifosine, and histone deacetylase inhibitor SAHA, individually or in combinations, on the expression of iodide-handling genes and radioiodide uptake in a large panel of thyroid cancer cell lines.The expression of a large number of iodide-handling genes could be restored, particularly the sodium/iodide symporter, TSH receptor, and thyroperoxidase, by treating cells with these inhibitors. The effect was particularly robust and synergistic when combinations of inhibitors containing SAHA were used. Robust expression of sodium/iodide symporter in the cell membrane, which plays the most important role in iodide uptake in thyroid cells, was confirmed by immunofluorescent microscopy. Radioiodide uptake by cells was correspondingly induced under these conditions. Thyroid gene expression and radioiodide uptake could both be further enhanced by TSH.Targeting major signaling pathways could restore thyroid gene expression and radioiodide uptake in thyroid cancer cells. Further studies are warranted to test this therapeutic potential in restoring radioiodine avidity of thyroid cancer cells for effective ablation treatment.

SUBMITTER: Hou P

PROVIDER: S-EPMC2840852 | biostudies-other | 2010 Feb

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Induction of thyroid gene expression and radioiodine uptake in thyroid cancer cells by targeting major signaling pathways.

Hou Peng P Bojdani Ermal E Xing Mingzhao M

The Journal of clinical endocrinology and metabolism 20091211 2

<h4>Context</h4>Radioiodine ablation is commonly used to treat thyroid cancer, but a major challenge is often the loss of radioiodine avidity of the cancer caused by aberrant silencing of iodide-handling genes.<h4>Objectives</h4>This study was conducted to test the therapeutic potential of targeting the aberrantly activated MAPK and PI3K/Akt/mTOR pathways and histone deacetylase to restore radioiodine avidity in thyroid cancer cells.<h4>Experimental design</h4>We tested the effects of specific i ...[more]

PMID: 20008023

Similar Datasets

Project description:BackgroundMetastatic thyroid cancers that are refractory to radioiodine (iodine-131) are associated with a poor prognosis. In mouse models of thyroid cancer, selective mitogen-activated protein kinase (MAPK) pathway antagonists increase the expression of the sodium-iodide symporter and uptake of iodine. Their effects in humans are not known.MethodsWe conducted a study to determine whether the MAPK kinase (MEK) 1 and MEK2 inhibitor selumetinib (AZD6244, ARRY-142886) could reverse refractoriness to radioiodine in patients with metastatic thyroid cancer. After stimulation with thyrotropin alfa, dosimetry with iodine-124 positron-emission tomography (PET) was performed before and 4 weeks after treatment with selumetinib (75 mg twice daily). If the second iodine-124 PET study indicated that a dose of iodine-131 of 2000 cGy or more could be delivered to the metastatic lesion or lesions, therapeutic radioiodine was administered while the patient was receiving selumetinib.ResultsOf 24 patients screened for the study, 20 could be evaluated. The median age was 61 years (range, 44 to 77), and 11 patients were men. Nine patients had tumors with BRAF mutations, and 5 patients had tumors with mutations of NRAS. Selumetinib increased the uptake of iodine-124 in 12 of the 20 patients (4 of 9 patients with BRAF mutations and 5 of 5 patients with NRAS mutations). Eight of these 12 patients reached the dosimetry threshold for radioiodine therapy, including all 5 patients with NRAS mutations. Of the 8 patients treated with radioiodine, 5 had confirmed partial responses and 3 had stable disease; all patients had decreases in serum thyroglobulin levels (mean reduction, 89%). No toxic effects of grade 3 or higher attributable by the investigators to selumetinib were observed. One patient received a diagnosis of myelodysplastic syndrome more than 51 weeks after radioiodine treatment, with progression to acute leukemia.ConclusionsSelumetinib produces clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease. (Funded by the American Thyroid Association and others; ClinicalTrials.gov number, NCT00970359.).

