RARE DISEASE
Anaplastic thyroid carcinoma
Anaplastic thyroid carcinoma
Anaplastic thyroid carcinoma
Drug discovery
6
drugs
With orphan designations
Overview
Anaplastic thyroid carcinoma (ATC) is a rare, undifferentiated malignancy representing 1-2% of thyroid cancers but responsible for 14-50% of thyroid cancer-related deaths [5][12][19]. Characterized by rapid growth (weeks), local invasion, and early metastasis, it has a dismal median survival of 3-9 months [5][16]. All cases are classified as stage IV at diagnosis [7]. Treatment requires aggressive multimodal approaches, including surgery (when feasible), radiotherapy, chemotherapy, and emerging targeted therapies [3][8][18].
Categories: rare endocrine diseases, rare neoplastic diseases
Research Papers
2,276 drug discovery papers about Anaplastic thyroid carcinoma, with 7 first-in-class and 10 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2,276 drug discovery papers about Anaplastic thyroid carcinoma, with 7 first-in-class and 10 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-29 | Triptolide in Combination with the Gli1 Inhibitor GANT61 Eradicates Anaplastic Thyroid Cancer by Suppressing Cancer Stem Cell Self-Renewal and Enhancing Apoptosis and Pyroptosis.
Anaplastic thyroid cancer (ATC) is a lethal malignancy characterized by therapy resistance and rapid recurrence, driven in part by a population of thyroid cancer stem cells (CSCs). While the Gli1 inhibitor GANT61 targets CSC self-renewal, its efficacy is limited by compensatory activation of the pro-survival TAK1-AMPK pathway. Our present study aims to determine whether triptolide (TPL), a natural compound that inhibits TAK1 and induces reactive oxygen species (ROS), can overcome this resistance and achieve a synergistic anticancer effect when use with GANT61. Here, we report that TPL blocked GANT61-induced TAK1-AMPK activation. TPL alone effectively inhibited the proliferation of two ATC cell lines (8505C and SW1736) and achieved a synergistic anti-proliferative effect when used in combination with GANT61. Consistently, TPL alone effectively suppressed SW1736 xenograft tumor growth but, when used in combination with GANT61, prevented tumor recurrence. TPL in combination with GANT61 synergistically inhibited thyroid CSC self-renewal and induced apoptosis and pyroptosis. Mechanistically, TPL blocked GANT61-mediated activation of the TAK1-AMPK axis and synergistically induced ROS generation, which potentiated pyroptotic activity of Gasdermin D and E (GSDMD/E). This was confirmed by the evidence that TAK1 and AMPK inhibition by gene knockout or their specific inhibitors enhanced apoptotic and pyroptotic activity of GANT61, whereas ROS scavenge blocked apoptosis and pyroptosis induced by TPL and/or GANT61. Taken together, our study provides mechanistic insights into how TPL overcomes a key resistance pathway in CSC target therapy and suggests that the TPL-GANT61 combination could be a promising strategy to eradicate ATC.
2026-09-28 | Unmasking LAT-1 and VDR Expressions: Potential Therapeutic Windows in Anaplastic Thyroid Carcinoma
Background/Objectives: Anaplastic thyroid cancer (ATC) is a rare and highly aggressive thyroid malignancy with limited treatment options. Loss of the sodium/iodide symporter makes ATC resistant to radioactive iodine therapy, highlighting the need for alternative therapeutic targets. This study evaluated L-type amino acid transporter 1 (LAT-1) and vitamin D receptor (VDR) as potential targets in ATC. Methods: We examined LAT-1 (SLC7A5) and VDR gene expression using TCGA data from the UALCAN database. Protein expression was evaluated by immunohistochemistry in 28 formalin-fixed, paraffin-embedded ATC specimens from Loma Linda University Health. We assessed staining intensity and distribution and compared expression between male and female patients. Results: TCGA analysis showed significantly higher SLC7A5 expression in thyroid tumors compared with normal thyroid tissue (*p = 0.0115), while VDR was strongly increased in tumors (**p < 0.001) and across all tumor stages. All 28 ATC specimens expressed both LAT-1 and VDR, although staining intensity and distribution varied among tumors. LAT-1 was primarily localized to the membrane and cytoplasm of tumor cells, with additional expression in stromal and endothelial cells. VDR showed membranous, cytoplasmic, and occasional nuclear expression. LAT-1 expression did not differ significantly by sex (ns, not significant, p = 0.19), whereas VDR expression was significantly higher in females than males (**p = 0.0014). Conclusions: LAT-1 and VDR are broadly expressed in ATC despite substantial intratumoral heterogeneity. Their consistent expression supports further investigation as potential targets for radioligand or other ligand-directed therapies. The higher VDR expression observed in female patients also suggests a potentially important sex-associated difference that warrants validation in larger ATC cohorts.
2026-09-15 | Macrophages as Drivers of Resistance to Dabrafenib Plus Trametinib Therapy in Anaplastic Thyroid Cancer.
Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy with poor response to standard therapies. While Dabrafenib plus Trametinib (DT) combination therapy has improved the survival of patients with BRAF-mutant ATC, resistance remains a challenge. Given the association of macrophages with poor prognosis, and that SPRY4 has emerged as a mediator in ATC-macrophage interactions, we investigated their role in DT resistance and evaluated the therapeutic potential of macrophage targeting. Transwell co-cultures of BRAF-mutant ATC cell lines (T235 and T238) with THP-1-derived macrophages were established, and viability, invasion, and macrophage phenotype were assessed. Macrophages were also characterised in tumour samples from eleven ATC patients treated with DT. In vitro, DT significantly reduced ATC cell viability and invasion. However, macrophage co-culture significantly restored these effects, also promoting cytoskeletal remodelling and increased vimentin expression, despite DT treatment. DT significantly downregulated SPRY4 and suppressed MAPK signalling and PD-L1. These effects were also significantly reversed by macrophages. Under DT, macrophages showed an increase in M2-like polarisation in co-culture. Patients' tumour samples were highly infiltrated with macrophages. In vitro targeting of macrophages with Edicotinib, in combination with DT, significantly enhanced the anti-tumour effects of DT and decreased the M2-like polarisation, bypassing the macrophage-mediated DT resistance. Overall, the in vitro findings suggest that macrophages modulate ATC response to DT by enhancing viability, invasion, MAPK signalling and PD-L1, supporting a pro-tumoural phenotype. Targeting macrophages overcomes this resistance, highlighting the CSF1/CSF1R signalling pathway within the ATC-macrophage axis as a promising therapeutic target to improve DT efficacy.
2026-09-11 | Spatial heterogeneity in anaplastic thyroid carcinoma: Mechanistic insights and clinical translation through single-cell and spatial transcriptomics.
Anaplastic thyroid carcinoma (ATC) is a highly lethal malignancy whose therapeutic resistance is driven by profound intra-tumor heterogeneity and a complex tumor microenvironment. This review synthesizes how single-cell and spatial transcriptomic technologies are transforming our understanding of ATC by systematically decoding its cellular composition and spatial architecture. These approaches have uncovered novel aggressive cell states, delineated immunosuppressive functional niches, and elucidated the critical cell-cell communication networks that underlie treatment failure. Consequently, the therapeutic paradigm for ATC is shifting from targeting isolated driver mutations towards strategically remodeling the entire tumor ecosystem. The integration of these high-resolution insights is paving the way for the development of novel precision medicine strategies aimed at overcoming resistance in this formidable disease.
2026-09-10 | Latin American Thyroid Society expert panel consensus on anaplastic thyroid cancer.
Anaplastic thyroid cancer (ATC) is a highly aggressive histologic subtype of thyroid malignancy. Its rarity, rapidly progressive clinical course, along with limitations in health-care resources make management particularly challenging in Latin America. In recent years, substantial advances in the understanding of ATC biology have led to modifications in therapeutic strategies. This consensus aims to raise awareness and provide practical, evidence-based guidance for the diagnosis and management of ATC, summarizing current diagnostic and therapeutic advances while offering an accessible framework tailored to the Latin American context. A multidisciplinary panel of experts in endocrinology, surgery, oncology, pathology, and genetics from Latin American countries developed a series of recommendations. Each recommendation is accompanied by its rationale and supporting evidence, adapted to the regional context to facilitate implementation. All recommendations were reviewed and voted on through a non-anonymous process. Recommendation wording was pre-specified and linked to voting thresholds: "should" indicated unanimous agreement (100%); "is recommended" indicated ≥70% agreement; and "may be considered" was used when agreement was <70% and/or when applicability depended on local availability, feasibility, or patient-specific clinical context. The consensus includes 37 recommendations covering the initial approach, diagnosis, and management of locoregional and advanced disease. By integrating current evidence with expert consensus and accounting for regional resource variability, this document aims to harmonize clinical practice, support multidisciplinary care, and facilitate timely diagnosis and treatment. These recommendations may also serve as a foundation for future research initiatives and the development and updating of regional health policies for this highly lethal disease.
antibodies
2026-09-28 | Clinical Outcomes of Pembrolizumab Combination Therapy in Heavily Pretreated PDTC and Anaplastic Thyroid Cancer.
Poorly differentiated (PDTC) and anaplastic thyroid carcinoma (ATC) are rare, aggressive malignancies with limited treatment options. Although targeted therapies for tumours harbouring BRAF V600E mutations or fusions involving NTRK1, NTRK2, NTRK3, or RET have expanded treatment options, most patients lack such actionable alterations and urgently require alternative therapeutic strategies. Immune checkpoint blockade (ICB) has emerged as a promising approach, but its real-world application is limited by restricted trial access, reimbursement challenges, and the aggressive course of these diseases. We retrospectively analysed the Essen ATC/PDTC cohort (June 2018 - February 2024) to evaluate the real-world efficacy of lenvatinib plus pembrolizumab (LEN-PEM) in heavily pretreated patients, including PDTC cases progressing after ≥2 prior tyrosine kinase inhibitors and ATC cases treated with upfront (radio-)chemotherapy. Among the five patients with PDTC, four achieved a partial response, and one achieved durable stable disease (>50 months), corresponding to an objective response rate (ORR) of 4/5 and a clinical benefit rate (CBR) of 5/5. Median progression-free survival (PFS) and overall survival (OS) from LEN-PEM initiation were 29.1 and 34.9 months, respectively; median OS from diagnosis was not reached. Among the ten patients with ATC, four achieved a partial response, and three achieved stable disease, corresponding to an ORR of 4/10 and a CBR of 7/10. Median PFS and OS from LEN-PEM initiation were 7.6 and 9.9 months, respectively, and median OS from diagnosis was 24.3 months. LEN-PEM demonstrates meaningful clinical activity in pretreated PDTC and ATC patients, supporting its use as a later-line therapeutic option.
2026-09-07 | Single-Cell Transcriptome of Anaplastic Thyroid Cancer Reveals Immunosuppressive Tumor Microenvironment Remodeling.
Anaplastic thyroid cancer (ATC) is a rare but extremely aggressive malignancy responsible for most thyroid cancer-related deaths. To elucidate molecular and immunological characteristics distinguishing ATC from aggressive papillary thyroid cancer (PTC), we performed single-cell RNA sequencing on three ATC and three lethal PTC samples. ATC tumor cells exhibited enhanced inflammatory and immune-related gene expression, and co-activation of MAPK and PI3K pathways. Notably, p53 pathway activity was suppressed in ATC, alongside activation of angiogenic and immune-evasion programs, indicating a shift from proliferation-driven to immune-evasion-oriented signaling. Transcriptional network analysis revealed E2F family activation, including E2F1, E2F7, and E2F8, suggesting CDK-RB-E2F axis dysregulation drives tumor dedifferentiation and proliferation, whereby p53 suppression unleashes E2F-dependent transcriptional reprogramming. Immunoprofiling revealed CD8+ T cells in ATC showed elevated exhaustion signatures and high expression of inhibitory immune checkpoint molecules, accompanied by enhanced Treg-CD8+ T cell interactions, indicating a dual-layered immunosuppressive mechanism involving both T-cell exhaustion and enhanced Treg-mediated suppression. In addition, we identified antigen-presenting CAFs with altered CD4+ T-cell interactions. These findings delineate a comprehensive single-cell landscape of ATC and demonstrate coordinated alterations in tumor-intrinsic signaling and the tumor microenvironment during dedifferentiation, provide a foundation for developing rational combination immunotherapies tailored to the molecular and immunological landscape of thyroid cancer.
2026-08-28 | TIM-3 as a therapeutic target in anaplastic thyroid carcinoma: Preclinical and transcriptomic evidence supporting a new immunotherapy avenue.
We recently characterized the microenvironment of Anaplastic Thyroid Carcinoma (ATC) as immune-exhausted, rich in TIM-3-expressing exhausted cytotoxic T lymphocytes (CTLs). PD-1 was notably the least frequently expressed immune checkpoint (ICP). The results provided a potential explanation for the limited efficacy of anti-PD-1/PD-L1 immunotherapy, highlighting TIM-3 as another promising target. This pilot study further evaluated the potential efficacy of targeting TIM-3 in ATC as a therapeutic strategy in an in vitro model. A co-culture model of ATC cell line 8505C with exhausted TIM-3+ve/PD-1+ve CTLs was established and treated with anti-TIM-3 and anti-PD-1 antibodies, alone and in combination. Antibody efficacy was evaluated using flow cytometry, measuring Granzyme B and Perforin for CTL cytotoxic activity, and Annexin V and propidium iodide for tumor cell death. Additionally, differential gene expression before and after ICP blockade was analyzed using the NanoString nCounter Immune-oncology panel. Both individual and combined antibody treatments enhanced CTL cytotoxicity and promoted tumor cell death. Interestingly, ICP inhibition induced an upregulation of immune-activating pathways and downregulation of genes associated with tumor progression. These findings support the potential of TIM-3 blockers as an alternative to or in combination with anti-PD-1 therapy, thereby providing a rationale for further clinical investigation.
2026-08-13 | Thyroid Cancer: From Potential Drivers to Real Modulators.
The advent of cancer immunotherapy opened a transformative era in oncology, shifting the focus from targeting mutated genes through precision oncology to harnessing the body's immune system via agnostic therapies. This paradigm has demonstrated that a deeper understanding of the tumor immune microenvironment (TIME) can transcend the challenges posed by cancer's genetic diversity and evolutionary dynamics. In the case of thyroid cancer, progress in immunotherapy has been comparatively slow. Much of the current research still centers on the genetic landscape of thyroid tumors rather than on comprehensive exploration of their TIME. The TIME, composed of immune cells such as macrophages, lymphocytes, natural killer cells, and mast cells, along with a network of signaling molecules, evolves alongside tumor growth and metastasis. It both influences and is influenced by genetic alterations, metabolic conditions, and therapeutic interventions. This dynamic crosstalk defines the clinical and biological heterogeneity of thyroid cancers; from the aggressive anaplastic thyroid carcinoma (ATC) to the more indolent papillary thyroid carcinoma (PTC). Mapping the spatial and temporal changes within the TIME offers the opportunity to design therapies that counter immune evasion and enhance treatment response. As understanding of the tumor microenvironment deepens, thyroid cancer therapy is undergoing a major shift; from strategies aimed merely at genetic mutations to integrated, combinational approaches incorporating personalized immunotherapy. Building on recent findings, which detail immune cell composition and therapeutic implications in thyroid malignancies, this review expands on the molecular and cellular mechanisms shaping the microenvironment. We highlight how oncogenic signaling, stromal remodeling, and metabolic reprogramming coordinate to influence tumor immunity, and we explore emerging strategies that aim to reengineer the tumor microenvironment for improved therapeutic outcomes.
2026-08-01 | EP1602 - ECE_2092 - Rapid malignant transformation of long-standing multinodular goiter into anaplastic thyroid carcinoma
Abstract Anaplastic thyroid carcinoma (ATC) is a rare, highly aggressive malignancy, frequently arising in elderly patients with pre-existing benign thyroid disease. It is characterized by rapid local progression, early distant metastases, and dismal prognosis. Early recognition of warning symptoms is critical. A 78-year-old woman with a >30-year history of non-toxic multinodular goiter and multiple cardiovascular comorbidities presented with a 3-month history of progressive left-sided neck enlargement, dysphagia, hoarseness, dyspnea, and stridor, accompanied by weight loss. Physical examination revealed a firm, fixed cervical mass (~15 cm) with airway deviation. Laboratory tests showed euthyroidism and normocytic anemia. Contrast-enhanced neck and chest CT demonstrated a markedly enlarged thyroid with a heterogeneous solid mass (68 × 76 mm axial, 96 mm craniocaudal) arising from the left lobe, displacing the trachea and laryngeal structures, with retrosternal extension. Multiple bilateral pulmonary nodules consistent with metastases and right-sided pulmonary embolism were identified. No overt tracheal lumen obstruction was present, but significant airway compromise was evident clinically. Fine-needle aspiration cytology and ultrasound-guided core biopsy revealed high-grade undifferentiated carcinoma consistent with anaplastic thyroid carcinoma. Immunohistochemistry demonstrated broad cytokeratin positivity (CK8/18) with negative TTF-1, PAX8, BRAF, pan-TRK, and HER2. PD-L1 expression was strikingly high (CPS 100; TPS 100%). Given ECOG performance status 2, extensive locoregional disease, pulmonary metastases, and acute pulmonary embolism, curative treatment was not feasible. The patient received anticoagulation (LMWH) and palliative hypofractionated radiotherapy to the thyroid mass (5 × 4 Gy) for airway protection and symptom relief. A nasogastric feeding tube was placed to secure nutrition. Multidisciplinary tumor board recommended further oncologic evaluation for systemic therapy; molecular profiling was initiated. This case highlights the catastrophic malignant transformation of long-standing multinodular goiter into ATC, presenting with rapidly progressive airway-threatening disease, distant pulmonary metastases, and thromboembolic complications. Red-flag symptoms—rapid neck mass growth, dysphagia, hoarseness, and stridor—in patients with benign thyroid disease mandate urgent evaluation. The exceptionally high PD-L1 expression underscores the potential role of immunotherapy in selected ATC patients. Despite modern multimodal approaches, ATC remains a devastating disease, emphasizing the need for early detection and personalized therapeutic strategies.
gene therapies
2025-11-11 | CRISPR/Cas9-mediated deletion of MADD induces cell cycle arrest and apoptosis in anaplastic thyroid cancer cells.
Anaplastic thyroid cancer (ATC) is an aggressive malignancy with a poor prognosis and limited treatment options. Previous studies have shown that selective downregulation of the MADD (MAP-kinase-activating death domain-containing protein) gene isoform increases ATC cell susceptibility to TRAIL-induced apoptosis. However, the existence of multiple MADD gene isoforms raised the possibility of functional compensation. This study aimed to definitively evaluate the role of MADD in ATC by employing CRISPR-Cas9 to Cas9 to target exon 3, a conserved exon expressed in all known MADD isoforms, resulting in functional knockout of MADD expression. CRISPR-Cas9-mediated MADD knockout, performed in three ATC cell lines (8505 C, C643, and HTH7) with distinct mutational backgrounds, significantly impaired ATC cell function in vitro, as indicated by reduced viability, increased apoptosis, decreased migration, and G0/G1 cell cycle arrest. RNA-seq analysis revealed alterations in genes related to cell survival, proliferation, and metastasis. In the orthotopic ATC mouse model, MADD deletion dramatically suppressed tumor growth, reduced lung metastases, and prolonged survival. Our findings demonstrate that MADD plays a crucial role in ATC cell survival, proliferation, and metastasis. The consistent effects observed across multiple cell lines and in vivo models suggest that MADD may represent a promising therapeutic target for this aggressive malignancy.
2025-09-26 | TMTP1-Modified Small Extracellular Vesicles Target BRAF Mutation in Anaplastic Thyroid Cancer Reversing Vemurafenib Resistance With CRISPR/Cas9 Delivery.
This study investigates a novel approach to overcome Vemurafenib resistance in BRAF-mutant Anaplastic thyroid carcinoma (ATC) using CRISPR/Cas9 gene editing and TMTP1-modified extracellular vesicles (TMTP1-sgBRAF-EVs). By knocking out the BRAF gene, the study elucidates Vemurafenib-induced ferroptosis mechanisms involving lipid peroxidation and reactive oxygen species (ROS) generation in ATC cells. The developed TMTP1-sgBRAF-EVs system demonstrates superior tumour-targeting and drug delivery capabilities, significantly enhancing Vemurafenib efficacy in both in vitro and in vivo models. This innovative combination of gene editing technology with a nanoparticle delivery system shows promising potential as a therapeutic strategy for treating aggressive BRAF-mutant ATC.
2025-03-17 | Identification of GPX3 and JUN as Tumor Suppressors in Thyroid Cancer through Integrated WGCNA and Mendelian Randomization.
Background: Thyroid cancer (TC) ranks among the most common malignancies globally, with an increasing incidence among younger populations. While papillary thyroid carcinoma (PTC) generally has a favorable prognosis, other forms of TC, such as anaplastic thyroid carcinoma (ATC), are associated with poor outcomes. Although specific mutations, such as BRAFV600E, have been identified in certain types of TC, the underlying mechanisms remain largely unclear. Therefore, there is a critical need to further explore therapeutic targets associated with malignant tumors to improve treatment outcomes. Method: We integrated eQTL data from European populations with RNA-Seq data from TC patients obtained from TCGA and multiple GEO databases. Through differential expression analysis, WGCNA, and Mendelian randomization (MR) analysis, we sought to identify potential gene therapy targets in TC. Additionally, we explored the biological behaviors of these targets using various cellular biology assays, such as MTT, colony formation, wound healing, and Transwell assays. Molecular biology techniques, including Western blot, were employed to investigate the underlying mechanisms. Result: Differential expression analysis across six GEO datasets identified 649 genes associated with TC. Subsequent WGCNA analysis of the GSE6339 dataset revealed 2,739 genes, and MR analysis further identified 189 genes. The intersection of these datasets highlighted four key genes: TIAM1, RAP1GAP, GPX3, and JUN. GO analysis linked these genes to "response to oxidative stress" and "regulation of GTPase activity". KEGG pathway analysis demonstrated significant enrichment in pathways including "Glutathione metabolism", "cAMP signaling pathway", "Rap1 signaling pathway", "Tight junction", and "Thyroid hormone synthesis". Further, single-gene GSEA analyses suggested distinct pathways through which each gene may influence TC progression. Immune profiling revealed marked differences in immune cell populations, notably CD8+ T cells, monocytic lineage cells, neutrophils, NK cells, and T cells, between normal and cancerous thyroid tissues. Notably, RAP1GAP, GPX3, and JUN were implicated in the regulation of Treg and follicular helper T cell functions. The differential expression of these genes was rigorously validated using TCGA dataset and six additional GEO datasets. While the tumor-suppressive roles of TIAM1 and RAP1GAP have been previously established, our findings reveal that the overexpression of GPX3 and JUN significantly impairs the proliferative and migratory capacities of TC cells, underscoring their potential as therapeutic targets. Conclusion: This study identifies GPX3 and JUN as critical tumor suppressor genes in TC, with their function closely linked to T regulatory cells and follicular helper T cells. The overexpression of GPX3 and JUN demonstrates significant tumor-suppressive activity, highlighting their potential as effective therapeutic targets in combating TC.
2024-08-01 | Activating transcription factor 3 mediates apoptosis and cell cycle arrest in TP53-mutated anaplastic thyroid cancer cells.
It is believed that loss of p53 function plays a crucial role in the progression of well to poorly differentiated thyroid cancers including anaplastic thyroid carcinoma (ATC). Given the poor prognosis of ATC due to its strong therapeutic resistance, there is a need to establish new therapeutic targets to extend the survival of ATC patients. Activating transcription factor 3 (ATF3) can inhibit the oncogenic activity of mutant p53 and, as a result, contribute to tumor suppression in several TP53-mutated cancers. Herein, we demonstrate that the ectopic overexpression of ATF3 leads to the suppression of oncogenic mutant p53 activity in chemo-resistant 8305 C thyroid cancer cells harboring R273C p53 gene mutation. The biological behavior of 8305 C cells was assessed pre- and post-transfection with pCMV6-ATF3 plasmid using MTT assay, fluorescent microscopy, cell cycle, and annexin V/PI flow cytometric analysis. The effect of ectopic ATF3 overexpression on the cellular level of p53 was examined by western blotting assay. The mRNA expression levels of TP53, TAp63, ΔNp63, and SHARP1 were evaluated in ectopic ATF3-expressing cells compared to controls. The overexpression of ATF3 in 8305 C thyroid cancer cells significantly decreased cell viability and induced apoptosis and cell cycle arrest in vitro. The immunoblotting of p53 protein revealed that ATF3 overexpression significantly increased the level of mutant p53 in 8305C cells compared to mock-transfected control cells. Additionally, elevated mRNA levels of TAp63 and SHARP1 and a decreased mRNA level of ΔNp63 were observed in PCMV6-AC-ATF3-transfected 8305 C cells with significant differences compared to the mock and untreated cells. In light of our findings, it is evident that therapeutic strategies aimed at increasing ATF3 expression or enhancing the interaction between ATF3 and mutant p53 can be a promising approach for the treatment of p53-mutated metastatic thyroid cancer.
2024-07-10 | Promising Therapeutic Targets for Recurrent/Metastatic Anaplastic Thyroid Cancer.
Anaplastic thyroid cancer presents formidable challenges, particularly in cases of recurrence or metastasis. Timely BRAF V600E testing is imperative at diagnosis, initially through immunohistochemistry, followed by comprehensive genomic profiling encompassing genes such as NTRK, RET, ALK, and assessment of tumor mutation burden (TMB). FDA-approved treatment options include dabrafenib and trametinib for patients with BRAF mutations, while those exhibiting high TMB may benefit from pembrolizumab. Further therapeutic decisions hinge upon mutational profile, urgency of response required, airway integrity, and access to targeted therapies There is growing use of immunotherapy for ATC based on published reports of activity, but currently there is no FDA approved agent for ATC. The off-label utilization of "precision medicine" combinations imposes a considerable financial strain, underscoring the necessity for further clinical trials to elucidate promising therapeutic avenues for this orphan disease. There is a pressing need for the development and support of clinical trials investigating genomically driven and immune-based therapies for anaplastic thyroid cancer.
oligonucleotides
2025-10-29 | The Interplay Between lncRNAs-microRNAs Network Dysregulation and Cellular Hallmarks of Thyroid Cancer.
Background/Objectives: Thyroid cancer (TC) is the most common type of endocrine neoplasm and is increasing in incidence, particularly papillary thyroid carcinoma (PTC). Early-stage disease has a favorable prognosis; however, advanced forms, such as anaplastic thyroid carcinoma, complicate treatment. Long non-coding RNAs (lncRNAs), longer than 200 nucleotides and non-coding, together with microRNAs, have emerged as major regulators of TC pathogenesis. This review summarizes data on how dysregulated lncRNAs influence the hallmarks of cancer in thyroid malignancies. Methods: We reviewed the literature on the role of lncRNAs and microRNAs in TC, focusing on their functions as competing endogenous RNAs (ceRNAs), regulators of PI3K/AKT and Wnt/β-catenin pathways, and controllers of epigenetic alterations. Results: Dysregulated lncRNAs contribute to hallmarks including sustained growth, evading suppressors, resisting death, replicative immortality, angiogenesis, invasion, metabolic reprogramming, immune evasion, genomic instability, and tumor-promoting inflammation. ceRNA mechanisms amplify immune evasion by regulating checkpoint proteins and cytokines, altering immune cell activity. Altered lncRNA profiles correlate with aggressiveness, metastasis, and prognosis. Notable lncRNAs, such as H19, MALAT1, and DOCK9-AS2, dysregulate oncogenic pathways and represent potential biomarkers. Conclusions: Advances in therapeutics suggest inhibiting oncogenic lncRNAs or restoring tumor-suppressive lncRNAs via RNA interference, antisense oligonucleotides, or CRISPR/Cas9 editing. New technologies, including single-cell RNA sequencing and spatial transcriptomics, will improve understanding of heterogeneous lncRNA-microRNA networks in TC and support precision medicine. LncRNAs signify both molecular drivers and clinical targets for thyroid cancer.
2024-09-18 | Macrophage-Induced Carboxypeptidase A4 Promotes the Progression of Anaplastic Thyroid Cancer.
Background: The density of tumor-associated macrophages in the tumor microenvironment of anaplastic thyroid cancer (ATC) is associated with poor prognosis. However, the crosstalk between macrophages and ATC cells is poorly understood. This study aimed to examine the impact of macrophages on cancer cell phenotypes. We found a new mediator between M2 macrophages and ATC cells through proteomics analysis. Methods: The role of macrophages in proliferation, migration, and invasion of ATC cells was evaluated using coculture assay and conditioned medium (CM). Secretory factors in the CM from single or coculture were identified using liquid chromatography-tandem mass spectrometry proteomics analysis. We evaluated the role of the secretory factor in proliferation, migration, and invasion of cancer cells. In vivo xenograft model was used to evaluate the effect of the factor. Results: M2 macrophages significantly increased the proliferation, migration, and invasion of ATC cells, whereas M1 macrophages decreased the proliferation, migration, and invasion of ATC cells. Based on proteomic analysis of CM, we identify carboxypeptidase A4 (CPA4) as a mediator of the crosstalk between macrophages and ATC cells. CPA4 was only detected in the coculture media of M2 macrophage/8505C, and its expression in cancer cells increased by M2 macrophage. The expression of CPA4 protein was significantly higher in human thyroid cancers, particularly in ATCs, than normal and benign tissues. A bioinformatics analysis of public data revealed that CPA4 expression was associated with poor prognosis and dedifferentiation of thyroid cancer. Knockdown of CPA4 suppressed proliferation, colony formation, migration, and invasion of ATC cells, consistent with the decrease of STAT3, ERK, and AKT/mTOR phosphorylation and epithelial-mesenchymal transition (EMT) marker expression. In addition, the increased expression of CPA4 in cancer cells by M2 macrophage stimulation induced the polarization of macrophages to the M2 phenotype, which formed a positive feedback loop. Xenograft tumors did not develop after CPA4 knockdown. Conclusions: Our data suggest that CPA4 stimulates the progression of thyroid cancer by mediating between M2 macrophages and ATC cells. CPA4 can be a new therapeutic target for the treatment of patients with ATC.
2024-07-12 | METTL3 regulates thyroid cancer differentiation and chemosensitivity by modulating PAX8.
Background: Thyroid cancer (TC) is a common endocrine cancer with a favourable prognosis. However, poor patient prognosis due to TC dedifferentiation is becoming an urgent challenge. Recently, methyltransferase-like 3 (METTL3)-mediated N6 -methyladenosine (m6A) modification has been demonstrated to play an important role in the occurrence and progression of various cancers and a tumour suppressor role in TC. However, the mechanism of METTL3 in TC remains unclear. Methods: The correlation between METTL3 and prognosis in TC patients was evaluated by immunohistochemistry. Mettl3fl/flBrafV600ETPO-cre TC mouse models and RNA-seq were used to investigate the underlying molecular mechanism, which was further validated by in vitro experiments. The target gene of METTL3 was identified, and the complete m6A modification process was described. The phenomenon of low expression of METTL3 in TC was explained by identifying miRNAs that regulate METTL3. Results: We observed that METTL3 expression was negatively associated with tumour progression and poor prognosis in TC. Mechanistically, silencing METTL3 promoted the progression and dedifferentiation of papillary thyroid carcinoma (PTC) both in vivo and in vitro. Moreover, overexpressing METTL3 promoted the sensitivity of PTC and anaplastic thyroid cancer (ATC) cells to chemotherapeutic drugs and iodine-131 (131I) administration. Overall, the METTL3/PAX8/YTHDC1 axis has been revealed to play a pivotal role in repressing tumour occurrence, and is antagonized by miR-493-5p.
2024-07-11 | OIP5-AS1/miR-455-3p/microfibril-associated protein 2 axis exacerbates the progression of thyroid carcinoma.
The long non-coding RNA (lncRNA) Opa interacting protein 5-antisense RNA 1 (OIP5-AS1) has been shown to participate in numerous biological and pathological processes, notably including oncogenesis. OIP5-AS1 modulates oncogenic or anti-tumor activities by controlling various microRNAs (miRs) in diverse cancer types. This study sought to examine the potential role of the lncRNA OIP5-AS1-mediated miR-455-3p/microfibril-associated protein 2 (MFAP2) axis and its influence on the progression of thyroid carcinoma. Cell proliferation, migration, and apoptosis were assessed through in vitro experimental measurements, which involved the use of Cell Counting Kit 8 (CCK8), transwell, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining techniques. The estimate algorithm was employed to examine the relationship between MFAP2 and the Stromal score, Immune score, and ESTIMATE score. OIP5-AS1 expression was significantly more elevated in the thyroid carcinoma tissues and cell lines than the corresponding normal non-tumor tissues and cell lines. Following transfection with short-hairpin (sh)-OIP5-AS1, the CAL62 and SW1736 cells upregulated miR-455-3p and downregulated the MFAP2 expression levels. The downregulation of OIP5-AS1 expedited cellular apoptosis and hindered cellular proliferation and migration in the CAL62 and SW1736 cells. The in vitro experiments showed that both the suppression of MFAP2 and the increased expression of miR-455-3p exerted significant anti-cancer effects. In addition, the overexpression of MFAP2 counteracted the in vitro antineoplastic effects of the sh-OIP5-AS1 and miR-455-3p mimics. The results suggest that lncRNA OIP5-AS1 plays a crucial role in the advancement of thyroid carcinoma by inhibiting miR-455-3p to activate MFAP2.
2024-05-14 | dsRNAi-mediated silencing of PIAS2beta specifically kills anaplastic carcinomas by mitotic catastrophe
The E3 SUMO ligase PIAS2 is expressed at high levels in differentiated papillary thyroid carcinomas but at low levels in anaplastic thyroid carcinomas (ATC), an undifferentiated cancer with high mortality. We show here that depletion of the PIAS2 beta isoform with a transcribed double-stranded RNA-directed RNA interference (PIAS2b-dsRNAi) specifically inhibits growth of ATC cell lines and patient primary cultures in vitro and of orthotopic patient-derived xenografts (oPDX) in vivo. Critically, PIAS2b-dsRNAi does not affect growth of normal or non-anaplastic thyroid tumor cultures (differentiated carcinoma, benign lesions) or cell lines. PIAS2b-dsRNAi also has an anti-cancer effect on other anaplastic human cancers (pancreas, lung, and gastric). Mechanistically, PIAS2b is required for proper mitotic spindle and centrosome assembly, and it is a dosage-sensitive protein in ATC. PIAS2b depletion promotes mitotic catastrophe at prophase. High-throughput proteomics reveals the proteasome (PSMC5) and spindle cytoskeleton (TUBB3) to be direct targets of PIAS2b SUMOylation at mitotic initiation. These results identify PIAS2b-dsRNAi as a promising therapy for ATC and other aggressive anaplastic carcinomas.
other
2026-09-18 | TP53/p53 alterations in thyroid cancer: Dedifferentiation, radioiodine refractoriness and risk stratification.
Most thyroid cancers are differentiated tumours with favourable outcomes, but a clinically important minority develops invasion, distant metastasis, loss of radioiodine uptake and histological dedifferentiation. TP53 encodes p53, a tumour suppressor that coordinates DNA-damage responses, cell-cycle arrest, apoptosis and genome stability. In thyroid cancer, TP53/p53 abnormalities show a stage-dependent pattern. They are uncommon in conventional low-risk differentiated thyroid cancer (DTC), but become enriched in high-grade DTC, poorly differentiated thyroid carcinoma, anaplastic thyroid carcinoma, radioiodine-refractory disease and rapidly progressive tumours. This Review integrates the 2022 WHO classification, the 2025 American Thyroid Association guideline, early pathology studies, modern genomic cohorts, mechanistic models and recent therapeutic evidence. Current data support TP53/p53 alteration as both a marker and a functional contributor to high-grade transformation and clonal progression. In radioiodine refractoriness, TP53 abnormality is best interpreted as part of a multistep progression background involving dedifferentiation and clonal selection, rather than as a single cause of iodine-uptake loss. Clinically, TP53 testing is most useful in high-risk, progressive or treatment-refractory disease and should be interpreted together with histology, radioiodine avidity, TERT, BRAF/RAS, PI3K/AKT alterations and treatment response.
2026-09-01 | Thirty years of NCI thyroid cancer research investment (1996-2025): a longitudinal portfolio analysis of funding trends, molecular target emphasis and thematic evolution.
Thyroid cancer research has shifted over the past three decades toward molecular classification, precision diagnostics and targeted therapy. However, the evolution of public research investment in this field has not been systematically characterized. This study analyzed National Cancer Institute (NCI)-administered thyroid cancer research funding from 1996 to 2025. We performed a longitudinal portfolio analysis of NIH RePORTER records from fiscal years 1996-2025. NCI-administered projects with explicit thyroid cancer research relevance were identified through review of project titles, abstracts, public health relevance statements and project terms. The final analytic cohort comprised 753 project-award years (AYs). Rule-based dictionaries were used to annotate research stage, disease subtype, molecular target and therapeutic or diagnostic modality. Deduplicated project text was further analyzed using MedCPT biomedical embeddings and BERTopic to identify higher-order thematic domains. The cohort represented approximately USD 343.8 million in cumulative NCI funding in BRDPI-adjusted 2025 U.S. dollars. Annual research activity increased over time, peaking in 2015 with 53 active AYs and approximately USD 24.8 million in BRDPI-adjusted 2025 U.S. dollars. Translational or mixed clinical-preclinical research accounted for the largest share of the portfolio (46.5%), and R01 awards were the dominant funding mechanism (48.5%). Papillary thyroid carcinoma was the most frequently annotated subtype, followed by anaplastic, differentiated, follicular, poorly differentiated and medullary thyroid cancers. BRAF, RET, MAPK/MEK, PI3K/AKT/mTOR and RAS were the leading molecular targets. Topic modelling identified five higher-order thematic domains, suggesting a relative shift from broad thyroid cancer characterization toward diagnosis and risk stratification, molecular signaling, treatment-response biology and therapeutics for aggressive or advanced disease. NCI-administered thyroid cancer research funding expanded between 1996 and 2025 and became increasingly translational, molecularly informed and clinically oriented. These findings provide an empirical map of public research investment in thyroid oncology and may help inform future funding priorities.
2026-07-23 | Cell-state transitions and microenvironmental remodeling in thyroid cancer progression revealed by single-cell and spatial transcriptomics.
Thyroid cancer ranges from indolent differentiated tumors to metastatic, radioiodine-refractory and anaplastic disease. Conventional histology and molecular classification define major risk groups but do not resolve the cell states and spatial heterogeneity that accompany progression. This review integrates recent single-cell RNA sequencing, spatial transcriptomics and validation studies across localized papillary thyroid carcinoma (PTC), metastatic or radioiodine-refractory differentiated thyroid cancer (DTC), poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC). Current evidence indicates that progression is accompanied by changes in malignant epithelial states, stromal regions and immune patterns. Malignant epithelial cells shift from follicular-like programs toward partial EMT-like, dedifferentiation-like and anaplastic states; stromal changes include invasive borders, stiff peritumoral matrix and CAF/ECM-rich poorly differentiated regions; and immune patterns differ between progressive PTC, indolent lymphoid-organized tumors and myeloid-rich ATC. Functionally supported examples, including POSTN-IL-4 signaling, CCL20/CXCL5 macrophage-tumor reciprocal signals and SIGLEC15-associated checkpoint signaling, show how these technologies can generate therapeutic hypotheses. Yet most datasets are cross-sectional, and many ligand-receptor interactions remain computational candidates. We use the available evidence to relate epithelial plasticity, genomic context, stromal regions, immune remodeling and candidate cell-cell interactions across disease states, while separating observed associations from established stepwise tumor evolution. This synthesis highlights mechanisms and therapeutic hypotheses that require functional and clinical validation.
2026-06-28 | HIF-1α enhances ferroptosis resistance in anaplastic thyroid carcinoma by suppressing ACSL4-mediated lipid metabolic homeostasis.
Anaplastic thyroid carcinoma (ATC) exhibits extreme malignancy with a median survival of less than 6 months. Traditional therapeutic approaches yield limited efficacy, necessitating the urgent identification of novel treatment strategies. The tumor hypoxic microenvironment serves as a key driver of ATC progression and drug resistance, in which the transcription factor hypoxia-inducible factor 1α (HIF-1α) orchestrates key processes in regulating tumor metabolism, immune evasion, and resistance to cell death. Ferroptosis is a novel iron-dependent form of programmed death, defined by excessive peroxidation of polyunsaturated fatty acid phospholipids (PUFA-PL) within cellular membranes. In this study, cellular and xenograft models were employed to demonstrate that hypoxia confers ferroptosis resistance to ATC cells. Lipid metabolomics analysis revealed HIF-1α regulates lipid metabolism, and acyl-CoA synthase 4 (ACSL4) was identified as key lipid metabolism-related candidate. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were used to assess the binding of HIF-1α to the hypoxia-response element (HRE) within the ACSL4 promoter region. Flow cytometric analysis was performed to investigate how HIF-1α inhibition augments the antitumor immunogenicity of PD-1 blockade, as evidenced by enhanced intratumoral CD8+ T-cell infiltration and cytokine secretion. This study identifies a key mechanism by which HIF-1α provides ferroptosis resistance in ATC under the intrinsically hypoxic tumor microenvironment. HIF-1α directly binds the HRE within the ACSL4 promoter, transcriptionally repressing ACSL4 and consequently curtailing PUFA-PL biosynthesis, thereby conferring ferroptosis resistance on ATC cells. In addition, combined treatment with HIF-1α inhibitor and PD-1 blockade effectively suppresses tumor progression and enhances intratumoral CD8+ T-cell infiltration. This study elucidates the molecular mechanism by which HIF-1α mediates anti-ferroptosis in ATC through regulating lipid metabolism and proposes a promising therapeutic strategy in which HIF-1α inhibition acts synergistically with PD-1 blockade for the treatment of ATC.
2026-05-27 | Myeloid-derived suppressor cells in anaplastic thyroid carcinoma: insights from prospective immune profiling and implications for targeted immunotherapy.
Anaplastic thyroid carcinoma (ATC) exhibits limited responsiveness to immunotherapy. The current study characterises the immune cell repertoire in ATC compared with differentiated thyroid carcinoma (DTC) and thyroid follicular nodular disease (TFND) and evaluates IFN-γ and TGF-β mRNA expression. Cytotoxic T lymphocytes (CTLs), regulatory T cells (TREGs), natural killer cells (NK), B lymphocytes and myeloid-derived suppressor cells (MDSCs) were analysed by multicolour flow cytometry in prospectively collected ATC, DTC and TFND tissues. IFN-γ and TGF-β mRNA expression was quantified using RT-PCR. ATC demonstrated significantly higher MDSC infiltration than DTC or TFND. CTLs were elevated in ATC relative to DTC, while TREGs, NK and B-cells were lower. IFN-γ and TGF-β expression did not differ significantly although IFN-γ expression was higher in DTC and ATC than in TFND. ATC microenvironment is rich in immunosuppressive MDSCs. These findings support MDSC-focused immunomodulation as a promising adjunct therapy in ATC.
small molecules
2026-09-29 | Triptolide in Combination with the Gli1 Inhibitor GANT61 Eradicates Anaplastic Thyroid Cancer by Suppressing Cancer Stem Cell Self-Renewal and Enhancing Apoptosis and Pyroptosis.
Anaplastic thyroid cancer (ATC) is a lethal malignancy characterized by therapy resistance and rapid recurrence, driven in part by a population of thyroid cancer stem cells (CSCs). While the Gli1 inhibitor GANT61 targets CSC self-renewal, its efficacy is limited by compensatory activation of the pro-survival TAK1-AMPK pathway. Our present study aims to determine whether triptolide (TPL), a natural compound that inhibits TAK1 and induces reactive oxygen species (ROS), can overcome this resistance and achieve a synergistic anticancer effect when use with GANT61. Here, we report that TPL blocked GANT61-induced TAK1-AMPK activation. TPL alone effectively inhibited the proliferation of two ATC cell lines (8505C and SW1736) and achieved a synergistic anti-proliferative effect when used in combination with GANT61. Consistently, TPL alone effectively suppressed SW1736 xenograft tumor growth but, when used in combination with GANT61, prevented tumor recurrence. TPL in combination with GANT61 synergistically inhibited thyroid CSC self-renewal and induced apoptosis and pyroptosis. Mechanistically, TPL blocked GANT61-mediated activation of the TAK1-AMPK axis and synergistically induced ROS generation, which potentiated pyroptotic activity of Gasdermin D and E (GSDMD/E). This was confirmed by the evidence that TAK1 and AMPK inhibition by gene knockout or their specific inhibitors enhanced apoptotic and pyroptotic activity of GANT61, whereas ROS scavenge blocked apoptosis and pyroptosis induced by TPL and/or GANT61. Taken together, our study provides mechanistic insights into how TPL overcomes a key resistance pathway in CSC target therapy and suggests that the TPL-GANT61 combination could be a promising strategy to eradicate ATC.
2026-09-28 | Unmasking LAT-1 and VDR Expressions: Potential Therapeutic Windows in Anaplastic Thyroid Carcinoma
Background/Objectives: Anaplastic thyroid cancer (ATC) is a rare and highly aggressive thyroid malignancy with limited treatment options. Loss of the sodium/iodide symporter makes ATC resistant to radioactive iodine therapy, highlighting the need for alternative therapeutic targets. This study evaluated L-type amino acid transporter 1 (LAT-1) and vitamin D receptor (VDR) as potential targets in ATC. Methods: We examined LAT-1 (SLC7A5) and VDR gene expression using TCGA data from the UALCAN database. Protein expression was evaluated by immunohistochemistry in 28 formalin-fixed, paraffin-embedded ATC specimens from Loma Linda University Health. We assessed staining intensity and distribution and compared expression between male and female patients. Results: TCGA analysis showed significantly higher SLC7A5 expression in thyroid tumors compared with normal thyroid tissue (*p = 0.0115), while VDR was strongly increased in tumors (**p < 0.001) and across all tumor stages. All 28 ATC specimens expressed both LAT-1 and VDR, although staining intensity and distribution varied among tumors. LAT-1 was primarily localized to the membrane and cytoplasm of tumor cells, with additional expression in stromal and endothelial cells. VDR showed membranous, cytoplasmic, and occasional nuclear expression. LAT-1 expression did not differ significantly by sex (ns, not significant, p = 0.19), whereas VDR expression was significantly higher in females than males (**p = 0.0014). Conclusions: LAT-1 and VDR are broadly expressed in ATC despite substantial intratumoral heterogeneity. Their consistent expression supports further investigation as potential targets for radioligand or other ligand-directed therapies. The higher VDR expression observed in female patients also suggests a potentially important sex-associated difference that warrants validation in larger ATC cohorts.
2026-09-15 | Macrophages as Drivers of Resistance to Dabrafenib Plus Trametinib Therapy in Anaplastic Thyroid Cancer.
Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy with poor response to standard therapies. While Dabrafenib plus Trametinib (DT) combination therapy has improved the survival of patients with BRAF-mutant ATC, resistance remains a challenge. Given the association of macrophages with poor prognosis, and that SPRY4 has emerged as a mediator in ATC-macrophage interactions, we investigated their role in DT resistance and evaluated the therapeutic potential of macrophage targeting. Transwell co-cultures of BRAF-mutant ATC cell lines (T235 and T238) with THP-1-derived macrophages were established, and viability, invasion, and macrophage phenotype were assessed. Macrophages were also characterised in tumour samples from eleven ATC patients treated with DT. In vitro, DT significantly reduced ATC cell viability and invasion. However, macrophage co-culture significantly restored these effects, also promoting cytoskeletal remodelling and increased vimentin expression, despite DT treatment. DT significantly downregulated SPRY4 and suppressed MAPK signalling and PD-L1. These effects were also significantly reversed by macrophages. Under DT, macrophages showed an increase in M2-like polarisation in co-culture. Patients' tumour samples were highly infiltrated with macrophages. In vitro targeting of macrophages with Edicotinib, in combination with DT, significantly enhanced the anti-tumour effects of DT and decreased the M2-like polarisation, bypassing the macrophage-mediated DT resistance. Overall, the in vitro findings suggest that macrophages modulate ATC response to DT by enhancing viability, invasion, MAPK signalling and PD-L1, supporting a pro-tumoural phenotype. Targeting macrophages overcomes this resistance, highlighting the CSF1/CSF1R signalling pathway within the ATC-macrophage axis as a promising therapeutic target to improve DT efficacy.
2026-09-11 | Spatial heterogeneity in anaplastic thyroid carcinoma: Mechanistic insights and clinical translation through single-cell and spatial transcriptomics.
Anaplastic thyroid carcinoma (ATC) is a highly lethal malignancy whose therapeutic resistance is driven by profound intra-tumor heterogeneity and a complex tumor microenvironment. This review synthesizes how single-cell and spatial transcriptomic technologies are transforming our understanding of ATC by systematically decoding its cellular composition and spatial architecture. These approaches have uncovered novel aggressive cell states, delineated immunosuppressive functional niches, and elucidated the critical cell-cell communication networks that underlie treatment failure. Consequently, the therapeutic paradigm for ATC is shifting from targeting isolated driver mutations towards strategically remodeling the entire tumor ecosystem. The integration of these high-resolution insights is paving the way for the development of novel precision medicine strategies aimed at overcoming resistance in this formidable disease.
2026-09-10 | Latin American Thyroid Society expert panel consensus on anaplastic thyroid cancer.
Anaplastic thyroid cancer (ATC) is a highly aggressive histologic subtype of thyroid malignancy. Its rarity, rapidly progressive clinical course, along with limitations in health-care resources make management particularly challenging in Latin America. In recent years, substantial advances in the understanding of ATC biology have led to modifications in therapeutic strategies. This consensus aims to raise awareness and provide practical, evidence-based guidance for the diagnosis and management of ATC, summarizing current diagnostic and therapeutic advances while offering an accessible framework tailored to the Latin American context. A multidisciplinary panel of experts in endocrinology, surgery, oncology, pathology, and genetics from Latin American countries developed a series of recommendations. Each recommendation is accompanied by its rationale and supporting evidence, adapted to the regional context to facilitate implementation. All recommendations were reviewed and voted on through a non-anonymous process. Recommendation wording was pre-specified and linked to voting thresholds: "should" indicated unanimous agreement (100%); "is recommended" indicated ≥70% agreement; and "may be considered" was used when agreement was <70% and/or when applicability depended on local availability, feasibility, or patient-specific clinical context. The consensus includes 37 recommendations covering the initial approach, diagnosis, and management of locoregional and advanced disease. By integrating current evidence with expert consensus and accounting for regional resource variability, this document aims to harmonize clinical practice, support multidisciplinary care, and facilitate timely diagnosis and treatment. These recommendations may also serve as a foundation for future research initiatives and the development and updating of regional health policies for this highly lethal disease.
antibodies
2026-09-28 | Clinical Outcomes of Pembrolizumab Combination Therapy in Heavily Pretreated PDTC and Anaplastic Thyroid Cancer.
Poorly differentiated (PDTC) and anaplastic thyroid carcinoma (ATC) are rare, aggressive malignancies with limited treatment options. Although targeted therapies for tumours harbouring BRAF V600E mutations or fusions involving NTRK1, NTRK2, NTRK3, or RET have expanded treatment options, most patients lack such actionable alterations and urgently require alternative therapeutic strategies. Immune checkpoint blockade (ICB) has emerged as a promising approach, but its real-world application is limited by restricted trial access, reimbursement challenges, and the aggressive course of these diseases. We retrospectively analysed the Essen ATC/PDTC cohort (June 2018 - February 2024) to evaluate the real-world efficacy of lenvatinib plus pembrolizumab (LEN-PEM) in heavily pretreated patients, including PDTC cases progressing after ≥2 prior tyrosine kinase inhibitors and ATC cases treated with upfront (radio-)chemotherapy. Among the five patients with PDTC, four achieved a partial response, and one achieved durable stable disease (>50 months), corresponding to an objective response rate (ORR) of 4/5 and a clinical benefit rate (CBR) of 5/5. Median progression-free survival (PFS) and overall survival (OS) from LEN-PEM initiation were 29.1 and 34.9 months, respectively; median OS from diagnosis was not reached. Among the ten patients with ATC, four achieved a partial response, and three achieved stable disease, corresponding to an ORR of 4/10 and a CBR of 7/10. Median PFS and OS from LEN-PEM initiation were 7.6 and 9.9 months, respectively, and median OS from diagnosis was 24.3 months. LEN-PEM demonstrates meaningful clinical activity in pretreated PDTC and ATC patients, supporting its use as a later-line therapeutic option.
2026-09-07 | Single-Cell Transcriptome of Anaplastic Thyroid Cancer Reveals Immunosuppressive Tumor Microenvironment Remodeling.
Anaplastic thyroid cancer (ATC) is a rare but extremely aggressive malignancy responsible for most thyroid cancer-related deaths. To elucidate molecular and immunological characteristics distinguishing ATC from aggressive papillary thyroid cancer (PTC), we performed single-cell RNA sequencing on three ATC and three lethal PTC samples. ATC tumor cells exhibited enhanced inflammatory and immune-related gene expression, and co-activation of MAPK and PI3K pathways. Notably, p53 pathway activity was suppressed in ATC, alongside activation of angiogenic and immune-evasion programs, indicating a shift from proliferation-driven to immune-evasion-oriented signaling. Transcriptional network analysis revealed E2F family activation, including E2F1, E2F7, and E2F8, suggesting CDK-RB-E2F axis dysregulation drives tumor dedifferentiation and proliferation, whereby p53 suppression unleashes E2F-dependent transcriptional reprogramming. Immunoprofiling revealed CD8+ T cells in ATC showed elevated exhaustion signatures and high expression of inhibitory immune checkpoint molecules, accompanied by enhanced Treg-CD8+ T cell interactions, indicating a dual-layered immunosuppressive mechanism involving both T-cell exhaustion and enhanced Treg-mediated suppression. In addition, we identified antigen-presenting CAFs with altered CD4+ T-cell interactions. These findings delineate a comprehensive single-cell landscape of ATC and demonstrate coordinated alterations in tumor-intrinsic signaling and the tumor microenvironment during dedifferentiation, provide a foundation for developing rational combination immunotherapies tailored to the molecular and immunological landscape of thyroid cancer.
2026-08-28 | TIM-3 as a therapeutic target in anaplastic thyroid carcinoma: Preclinical and transcriptomic evidence supporting a new immunotherapy avenue.
We recently characterized the microenvironment of Anaplastic Thyroid Carcinoma (ATC) as immune-exhausted, rich in TIM-3-expressing exhausted cytotoxic T lymphocytes (CTLs). PD-1 was notably the least frequently expressed immune checkpoint (ICP). The results provided a potential explanation for the limited efficacy of anti-PD-1/PD-L1 immunotherapy, highlighting TIM-3 as another promising target. This pilot study further evaluated the potential efficacy of targeting TIM-3 in ATC as a therapeutic strategy in an in vitro model. A co-culture model of ATC cell line 8505C with exhausted TIM-3+ve/PD-1+ve CTLs was established and treated with anti-TIM-3 and anti-PD-1 antibodies, alone and in combination. Antibody efficacy was evaluated using flow cytometry, measuring Granzyme B and Perforin for CTL cytotoxic activity, and Annexin V and propidium iodide for tumor cell death. Additionally, differential gene expression before and after ICP blockade was analyzed using the NanoString nCounter Immune-oncology panel. Both individual and combined antibody treatments enhanced CTL cytotoxicity and promoted tumor cell death. Interestingly, ICP inhibition induced an upregulation of immune-activating pathways and downregulation of genes associated with tumor progression. These findings support the potential of TIM-3 blockers as an alternative to or in combination with anti-PD-1 therapy, thereby providing a rationale for further clinical investigation.
2026-08-13 | Thyroid Cancer: From Potential Drivers to Real Modulators.
The advent of cancer immunotherapy opened a transformative era in oncology, shifting the focus from targeting mutated genes through precision oncology to harnessing the body's immune system via agnostic therapies. This paradigm has demonstrated that a deeper understanding of the tumor immune microenvironment (TIME) can transcend the challenges posed by cancer's genetic diversity and evolutionary dynamics. In the case of thyroid cancer, progress in immunotherapy has been comparatively slow. Much of the current research still centers on the genetic landscape of thyroid tumors rather than on comprehensive exploration of their TIME. The TIME, composed of immune cells such as macrophages, lymphocytes, natural killer cells, and mast cells, along with a network of signaling molecules, evolves alongside tumor growth and metastasis. It both influences and is influenced by genetic alterations, metabolic conditions, and therapeutic interventions. This dynamic crosstalk defines the clinical and biological heterogeneity of thyroid cancers; from the aggressive anaplastic thyroid carcinoma (ATC) to the more indolent papillary thyroid carcinoma (PTC). Mapping the spatial and temporal changes within the TIME offers the opportunity to design therapies that counter immune evasion and enhance treatment response. As understanding of the tumor microenvironment deepens, thyroid cancer therapy is undergoing a major shift; from strategies aimed merely at genetic mutations to integrated, combinational approaches incorporating personalized immunotherapy. Building on recent findings, which detail immune cell composition and therapeutic implications in thyroid malignancies, this review expands on the molecular and cellular mechanisms shaping the microenvironment. We highlight how oncogenic signaling, stromal remodeling, and metabolic reprogramming coordinate to influence tumor immunity, and we explore emerging strategies that aim to reengineer the tumor microenvironment for improved therapeutic outcomes.
2026-08-01 | EP1602 - ECE_2092 - Rapid malignant transformation of long-standing multinodular goiter into anaplastic thyroid carcinoma
Abstract Anaplastic thyroid carcinoma (ATC) is a rare, highly aggressive malignancy, frequently arising in elderly patients with pre-existing benign thyroid disease. It is characterized by rapid local progression, early distant metastases, and dismal prognosis. Early recognition of warning symptoms is critical. A 78-year-old woman with a >30-year history of non-toxic multinodular goiter and multiple cardiovascular comorbidities presented with a 3-month history of progressive left-sided neck enlargement, dysphagia, hoarseness, dyspnea, and stridor, accompanied by weight loss. Physical examination revealed a firm, fixed cervical mass (~15 cm) with airway deviation. Laboratory tests showed euthyroidism and normocytic anemia. Contrast-enhanced neck and chest CT demonstrated a markedly enlarged thyroid with a heterogeneous solid mass (68 × 76 mm axial, 96 mm craniocaudal) arising from the left lobe, displacing the trachea and laryngeal structures, with retrosternal extension. Multiple bilateral pulmonary nodules consistent with metastases and right-sided pulmonary embolism were identified. No overt tracheal lumen obstruction was present, but significant airway compromise was evident clinically. Fine-needle aspiration cytology and ultrasound-guided core biopsy revealed high-grade undifferentiated carcinoma consistent with anaplastic thyroid carcinoma. Immunohistochemistry demonstrated broad cytokeratin positivity (CK8/18) with negative TTF-1, PAX8, BRAF, pan-TRK, and HER2. PD-L1 expression was strikingly high (CPS 100; TPS 100%). Given ECOG performance status 2, extensive locoregional disease, pulmonary metastases, and acute pulmonary embolism, curative treatment was not feasible. The patient received anticoagulation (LMWH) and palliative hypofractionated radiotherapy to the thyroid mass (5 × 4 Gy) for airway protection and symptom relief. A nasogastric feeding tube was placed to secure nutrition. Multidisciplinary tumor board recommended further oncologic evaluation for systemic therapy; molecular profiling was initiated. This case highlights the catastrophic malignant transformation of long-standing multinodular goiter into ATC, presenting with rapidly progressive airway-threatening disease, distant pulmonary metastases, and thromboembolic complications. Red-flag symptoms—rapid neck mass growth, dysphagia, hoarseness, and stridor—in patients with benign thyroid disease mandate urgent evaluation. The exceptionally high PD-L1 expression underscores the potential role of immunotherapy in selected ATC patients. Despite modern multimodal approaches, ATC remains a devastating disease, emphasizing the need for early detection and personalized therapeutic strategies.
gene therapies
2025-11-11 | CRISPR/Cas9-mediated deletion of MADD induces cell cycle arrest and apoptosis in anaplastic thyroid cancer cells.
Anaplastic thyroid cancer (ATC) is an aggressive malignancy with a poor prognosis and limited treatment options. Previous studies have shown that selective downregulation of the MADD (MAP-kinase-activating death domain-containing protein) gene isoform increases ATC cell susceptibility to TRAIL-induced apoptosis. However, the existence of multiple MADD gene isoforms raised the possibility of functional compensation. This study aimed to definitively evaluate the role of MADD in ATC by employing CRISPR-Cas9 to Cas9 to target exon 3, a conserved exon expressed in all known MADD isoforms, resulting in functional knockout of MADD expression. CRISPR-Cas9-mediated MADD knockout, performed in three ATC cell lines (8505 C, C643, and HTH7) with distinct mutational backgrounds, significantly impaired ATC cell function in vitro, as indicated by reduced viability, increased apoptosis, decreased migration, and G0/G1 cell cycle arrest. RNA-seq analysis revealed alterations in genes related to cell survival, proliferation, and metastasis. In the orthotopic ATC mouse model, MADD deletion dramatically suppressed tumor growth, reduced lung metastases, and prolonged survival. Our findings demonstrate that MADD plays a crucial role in ATC cell survival, proliferation, and metastasis. The consistent effects observed across multiple cell lines and in vivo models suggest that MADD may represent a promising therapeutic target for this aggressive malignancy.
2025-09-26 | TMTP1-Modified Small Extracellular Vesicles Target BRAF Mutation in Anaplastic Thyroid Cancer Reversing Vemurafenib Resistance With CRISPR/Cas9 Delivery.
This study investigates a novel approach to overcome Vemurafenib resistance in BRAF-mutant Anaplastic thyroid carcinoma (ATC) using CRISPR/Cas9 gene editing and TMTP1-modified extracellular vesicles (TMTP1-sgBRAF-EVs). By knocking out the BRAF gene, the study elucidates Vemurafenib-induced ferroptosis mechanisms involving lipid peroxidation and reactive oxygen species (ROS) generation in ATC cells. The developed TMTP1-sgBRAF-EVs system demonstrates superior tumour-targeting and drug delivery capabilities, significantly enhancing Vemurafenib efficacy in both in vitro and in vivo models. This innovative combination of gene editing technology with a nanoparticle delivery system shows promising potential as a therapeutic strategy for treating aggressive BRAF-mutant ATC.
2025-03-17 | Identification of GPX3 and JUN as Tumor Suppressors in Thyroid Cancer through Integrated WGCNA and Mendelian Randomization.
Background: Thyroid cancer (TC) ranks among the most common malignancies globally, with an increasing incidence among younger populations. While papillary thyroid carcinoma (PTC) generally has a favorable prognosis, other forms of TC, such as anaplastic thyroid carcinoma (ATC), are associated with poor outcomes. Although specific mutations, such as BRAFV600E, have been identified in certain types of TC, the underlying mechanisms remain largely unclear. Therefore, there is a critical need to further explore therapeutic targets associated with malignant tumors to improve treatment outcomes. Method: We integrated eQTL data from European populations with RNA-Seq data from TC patients obtained from TCGA and multiple GEO databases. Through differential expression analysis, WGCNA, and Mendelian randomization (MR) analysis, we sought to identify potential gene therapy targets in TC. Additionally, we explored the biological behaviors of these targets using various cellular biology assays, such as MTT, colony formation, wound healing, and Transwell assays. Molecular biology techniques, including Western blot, were employed to investigate the underlying mechanisms. Result: Differential expression analysis across six GEO datasets identified 649 genes associated with TC. Subsequent WGCNA analysis of the GSE6339 dataset revealed 2,739 genes, and MR analysis further identified 189 genes. The intersection of these datasets highlighted four key genes: TIAM1, RAP1GAP, GPX3, and JUN. GO analysis linked these genes to "response to oxidative stress" and "regulation of GTPase activity". KEGG pathway analysis demonstrated significant enrichment in pathways including "Glutathione metabolism", "cAMP signaling pathway", "Rap1 signaling pathway", "Tight junction", and "Thyroid hormone synthesis". Further, single-gene GSEA analyses suggested distinct pathways through which each gene may influence TC progression. Immune profiling revealed marked differences in immune cell populations, notably CD8+ T cells, monocytic lineage cells, neutrophils, NK cells, and T cells, between normal and cancerous thyroid tissues. Notably, RAP1GAP, GPX3, and JUN were implicated in the regulation of Treg and follicular helper T cell functions. The differential expression of these genes was rigorously validated using TCGA dataset and six additional GEO datasets. While the tumor-suppressive roles of TIAM1 and RAP1GAP have been previously established, our findings reveal that the overexpression of GPX3 and JUN significantly impairs the proliferative and migratory capacities of TC cells, underscoring their potential as therapeutic targets. Conclusion: This study identifies GPX3 and JUN as critical tumor suppressor genes in TC, with their function closely linked to T regulatory cells and follicular helper T cells. The overexpression of GPX3 and JUN demonstrates significant tumor-suppressive activity, highlighting their potential as effective therapeutic targets in combating TC.
2024-08-01 | Activating transcription factor 3 mediates apoptosis and cell cycle arrest in TP53-mutated anaplastic thyroid cancer cells.
It is believed that loss of p53 function plays a crucial role in the progression of well to poorly differentiated thyroid cancers including anaplastic thyroid carcinoma (ATC). Given the poor prognosis of ATC due to its strong therapeutic resistance, there is a need to establish new therapeutic targets to extend the survival of ATC patients. Activating transcription factor 3 (ATF3) can inhibit the oncogenic activity of mutant p53 and, as a result, contribute to tumor suppression in several TP53-mutated cancers. Herein, we demonstrate that the ectopic overexpression of ATF3 leads to the suppression of oncogenic mutant p53 activity in chemo-resistant 8305 C thyroid cancer cells harboring R273C p53 gene mutation. The biological behavior of 8305 C cells was assessed pre- and post-transfection with pCMV6-ATF3 plasmid using MTT assay, fluorescent microscopy, cell cycle, and annexin V/PI flow cytometric analysis. The effect of ectopic ATF3 overexpression on the cellular level of p53 was examined by western blotting assay. The mRNA expression levels of TP53, TAp63, ΔNp63, and SHARP1 were evaluated in ectopic ATF3-expressing cells compared to controls. The overexpression of ATF3 in 8305 C thyroid cancer cells significantly decreased cell viability and induced apoptosis and cell cycle arrest in vitro. The immunoblotting of p53 protein revealed that ATF3 overexpression significantly increased the level of mutant p53 in 8305C cells compared to mock-transfected control cells. Additionally, elevated mRNA levels of TAp63 and SHARP1 and a decreased mRNA level of ΔNp63 were observed in PCMV6-AC-ATF3-transfected 8305 C cells with significant differences compared to the mock and untreated cells. In light of our findings, it is evident that therapeutic strategies aimed at increasing ATF3 expression or enhancing the interaction between ATF3 and mutant p53 can be a promising approach for the treatment of p53-mutated metastatic thyroid cancer.
2024-07-10 | Promising Therapeutic Targets for Recurrent/Metastatic Anaplastic Thyroid Cancer.
Anaplastic thyroid cancer presents formidable challenges, particularly in cases of recurrence or metastasis. Timely BRAF V600E testing is imperative at diagnosis, initially through immunohistochemistry, followed by comprehensive genomic profiling encompassing genes such as NTRK, RET, ALK, and assessment of tumor mutation burden (TMB). FDA-approved treatment options include dabrafenib and trametinib for patients with BRAF mutations, while those exhibiting high TMB may benefit from pembrolizumab. Further therapeutic decisions hinge upon mutational profile, urgency of response required, airway integrity, and access to targeted therapies There is growing use of immunotherapy for ATC based on published reports of activity, but currently there is no FDA approved agent for ATC. The off-label utilization of "precision medicine" combinations imposes a considerable financial strain, underscoring the necessity for further clinical trials to elucidate promising therapeutic avenues for this orphan disease. There is a pressing need for the development and support of clinical trials investigating genomically driven and immune-based therapies for anaplastic thyroid cancer.
oligonucleotides
2025-10-29 | The Interplay Between lncRNAs-microRNAs Network Dysregulation and Cellular Hallmarks of Thyroid Cancer.
Background/Objectives: Thyroid cancer (TC) is the most common type of endocrine neoplasm and is increasing in incidence, particularly papillary thyroid carcinoma (PTC). Early-stage disease has a favorable prognosis; however, advanced forms, such as anaplastic thyroid carcinoma, complicate treatment. Long non-coding RNAs (lncRNAs), longer than 200 nucleotides and non-coding, together with microRNAs, have emerged as major regulators of TC pathogenesis. This review summarizes data on how dysregulated lncRNAs influence the hallmarks of cancer in thyroid malignancies. Methods: We reviewed the literature on the role of lncRNAs and microRNAs in TC, focusing on their functions as competing endogenous RNAs (ceRNAs), regulators of PI3K/AKT and Wnt/β-catenin pathways, and controllers of epigenetic alterations. Results: Dysregulated lncRNAs contribute to hallmarks including sustained growth, evading suppressors, resisting death, replicative immortality, angiogenesis, invasion, metabolic reprogramming, immune evasion, genomic instability, and tumor-promoting inflammation. ceRNA mechanisms amplify immune evasion by regulating checkpoint proteins and cytokines, altering immune cell activity. Altered lncRNA profiles correlate with aggressiveness, metastasis, and prognosis. Notable lncRNAs, such as H19, MALAT1, and DOCK9-AS2, dysregulate oncogenic pathways and represent potential biomarkers. Conclusions: Advances in therapeutics suggest inhibiting oncogenic lncRNAs or restoring tumor-suppressive lncRNAs via RNA interference, antisense oligonucleotides, or CRISPR/Cas9 editing. New technologies, including single-cell RNA sequencing and spatial transcriptomics, will improve understanding of heterogeneous lncRNA-microRNA networks in TC and support precision medicine. LncRNAs signify both molecular drivers and clinical targets for thyroid cancer.
2024-09-18 | Macrophage-Induced Carboxypeptidase A4 Promotes the Progression of Anaplastic Thyroid Cancer.
Background: The density of tumor-associated macrophages in the tumor microenvironment of anaplastic thyroid cancer (ATC) is associated with poor prognosis. However, the crosstalk between macrophages and ATC cells is poorly understood. This study aimed to examine the impact of macrophages on cancer cell phenotypes. We found a new mediator between M2 macrophages and ATC cells through proteomics analysis. Methods: The role of macrophages in proliferation, migration, and invasion of ATC cells was evaluated using coculture assay and conditioned medium (CM). Secretory factors in the CM from single or coculture were identified using liquid chromatography-tandem mass spectrometry proteomics analysis. We evaluated the role of the secretory factor in proliferation, migration, and invasion of cancer cells. In vivo xenograft model was used to evaluate the effect of the factor. Results: M2 macrophages significantly increased the proliferation, migration, and invasion of ATC cells, whereas M1 macrophages decreased the proliferation, migration, and invasion of ATC cells. Based on proteomic analysis of CM, we identify carboxypeptidase A4 (CPA4) as a mediator of the crosstalk between macrophages and ATC cells. CPA4 was only detected in the coculture media of M2 macrophage/8505C, and its expression in cancer cells increased by M2 macrophage. The expression of CPA4 protein was significantly higher in human thyroid cancers, particularly in ATCs, than normal and benign tissues. A bioinformatics analysis of public data revealed that CPA4 expression was associated with poor prognosis and dedifferentiation of thyroid cancer. Knockdown of CPA4 suppressed proliferation, colony formation, migration, and invasion of ATC cells, consistent with the decrease of STAT3, ERK, and AKT/mTOR phosphorylation and epithelial-mesenchymal transition (EMT) marker expression. In addition, the increased expression of CPA4 in cancer cells by M2 macrophage stimulation induced the polarization of macrophages to the M2 phenotype, which formed a positive feedback loop. Xenograft tumors did not develop after CPA4 knockdown. Conclusions: Our data suggest that CPA4 stimulates the progression of thyroid cancer by mediating between M2 macrophages and ATC cells. CPA4 can be a new therapeutic target for the treatment of patients with ATC.
2024-07-12 | METTL3 regulates thyroid cancer differentiation and chemosensitivity by modulating PAX8.
Background: Thyroid cancer (TC) is a common endocrine cancer with a favourable prognosis. However, poor patient prognosis due to TC dedifferentiation is becoming an urgent challenge. Recently, methyltransferase-like 3 (METTL3)-mediated N6 -methyladenosine (m6A) modification has been demonstrated to play an important role in the occurrence and progression of various cancers and a tumour suppressor role in TC. However, the mechanism of METTL3 in TC remains unclear. Methods: The correlation between METTL3 and prognosis in TC patients was evaluated by immunohistochemistry. Mettl3fl/flBrafV600ETPO-cre TC mouse models and RNA-seq were used to investigate the underlying molecular mechanism, which was further validated by in vitro experiments. The target gene of METTL3 was identified, and the complete m6A modification process was described. The phenomenon of low expression of METTL3 in TC was explained by identifying miRNAs that regulate METTL3. Results: We observed that METTL3 expression was negatively associated with tumour progression and poor prognosis in TC. Mechanistically, silencing METTL3 promoted the progression and dedifferentiation of papillary thyroid carcinoma (PTC) both in vivo and in vitro. Moreover, overexpressing METTL3 promoted the sensitivity of PTC and anaplastic thyroid cancer (ATC) cells to chemotherapeutic drugs and iodine-131 (131I) administration. Overall, the METTL3/PAX8/YTHDC1 axis has been revealed to play a pivotal role in repressing tumour occurrence, and is antagonized by miR-493-5p.
2024-07-11 | OIP5-AS1/miR-455-3p/microfibril-associated protein 2 axis exacerbates the progression of thyroid carcinoma.
The long non-coding RNA (lncRNA) Opa interacting protein 5-antisense RNA 1 (OIP5-AS1) has been shown to participate in numerous biological and pathological processes, notably including oncogenesis. OIP5-AS1 modulates oncogenic or anti-tumor activities by controlling various microRNAs (miRs) in diverse cancer types. This study sought to examine the potential role of the lncRNA OIP5-AS1-mediated miR-455-3p/microfibril-associated protein 2 (MFAP2) axis and its influence on the progression of thyroid carcinoma. Cell proliferation, migration, and apoptosis were assessed through in vitro experimental measurements, which involved the use of Cell Counting Kit 8 (CCK8), transwell, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining techniques. The estimate algorithm was employed to examine the relationship between MFAP2 and the Stromal score, Immune score, and ESTIMATE score. OIP5-AS1 expression was significantly more elevated in the thyroid carcinoma tissues and cell lines than the corresponding normal non-tumor tissues and cell lines. Following transfection with short-hairpin (sh)-OIP5-AS1, the CAL62 and SW1736 cells upregulated miR-455-3p and downregulated the MFAP2 expression levels. The downregulation of OIP5-AS1 expedited cellular apoptosis and hindered cellular proliferation and migration in the CAL62 and SW1736 cells. The in vitro experiments showed that both the suppression of MFAP2 and the increased expression of miR-455-3p exerted significant anti-cancer effects. In addition, the overexpression of MFAP2 counteracted the in vitro antineoplastic effects of the sh-OIP5-AS1 and miR-455-3p mimics. The results suggest that lncRNA OIP5-AS1 plays a crucial role in the advancement of thyroid carcinoma by inhibiting miR-455-3p to activate MFAP2.
2024-05-14 | dsRNAi-mediated silencing of PIAS2beta specifically kills anaplastic carcinomas by mitotic catastrophe
The E3 SUMO ligase PIAS2 is expressed at high levels in differentiated papillary thyroid carcinomas but at low levels in anaplastic thyroid carcinomas (ATC), an undifferentiated cancer with high mortality. We show here that depletion of the PIAS2 beta isoform with a transcribed double-stranded RNA-directed RNA interference (PIAS2b-dsRNAi) specifically inhibits growth of ATC cell lines and patient primary cultures in vitro and of orthotopic patient-derived xenografts (oPDX) in vivo. Critically, PIAS2b-dsRNAi does not affect growth of normal or non-anaplastic thyroid tumor cultures (differentiated carcinoma, benign lesions) or cell lines. PIAS2b-dsRNAi also has an anti-cancer effect on other anaplastic human cancers (pancreas, lung, and gastric). Mechanistically, PIAS2b is required for proper mitotic spindle and centrosome assembly, and it is a dosage-sensitive protein in ATC. PIAS2b depletion promotes mitotic catastrophe at prophase. High-throughput proteomics reveals the proteasome (PSMC5) and spindle cytoskeleton (TUBB3) to be direct targets of PIAS2b SUMOylation at mitotic initiation. These results identify PIAS2b-dsRNAi as a promising therapy for ATC and other aggressive anaplastic carcinomas.
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2026-09-18 | TP53/p53 alterations in thyroid cancer: Dedifferentiation, radioiodine refractoriness and risk stratification.
Most thyroid cancers are differentiated tumours with favourable outcomes, but a clinically important minority develops invasion, distant metastasis, loss of radioiodine uptake and histological dedifferentiation. TP53 encodes p53, a tumour suppressor that coordinates DNA-damage responses, cell-cycle arrest, apoptosis and genome stability. In thyroid cancer, TP53/p53 abnormalities show a stage-dependent pattern. They are uncommon in conventional low-risk differentiated thyroid cancer (DTC), but become enriched in high-grade DTC, poorly differentiated thyroid carcinoma, anaplastic thyroid carcinoma, radioiodine-refractory disease and rapidly progressive tumours. This Review integrates the 2022 WHO classification, the 2025 American Thyroid Association guideline, early pathology studies, modern genomic cohorts, mechanistic models and recent therapeutic evidence. Current data support TP53/p53 alteration as both a marker and a functional contributor to high-grade transformation and clonal progression. In radioiodine refractoriness, TP53 abnormality is best interpreted as part of a multistep progression background involving dedifferentiation and clonal selection, rather than as a single cause of iodine-uptake loss. Clinically, TP53 testing is most useful in high-risk, progressive or treatment-refractory disease and should be interpreted together with histology, radioiodine avidity, TERT, BRAF/RAS, PI3K/AKT alterations and treatment response.
2026-09-01 | Thirty years of NCI thyroid cancer research investment (1996-2025): a longitudinal portfolio analysis of funding trends, molecular target emphasis and thematic evolution.
Thyroid cancer research has shifted over the past three decades toward molecular classification, precision diagnostics and targeted therapy. However, the evolution of public research investment in this field has not been systematically characterized. This study analyzed National Cancer Institute (NCI)-administered thyroid cancer research funding from 1996 to 2025. We performed a longitudinal portfolio analysis of NIH RePORTER records from fiscal years 1996-2025. NCI-administered projects with explicit thyroid cancer research relevance were identified through review of project titles, abstracts, public health relevance statements and project terms. The final analytic cohort comprised 753 project-award years (AYs). Rule-based dictionaries were used to annotate research stage, disease subtype, molecular target and therapeutic or diagnostic modality. Deduplicated project text was further analyzed using MedCPT biomedical embeddings and BERTopic to identify higher-order thematic domains. The cohort represented approximately USD 343.8 million in cumulative NCI funding in BRDPI-adjusted 2025 U.S. dollars. Annual research activity increased over time, peaking in 2015 with 53 active AYs and approximately USD 24.8 million in BRDPI-adjusted 2025 U.S. dollars. Translational or mixed clinical-preclinical research accounted for the largest share of the portfolio (46.5%), and R01 awards were the dominant funding mechanism (48.5%). Papillary thyroid carcinoma was the most frequently annotated subtype, followed by anaplastic, differentiated, follicular, poorly differentiated and medullary thyroid cancers. BRAF, RET, MAPK/MEK, PI3K/AKT/mTOR and RAS were the leading molecular targets. Topic modelling identified five higher-order thematic domains, suggesting a relative shift from broad thyroid cancer characterization toward diagnosis and risk stratification, molecular signaling, treatment-response biology and therapeutics for aggressive or advanced disease. NCI-administered thyroid cancer research funding expanded between 1996 and 2025 and became increasingly translational, molecularly informed and clinically oriented. These findings provide an empirical map of public research investment in thyroid oncology and may help inform future funding priorities.
2026-07-23 | Cell-state transitions and microenvironmental remodeling in thyroid cancer progression revealed by single-cell and spatial transcriptomics.
Thyroid cancer ranges from indolent differentiated tumors to metastatic, radioiodine-refractory and anaplastic disease. Conventional histology and molecular classification define major risk groups but do not resolve the cell states and spatial heterogeneity that accompany progression. This review integrates recent single-cell RNA sequencing, spatial transcriptomics and validation studies across localized papillary thyroid carcinoma (PTC), metastatic or radioiodine-refractory differentiated thyroid cancer (DTC), poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC). Current evidence indicates that progression is accompanied by changes in malignant epithelial states, stromal regions and immune patterns. Malignant epithelial cells shift from follicular-like programs toward partial EMT-like, dedifferentiation-like and anaplastic states; stromal changes include invasive borders, stiff peritumoral matrix and CAF/ECM-rich poorly differentiated regions; and immune patterns differ between progressive PTC, indolent lymphoid-organized tumors and myeloid-rich ATC. Functionally supported examples, including POSTN-IL-4 signaling, CCL20/CXCL5 macrophage-tumor reciprocal signals and SIGLEC15-associated checkpoint signaling, show how these technologies can generate therapeutic hypotheses. Yet most datasets are cross-sectional, and many ligand-receptor interactions remain computational candidates. We use the available evidence to relate epithelial plasticity, genomic context, stromal regions, immune remodeling and candidate cell-cell interactions across disease states, while separating observed associations from established stepwise tumor evolution. This synthesis highlights mechanisms and therapeutic hypotheses that require functional and clinical validation.
2026-06-28 | HIF-1α enhances ferroptosis resistance in anaplastic thyroid carcinoma by suppressing ACSL4-mediated lipid metabolic homeostasis.
Anaplastic thyroid carcinoma (ATC) exhibits extreme malignancy with a median survival of less than 6 months. Traditional therapeutic approaches yield limited efficacy, necessitating the urgent identification of novel treatment strategies. The tumor hypoxic microenvironment serves as a key driver of ATC progression and drug resistance, in which the transcription factor hypoxia-inducible factor 1α (HIF-1α) orchestrates key processes in regulating tumor metabolism, immune evasion, and resistance to cell death. Ferroptosis is a novel iron-dependent form of programmed death, defined by excessive peroxidation of polyunsaturated fatty acid phospholipids (PUFA-PL) within cellular membranes. In this study, cellular and xenograft models were employed to demonstrate that hypoxia confers ferroptosis resistance to ATC cells. Lipid metabolomics analysis revealed HIF-1α regulates lipid metabolism, and acyl-CoA synthase 4 (ACSL4) was identified as key lipid metabolism-related candidate. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were used to assess the binding of HIF-1α to the hypoxia-response element (HRE) within the ACSL4 promoter region. Flow cytometric analysis was performed to investigate how HIF-1α inhibition augments the antitumor immunogenicity of PD-1 blockade, as evidenced by enhanced intratumoral CD8+ T-cell infiltration and cytokine secretion. This study identifies a key mechanism by which HIF-1α provides ferroptosis resistance in ATC under the intrinsically hypoxic tumor microenvironment. HIF-1α directly binds the HRE within the ACSL4 promoter, transcriptionally repressing ACSL4 and consequently curtailing PUFA-PL biosynthesis, thereby conferring ferroptosis resistance on ATC cells. In addition, combined treatment with HIF-1α inhibitor and PD-1 blockade effectively suppresses tumor progression and enhances intratumoral CD8+ T-cell infiltration. This study elucidates the molecular mechanism by which HIF-1α mediates anti-ferroptosis in ATC through regulating lipid metabolism and proposes a promising therapeutic strategy in which HIF-1α inhibition acts synergistically with PD-1 blockade for the treatment of ATC.
2026-05-27 | Myeloid-derived suppressor cells in anaplastic thyroid carcinoma: insights from prospective immune profiling and implications for targeted immunotherapy.
Anaplastic thyroid carcinoma (ATC) exhibits limited responsiveness to immunotherapy. The current study characterises the immune cell repertoire in ATC compared with differentiated thyroid carcinoma (DTC) and thyroid follicular nodular disease (TFND) and evaluates IFN-γ and TGF-β mRNA expression. Cytotoxic T lymphocytes (CTLs), regulatory T cells (TREGs), natural killer cells (NK), B lymphocytes and myeloid-derived suppressor cells (MDSCs) were analysed by multicolour flow cytometry in prospectively collected ATC, DTC and TFND tissues. IFN-γ and TGF-β mRNA expression was quantified using RT-PCR. ATC demonstrated significantly higher MDSC infiltration than DTC or TFND. CTLs were elevated in ATC relative to DTC, while TREGs, NK and B-cells were lower. IFN-γ and TGF-β expression did not differ significantly although IFN-γ expression was higher in DTC and ATC than in TFND. ATC microenvironment is rich in immunosuppressive MDSCs. These findings support MDSC-focused immunomodulation as a promising adjunct therapy in ATC.
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Drug Discovery Landscape
6 orphan drug designations for Anaplastic thyroid carcinoma, including 4 approved therapies.
6 orphan drug designations for Anaplastic thyroid carcinoma, including 4 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
pralsetinib [Gavreto] | small molecules | FDA | Approved | Rigel Pharmaceuticals, Inc. |
autologous chimeric antigen receptor (CAR) T cells targeting intercellular adhesion molecule-1 (ICAM-1) | cell therapies | FDA | AffyImmune Therapeutics, Inc. | |
dabrafenib and trametinib [Tafinlar(r) Capsules a nd Mekinist(r) Tablets] | small molecules | FDA | Approved | Novartis Pharmaceuticals Corporation |
vemurafenib | small molecules | FDA | Genentech, Inc. | |
cabozantinib [Cometriq] | small molecules | FDA | Approved | Exelixis, Inc. |
vandetanib [CAPRELSA(r)] | small molecules | FDA | Approved | Genzyme Corporation |
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