Search Results (28)

Over the past several decades, rapid advances in molecular genomics have transformed our understanding of thyroid malignancies and are increasingly integrated into international clinical guidelines. Mutational profiles and epigenetic events are now recognized not only as diagnostic and prognostic tools but also as predictors of therapeutic response. Papillary, follicular, oncocytic, medullary, and anaplastic thyroid carcinomas harbor distinct early driver mutations, such as BRAFV600E, RAS, and fusion events (RET, NTRK, and ALK), that cooperate with secondary alterations (TERT promoter, TP53, PIK3CA, and CDKN2A/B loss) to drive dedifferentiation, metastasis, and therapeutic resistance. Insights from The Cancer Genome Atlas (TCGA) and transcriptomic scoring systems (e.g., BRAF–RAS score) now link genotype to tumor morphology, metastatic tropism, and radioactive iodine refractoriness. These molecular insights have been incorporated into updated risk stratification frameworks, preoperative surgical planning, and treatment algorithms, informing the selection of kinase inhibitors, redifferentiation strategies, and enrollment in genotype-directed clinical trials for radioiodine-refractory disease. This review synthesizes recent evidence connecting genomic alterations to clinical behavior and highlights their translation into evolving approaches for thyroid cancer management. Full article

Thyroid cancer (TC) represents the most prevalent endocrine malignancy, with papillary thyroid cancer (PTC) comprising approximately 80% of cases and accounting for the majority of annual incidence and mortality. PTC is generally confined to the thyroid gland and demonstrates an excellent prognosis after surgery, with a five-year survival rate exceeding 90%. Nevertheless, recurrence can occur, and the ten-year survival rate for the advanced PTC is below 50%. Even after effective successful surgical intervention, many still require ongoing surveillance, additional treatment, and lifelong thyroid hormone replacement, while facing the potential adverse effects such as hormone fluctuations, surgical complications, and sequelae of radioactive iodine exposure. Naturally occurring compounds have demonstrated anti-cancer properties and hence the potential to be used as therapeutic options, impacting the same drivers and pathways involved in the tumorigenesis of thyroid cancer. This narrative review focuses on the natural compounds’ convergence on molecular nodes of PI3K/Akt, MAPK, and JAK/STAT to overcome therapeutic resistance and restore apoptosis, highlighting their potential in advanced and recurrent PTC. Full article

Background: Differentiated thyroid cancer (DTC) is commonly treated with radioactive iodine (RAI), but resistance to RAI remains a significant clinical challenge. The molecular mechanisms driving dedifferentiation and RAI refractoriness, particularly in BRAF^V600E-mutated tumors, are not fully understood. Methods: RNA sequencing was conducted on BRAF^V600E-mutated DTC and RAIR-DTC tissue samples to identify differentially expressed genes. Gadd45B was identified as significantly downregulated in RAIR-DTC. Functional studies including overexpression and knockdown experiments were performed in thyroid cancer cell lines and xenograft models. Downstream targets, including MAP3K4 and MYCBP, were evaluated through co-immunoprecipitation, luciferase assays, and Western blot. The therapeutic efficacy of recombinant Gadd45B protein in combination with BRAF^V600E and TERT inhibitors was assessed in patient-derived xenograft (PDX) models. Results: Gadd45B overexpression suppressed MAPK pathway activity by interacting with MAP3K4 and downregulated c-MYC stability through competition with MYCBP. These interactions enhanced the expression of iodine-metabolism genes (NIS, TPO, Tg), increased RAI uptake, and reversed tumor dedifferentiation. In vivo, Gadd45B restoration reduced tumor burden and improved RAI uptake. Combined treatment with Gadd45B protein, PLX4720, and BIBR1532 produced synergistic therapeutic effects in PDX models. Conclusions: Gadd45B plays a pivotal role in regulating the differentiation status and RAI sensitivity of BRAF^V600E-mutated thyroid cancer. These findings identify Gadd45B as a promising therapeutic target for restoring RAI responsiveness in RAIR-DTC patients. Full article

Differentiated thyroid carcinoma (DTC) is the most common endocrine malignancy and typically has a favorable prognosis. However, a subset of patients experience aggressive disease, recurrence, or treatment resistance, underscoring the need for more precise diagnostic and therapeutic strategies. Advances in molecular profiling have improved the management of thyroid cancer by enabling risk-adapted treatment and targeted interventions. This narrative review offers a clinically focused synthesis of the current role of molecular diagnostics and personalized therapeutics in DTC. We examine key genetic alterations and their diagnostic, prognostic, and therapeutic implications, and discuss how molecular markers enhance traditional risk stratification systems, informing surgical decisions, radioactive iodine (RAI) use, and surveillance. The growing role of targeted therapies, such as tyrosine kinase inhibitors and agents against specific oncogenic drivers, is reviewed, particularly for RAI-refractory DTC. We also address real-world challenges in implementing precision medicine, including access, cost, and standardization. Future directions, such as liquid biopsy, artificial intelligence, and multi-omic integration, are explored as tools to achieve fully personalized care. This review aims to bridge the gap between molecular discovery and clinical application, offering practical insights for endocrinologists, surgeons, oncologists, and multidisciplinary teams managing DTC. Full article

As the hub of energy metabolism and the cell’s fate arbiter, mitochondria are essential for preserving cellular homeostasis and converting it from pathological states. Therefore, through mechanisms that drive metabolic reprogramming, oxidative stress, and apoptosis resistance, mitochondrial dysfunction (including mitochondrial DNA mutations, mitochondrial dynamics imbalance, mitochondrial autophagy abnormalities, mitochondrial permeability abnormalities, and metabolic disorder) can promote the progression of thyroid cancer (TC), resistance to treatment, and reshaping of the immune microenvironment. This article reviews the molecular mechanisms and characteristic manifestations of mitochondrial dysfunction in TC. It focuses on providing a summary of the main strategies currently used to target the mitochondria, such as dietary intervention and targeted medications like curcumin, as well as the clinical translational value of these medications when used in conjunction with current targeted therapies for TC and radioactive iodine (RAI) therapy in patients with advanced or RAI-refractory TC who rely on targeted therapies. The application prospects and existing challenges of emerging therapeutic methods, such as mitochondrial transplantation, are also discussed in depth, aiming to provide new perspectives for revealing the molecular mechanisms by which mitochondrial dysfunction drives the progression of TC, drug resistance, and the reshaping of its immune microenvironment, as well as providing new diagnostic and therapeutic strategies for patients with advanced or RAI-refractory TC who are reliant on targeted therapies. Full article

Thyroid cancer, the most frequently occurring endocrine neoplasm, comprises a heterogeneous group of histological subtypes, spanning from the indolent papillary thyroid carcinoma (PTC) to the rapidly progressive and lethal anaplastic thyroid carcinoma (ATC). Although conventional therapies, such as surgery and radioactive iodine (RAI), are effective for differentiated thyroid cancers, treatment resistance and poor prognosis remain major challenges in advanced and undifferentiated forms. In current times, growing attention has been directed toward the potential of Natural Killer (NK) cells as a promising immunotherapeutic avenue. These innate immune cells are capable of direct cytotoxicity against tumor cells, but their efficiency is frequently compromised by the immunosuppressive tumor microenvironment (TME), which inhibits NK cell activation, infiltration, and persistence. This review explores the dynamic interaction between NK cells and the TME in thyroid cancer, detailing key mechanisms of immune evasion, including the impact of suppressive cytokines, altered chemokine landscapes, and inhibitory ligand expression. We further discuss latest advancements in NK cell-based immunotherapies, including strategies for ex vivo expansion, genetic modification, and combinatorial approaches with checkpoint inhibitors or cytokines. Additionally, emerging modalities, such as NK cell-derived extracellular vesicles, are addressed. By combining mechanistic insights with advancing therapeutic techniques, this review provides a comprehensive perspective on NK cell-based interventions and their future potential in improving outcomes for patients with thyroid cancer. Full article

Radioactive iodine (¹²⁹I), released into the environment from human nuclear activities, poses significant health risks to the biosphere due to its long half-life and mobility. This study investigates the toxic effects of wet-deposited iodine on the growth of chili pepper seedlings (Capsicum annuum L.) under soil cultivation conditions. Using sodium iodide (NaI) as the exposure agent, transcriptomic analysis was conducted to evaluate the molecular responses of chili pepper leaves to iodine at concentrations of 2, 4, and 8 ppm. The study identified 2440 and 1543 differentially expressed genes (DEGs) in leaves exposed to 2 ppm vs. 4 ppm iodine and 2 ppm vs. 8 ppm iodine, respectively. GO enrichment analysis showed that DEGs at 4 ppm were significantly associated with protein–chromophore linkage, extracellular region, and iron ion binding, while those at 8 ppm were enriched in defense response, cell wall components, and iron ion binding. Iodine stress disrupted key pathways associated with photosynthesis, antioxidant defense, and cuticle biosynthesis. In particular, the downregulation of key genes related to protein–chromophore binding, lipid metabolism, and cell wall organization indicated reduced photosynthetic efficiency and weakened stress resistance. This study provides molecular-level insights into the ecological risks of iodine stress in plants and offers a scientific basis for managing iodine contamination and breeding iodine-tolerant chili pepper cultivars. Full article

Background: Differentiated thyroid cancer (DTC) patients have an outstanding overall long-term survival rate, and certain subsets of DTC patients have a very high likelihood of disease recurrence. Radioactive iodine (RAI) therapy is a cornerstone in DTC management, but cancer cells can eventually develop resistance to RAI. Radioactive iodine-refractory DTC (RAIR-DTC) is a condition defined by ATA 2015 guidelines when DTC cannot concentrate RAI ab initio or loses RAI uptake ability after the initial therapy. The RAIR condition implies that RAI cannot reveal new met-astatic foci, so RAIR-DTC metabolic imaging needs new tracers. ¹⁸F-FDG PET/CT has been widely used and has demonstrated prognostic value, but ¹⁸F-FDG DTC avidity may remain low. Fibroblast activation protein inhibitors (FA-Pi)s, prostatic-specific membrane antigen (PSMA), and somatostatin receptor (SSTR) tracers have been proposed as theragnostic agents in experimental settings and Arg-Gly-Asp (RGD) peptides in the diagnostic trial field. Multi-targeted tyrosine kinase inhibitors are relatively new drugs approved in RAIR-DTC therapy. Despite the promising targeted setting, they relate to frequent adverse-event onset. Sorafenib and trametinib have been included in re-differentiation protocols aimed at re-inducing RAI accumulation in DTC cells. Results appear promising, but not excellent. Conclusions: RAIR-DTC remains a challenging nosological entity. There are still controversies on RAIR-DTC definition and post-RAI therapy evaluation, with post-therapy whole-body scan (PT-WBS) the only validated criterion of response. The recent introduction of multiple diagnostic and therapeutic agents obliges physicians to pursue a multidisciplinary approach aiming to correct drug introduction and timing choice. Full article

Background: Poorly differentiated thyroid carcinoma (PDTC) has an intermediate prognosis between indolent well-differentiated thyroid carcinoma (TC) and anaplastic carcinoma. Herein, we present a case report with a PDTC component, along with a systematic review of the literature. Case Report: We report a case of a 45-year-old man diagnosed with a PDTC component, along with hobnail and tall-cell variant features positive for BRAFV600E mutation, after a total thyroidectomy and neck dissection. Radioactive iodine (RAI)-131 therapy was applied, but an early recurrence led to complementary surgeries. The anti-Tg rise, the presence of new lymph nodes, and the negative whole-bodyradioiodine scan were suggestive of a radioiodine-resistant tumor. Lenvatinib, sorafenib, dabrafenib/trametinib, cabozantinib and radiotherapy were all administered, controlling the tumor for a period of time before the patient ultimately died post-COVID infection. Systematic Review: We searched PubMed, Scopus, and WebofScience to identify studies reporting clinicopathological characteristics, molecular marker expression, and management of non-anaplastic TC with any proportion of PDTC in adult patients. Of the 2007 records retrieved, 82were included in our review (PROSPERO-ID545847). Conclusions: Our case, together with the systematic review, imply that a combination of molecular-targetedtreatments may be safe and effective in patients with RAI-resistantBRAF-mutated advanced PDTC when surgery has failed to control tumor progression. Full article

Thyroid cancer is the most common endocrine neoplasm, and despite its overall high survival rate, patients with metastatic disease or tumors that resist radioactive iodine experience a significantly worse prognosis. Helping these patients requires a better understanding of how therapeutics alter cellular function. Here, we describe the change in metabolite profiles after treating thyroid cancer cells with the kinase inhibitors dasatinib and trametinib. We reveal alterations to glycolysis, the TCA cycle, and amino acid levels. We also highlight how these drugs promote short-term accumulation of the tumor-suppressive metabolite 2-oxoglutarate, and demonstrate that it reduces the viability of thyroid cancer cells in vitro. These results show that kinase inhibition profoundly alters the metabolome of cancer cells and highlight the need to better understand how therapeutics reprogram metabolic processes, and ultimately, cancer cell behavior. Full article

Previously, we reported that an inverse agonist of estrogen-related receptor gamma (ERRγ), GSK5182, enhances sodium iodide (Na⁺/I⁻) symporter (NIS) function through mitogen-activated protein (MAP) kinase signaling in anaplastic thyroid cancer cells. This finding helped us to further investigate the effects of GSK5182 on NIS function in papillary thyroid cancer (PTC) refractory to radioactive iodine (RAI) therapy. Herein, we report the effects of ERRγ on the regulation of NIS function in RAI-resistant PTC cells using GSK5182. RAI-refractory BCPAP cells were treated with GK5182 for 24 h at various concentrations, and radioiodine avidity was determined with or without potassium perchlorate (KClO₄) as an NIS inhibitor. We explored the effects of GSK5182 on ERRγ, the mitogen-activated protein (MAP) kinase pathway, and iodide metabolism-related genes. We examined whether the MAP pathway affected GSK5182-mediated NIS function using U0126, a selective MEK inhibitor. A clonogenic assay was performed to evaluate the cytotoxic effects of I-131. GSK5182 induced an increase in radioiodine avidity in a dose-dependent manner, and the enhanced uptake was completely inhibited by KClO₄ in BCPAP cells. We found that ERRγ was downregulated and phosphorylated extracellular signal-regulated kinase (ERK)1/2 was upregulated in BCPAP cells, with an increase in total and membranous NIS and iodide metabolism-related genes. MEK inhibitors reversed the increase in radioiodine avidity induced by GSK5182. Clonogenic examination revealed the lowest survival in cells treated with a combination of GSK5182 and I-131 compared to those treated with either GSK518 or I-131 alone. We demonstrate that an inverse agonist of ERRγ, GSK5182, enhances the function of NIS protein via the modulation of ERRγ and MAP kinase signaling, thereby leading to increased responsiveness to radioiodine in RAI-refractory papillary thyroid cancer cells. Full article

Thyroid cancer is the most common endocrine cancer, with a good prognosis in most cases. However, some cancers of follicular origin are metastatic or recurrent and eventually become radioiodine refractory thyroid cancers (RAIR-TC). These more aggressive cancers are a clinical concern for which the therapeutic arsenal remains limited. Molecular biology of these tumors has highlighted a hyper-activation of the Mitogen-Activated Protein Kinases (MAPK) pathway (RAS-RAF-MEK-ERK), mostly secondary to the BRAF^V600E hotspot mutation occurring in about 60% of papillary cancers and 45% of anaplastic cancers. Therapies targeting the different protagonists of this signaling pathway have been tested in preclinical and clinical models: first and second generation RAF inhibitors and MEK inhibitors. In clinical practice, dual therapies with a BRAF inhibitor and a MEK inhibitor are being recommended in anaplastic cancers with the BRAF^V600E mutation. Concerning RAIR-TC, these inhibitors can be used as anti-proliferative drugs, but their efficacy is inconsistent due to primary or secondary resistance. A specific therapeutic approach in thyroid cancers consists of performing a short-term treatment with these MAPK pathway inhibitors to evaluate their capacity to redifferentiate a refractory tumor, with the aim of retreating the patients by radioactive iodine therapy in case of re-expression of the sodium–iodide symporter (NIS). In this work, we report data from recent preclinical and clinical studies on the efficacy of MAPK pathway inhibitors and their resistance mechanisms. We will also report the different preclinical and clinical studies that have investigated the redifferentiation with these therapies. Full article

Rapid and highly sensitive detection of iodine gaseous species is crucial as the first response in case of nuclear accidents and nuclear waste clean-up. A robust and user-friendly sensor-based technology that allows online monitoring is highly desirable. Herein, we report the success of using a covalent organic framework (AQ-COF)-based sensor for real-time iodine gas adsorption and detection by the electrochemical impedance spectroscopy (EIS) technique. The sensor exhibits a high sensitivity and a pronounced electrical response to trace amounts of iodine vapor. Gaseous iodine was readily detected with a significant change in resistance (10⁴×) at 70 °C within 5 min exposure to air. Notably, the EIS response is quite chemoselective to iodine over other common species such as air, methanol, ethanol, and water, with a selectivity of 320, 14, 49, and 1030, respectively. A mechanical study shows that the adsorption of iodine can reduce the optical bandgap of the AQ-COF, causing the impedance to drop significantly. This study demonstrates how the adsorption enrichment effect of selective I₂ adsorption by a covalent organic framework can be leveraged to create a highly selective sensor for the direct online electrical detection of radioactive gaseous toxins. Full article

Papillary thyroid cancer (PTC) is the most prevalent histological type of thyroid cancer (TC) worldwide. Although tumor metastasis occurs in regional lymph nodes, distant metastasis (DM) may also occur. Radioactive iodine (RAI) therapy is an effective treatment for TC; however, resistance to RAI occurs in patients with DM. Therefore, in this study, we investigated the efficacy of DM-related biomarkers as therapeutic targets for PTC therapy. ABCA1 expression was higher in aggressive BCPAP cells than in other PTC cells in terms of migration and invasion capacity. The knockdown of ABCA1 substantially decreased the expression of the epithelial–mesenchymal transition (EMT) marker, N-cadherin, and EMT regulator (ZEB1), resulting in suppressed migration and invasion of BCPAP cells. ABCA1 knockdown also reduced ERK activity and Fra-1 expression, which correlated with the effects of an ERK inhibitor or siRNA-mediated inhibition of ERK or Fra-1 expression. Furthermore, ABCA1-knocked-down BCPAP cells suppressed cell migration and invasion by reducing Fra-1 recruitment to Zeb1 promoter; lung metastasis was not observed in mice injected with ABCA1-knocked-down cells. Overall, our findings suggest that ABCA1 regulates lung metastasis in TC cells. Full article

Two-thirds of differentiated thyroid cancer (DTC) patients with distant metastases would be classified as radioactive iodine-refractory (RAIR-DTC), evolving into a poor outcome. Recent advances underlying DTC molecular mechanisms have shifted the therapy focus from the standard approach to targeting specific genetic dysregulations. Lenvatinib and sorafenib are first-line, multitargeted tyrosine kinase inhibitors (TKIs) approved to treat advanced, progressive RAIR-DTC. However, other anti-angiogenic drugs, including single targeted TKIs, are currently being evaluated as alternative or salvage therapy after the failure of first-line TKIs. Combinatorial therapy of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signalling cascade inhibitors has become a highly advocated strategy to improve the low efficiency of the single agent treatment. Recent studies pointed out targetable alternative pathways to overcome the resistance to MAPK and PI3K pathways’ inhibitors. Because radioiodine resistance originates in DTC loss of differentiation, redifferentiation therapies are currently being explored for efficacy. The present review will summarize the conventional management of DTC, the first-line and alternative TKIs in RAIR-DTC, and the approaches that seek to overcome the resistance to MAPK and PI3K pathways’ inhibitors. We also aim to emphasize the latest achievements in the research of redifferentiation therapy, immunotherapy, and agents targeting gene rearrangements in advanced DTC. Full article