Project description:BackgroundPapillary thyroid cancer (PTC) is the most frequent endocrine tumor. Radioiodine (RAI) treatment is highly effective in these tumors, but up to 60% of metastatic cases become RAI-refractory. Scanty data are available on either the molecular pattern of radioiodine refractory papillary thyroid cancers (PTC) or the mechanisms responsible for RAI resistance.MethodsWe analyzed the molecular profile and gene/miRNA expression in primary PTCs, synchronous and RAI-refractory lymph node metastases (LNMs) in correlation to RAI avidity or refractoriness. We classified patients as RAI+/D+ (RAI uptake/disease persistence), RAI-/D+ (absent RAI uptake/disease persistence), and RAI+/D- (RAI uptake/disease remission), and analyzed the molecular and gene/miRNA profiles, and the expression of thyroid differentiation (TD) related genes.ResultsA different molecular profile according to the RAI class was observed: BRAFV600E cases were more frequent in RAI-/D+ (P = 0.032), and fusion genes in RAI+/D+ cases. RAI+/D- patients were less frequently pTERT mutations positive, and more frequently wild type for the tested mutations/fusions. Expression profiles clearly distinguished PTC from normal thyroid. On the other hand, in refractory cases (RAI+/D+ and RAI-/D+) no distinctive PTC expression patterns were associated with either tissue type, or RAI uptake, but with the driving lesion and BRAF-/RAS-like subtype. Primary tumors and RAI-refractory LNMs with BRAFV600E mutation display transcriptome similarity suggesting that RAI minimally affects the expression profiles of RAI-refractory metastases. Molecular profiles associated with the expression of TPO, SLC26A4 and TD genes, that were found more downregulated in BRAFV600E than in gene fusions tumors.ConclusionsThe present data indicate a different molecular profile in RAI-avid and RAI-refractory metastatic PTCs. Moreover, BRAFV600E tumors displayed reduced differentiation and intrinsic RAI refractoriness, while PTCs with fusion oncogenes are RAI-avid but persistent, suggesting different oncogene-driven mechanisms leading to RAI refractoriness.

Project description:BACKGROUNDMolecular characterization in pediatric papillary thyroid cancer (PTC), distinct from adult PTC, is important for developing molecularly targeted therapies for progressive radioiodine-refractory (131I-refractory) PTC.METHODSPTC samples from 106 pediatric patients (age range: 4.3-19.8 years; n = 84 girls, n = 22 boys) who were admitted to SNUH (January 1983-March 2020) were available for genomic profiling. Previous transcriptomic data from 125 adult PTC samples were used for comparison.RESULTSWe identified genetic drivers in 80 tumors: 31 with fusion oncogenes (RET in 21 patients, ALK in 6 patients, and NTRK1/3 in 4 patients); 47 with point mutations (BRAFV600E in 41 patients, TERTC228T in 2 patients [1 of whom had a coexisting BRAFV600E], and DICER1 variants in 5 patients); and 2 with amplifications. Fusion oncogene PTCs, which are predominantly detected in younger patients, were at a more advanced stage and showed more recurrent or persistent disease compared with BRAFV600E PTCs, which are detected mostly in adolescents. Pediatric fusion PTCs (in patients <10 years of age) had lower expression of thyroid differentiation genes, including SLC5A5, than did adult fusion PTCs. Two girls with progressive 131I-refractory lung metastases harboring a TPR-NTRK1 or CCDC6-RET fusion oncogene received fusion-targeted therapy; larotrectinib and selpercatinib decreased the size of the tumor and restored 125I radioiodine uptake. The girl with the CCDC6-RET fusion oncogene received 131I therapy combined with selpercatinib, resulting in a tumor response. In vitro 125I uptake and 131I clonogenic assays showed that larotrectinib inhibited tumor growth and restored radioiodine avidity.CONCLUSIONSIn pediatric patients with fusion oncogene PTC who have 131I-refractory advanced disease, selective fusion-directed therapy may restore radioiodine avidity and lead to a dramatic tumor response, underscoring the importance of molecular testing in pediatric patients with PTC.FUNDINGThe Ministry of Science, ICT and Future Planning (NRF-2016R1A2B4012417 and 2019R1A2C2084332); the Korean Ministry of Health and Welfare (H14C1277); the Ministry of Education (2020R1A6A1A03047972); and the SNUH Research Fund (04-2015-0830).TRIAL REGISTRATIONTwo patients received fusion-targeted therapy with larotrectinib (NCT02576431; NAVIGATE) or selpercatinib (LOXO-RET-18018).

Dataset Information

Induction of thyroid gene expression and radioiodine uptake in thyroid cancer cells by targeting major signaling pathways.

Publications

Induction of thyroid gene expression and radioiodine uptake in thyroid cancer cells by targeting major signaling pathways.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets