RARE DISEASE
Medullary thyroid carcinoma
Medullary thyroid carcinoma
Medullary thyroid carcinoma
Synonyms: MTC
Synonyms: MTC
Synonyms: MTC
Drug discovery
10
drugs
With orphan designations
Overview
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from parafollicular C cells of the thyroid, accounting for 1%–5% of thyroid cancers [1][11]. Approximately 25% of cases are hereditary, linked to RET proto-oncogene mutations (MEN2 syndromes) [1][6], while 75% are sporadic. Diagnosis hinges on elevated serum calcitonin and imaging [10][11]. Early lymph node metastasis occurs in 50%–80% of cases [4][6], impacting prognosis [4][13]. Primary treatment involves total thyroidectomy with lymph node dissection [1][8][12], with advanced/metastatic disease managed via RET inhibitors (selpercatinib, pralsetinib) or multi-kinase inhibitors (vandetanib, cabozantinib) [3][8][12].
Burden
Survival: 93% 5-year survival for localized disease vs. 28% for stage IV [1][9].
Prognostic factors: >10 metastatic lymph nodes reduce survival (HR 3.56) [4][13]; delayed diagnosis increases mortality [9][15].
Disparities: Lower lymph node evaluation rates and survival in Black vs. non-Hispanic White patients [2][9].
Early genetic testing for RET mutations and multidisciplinary care improve outcomes [6][11].
Categories: rare endocrine diseases, rare neoplastic diseases
Research Papers
1,869 drug discovery papers about Medullary thyroid carcinoma, with 3 first-in-class and 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,869 drug discovery papers about Medullary thyroid carcinoma, with 3 first-in-class and 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-07-31 | Application of Theranostics in Thyroid Cancer Management.
The incidental thyroid uptake of radiolabeled ligands used in positron emission tomography/computed tomography (PET/CT) targeting cell-surface proteins is observed in up to 6% of all scans. While diffuse thyroid uptake of ligands targeting somatostatin receptor type 2 (SSTR2), prostate-specific membrane antigen (PSMA), fibroblast activation protein (FAPI), or choline, is observed in normal thyroid or usually signifies a benign thyroid abnormality, a heterogenous or focal uptake is associated with malignant lesions in up to 19.7% of patients. The PET/CTs utilizing these ligands are characterized by decreased diagnostic sensitivity for detection of thyroid cancer metastases than cross-sectional imaging or 18-fluorodeoxyglucose (18FDG)-PET/CT but are highly specific for detection of a subset of thyroid cancers characterized by a high target protein expression. Increased uptake of radiolabeled ligands targeting SSTR2, PSMA, FAPI, integrin αvβ3 and minigastrin can be used for patients' selection for peptide receptor radionuclide therapy (PRRT). PRRT can be applied in clinical trials and/or off label for patients with advanced radioactive iodine-refractory thyroid cancer who have limited treatment options or for medullary thyroid carcinoma of neuroendocrine origin. The PRRT-induced disease control rate approaches 60% and PRRT is well tolerated with limited side effects. Efficacy could be improved with careful patients' selection based on the expression of molecular targets and their function, quantified by standard uptake values (SUVmax) in diagnostic PET/CT imaging. Adopting an individualized dosimetry-based approach and synthesizing ligands with better tumor retention and residence time may help optimize treatment response.
2026-02-19 | Safety and efficacy of peptide receptor radionuclide therapy for advanced medullary thyroid cancer: a systematic review and meta-analysis.
This systematic review and meta-analysis evaluated the safety and efficacy of somatostatin receptor (SSTR) peptide receptor radionuclide therapy (PRRT) in patients with metastatic or progressive medullary thyroid cancer (MTC). PubMed, Scopus, and Web of Science databases were systematically searched from inception to April 22, 2025, to identify relevant clinical studies. Methodological quality was assessed via the National Institutes of Health Quality Assessment Tool. Pooled estimates of the disease control rate (DCR), overall response rate (ORR), and adverse events (AEs) following SSTR PRRT administration were calculated for both the imaging and biochemical endpoints via Stata software version 17. The analysis revealed pooled DCRs of 52% (95% CI: 43–61%) and 58% (95% CI: 46–70%) for the biochemical and imaging endpoints, respectively. The pooled ORRs were 32% (95% CI: 23–42%) for the biochemical endpoints and 17% (95% CI: 7–26%) for the imaging endpoints. Compared with [90Y]Y-DOTATOC, [177Lu]Lu-DOTATATE had a slightly greater pooled imaging DCR (64% vs. 50%) and a lower overall toxicity rate (7% vs. 24%). The biochemical DCRs were comparable (51–52%), although [177Lu]Lu-DOTATATE achieved a higher biochemical ORR (37% vs. 29%). The [90Y]Y-DOTATOC group reported relatively higher rates of gastrointestinal and hematologic toxicities, with only limited cases of high-grade events reported in three studies. [177Lu]Lu-DOTATATE showed no renal toxicity, unlike [90Y]Y-DOTATOC, which mainly caused low-grade nephrotoxicity events at a pooled rate of 6%. Overall, this meta-analysis suggests that SSTR PRRT is a promising therapeutic option for metastatic or progressive MTC, achieving reliable disease control with a favorable safety profile.
2026-02-14 | Peptide receptor radionuclide therapy in neuroendocrine tumours: advances, combination strategies, and future directions.
Peptide receptor radionuclide therapy (PRRT) has established itself as a pivotal component in the management of advanced, somatostatin receptor (SSTR)-positive neuroendocrine tumours (NETs). The NETTER-1 phase III trial demonstrated that [177Lu]Lu-DOTATATE significantly prolongs progression-free survival (PFS) and improves quality of life in patients with midgut NETs refractory to somatostatin analogues, leading to regulatory approval by both EMA (2017) and FDA (2018). The recent NETTER-2 phase III trial further extended these findings by supporting the first-line use of PRRT in Grade 2 and 3 gastroentero-pancreatic (GEP)-NETs (Ki-67 ≥ 10 ≤ 55%). Beyond standard β-emitting therapy, several developments are reshaping the field: the clinical adoption of SSTR antagonists such as radiolabelled JR-11 and LM3, targeted α-particle-emitting therapies (225Ac, 212Pb, 213Bi) for resistant disease, and rational combination strategies with chemotherapy, DNA-repair inhibitors, and immunotherapy. Parallel innovation in radiopharmaceutical chemistry has yielded new peptide ligands, including cholecystokinin-2 receptor (CCK2R)-targeted compounds such as DOTA-MGS5, which show promise for rare NETs such as medullary thyroid carcinoma (MTC) and small-cell lung cancer (SCLC). This review summarises clinical evidence, translational advances, and future perspectives for PRRT as a cornerstone of precision nuclear oncology. Emphasis is placed on expanding indications, integrating α-emitters, improving safety and dosimetry, and developing novel theragnostic ligands that enable personalised treatment strategies for NETs patients.
2025-10-26 | Incretin signaling at the crossroads of metabolism, inflammation, and tumorigenesis: implications for obesity patients.
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for type 2 diabetes and obesity, delivering robust metabolic and cardiovascular benefits. However, their potential impact on tumorigenesis remains debated. Preclinical findings in rodents have suggested that GLP-1R activation may influence thyroid C-cells and pancreatic ducts, while human studies have yielded inconsistent cancer risk signals. This review synthesizes current evidence on GLP-1R and glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling in cancer biology, emphasizing the role of biased agonism and context-dependent effects. GLP-1R activation, predominantly via cAMP/PKA signaling, has shown antiproliferative effects in gastrointestinal adenocarcinomas and pancreatic ductal adenocarcinoma models, whereas GIPR activation frequently engages PI3K/Akt (PI3K, phosphoinositide 3-kinase; Akt, protein kinase B) and ERK/MAPK cascades (ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase), enhancing proliferation in colorectal and neuroendocrine tumors. Conversely, GLP-1R stimulation can promote growth in GLP-1R-high neuroendocrine tumors, reflecting ligand- and tissue-specific signaling biases. Beyond direct tumor cell effects, GLP-1RAs modulate the tumor microenvironment by reducing NF-κB-driven inflammation, altering stromal activity, and potentially enhancing immune surveillance. Current clinical evidence does not support a generalized increase in cancer risk with GLP-1RA therapy; benefits in metabolic control may even reduce obesity-related cancer incidence. Nonetheless, caution is advised in patients with medullary thyroid carcinoma, MEN2, or GLP-1R-high neuroendocrine tumors. The emerging paradigm suggests precision approaches, integrating receptor profiling, biased agonist design, and risk stratification, will be key to safely leveraging incretin-based therapies in oncology.
2025-09-18 | Dimeric CCK2R radiotheranostic tracers synergize with mTOR inhibition for enhanced tumor therapy.
Purpose: The cholecystokinin-2 receptor (CCK2R) is highly expressed in several neuroendocrine cancers, particularly in medullary thyroid carcinoma (MTC) and small cell lung cancer (SCLC) and represents a promising target for radiotheranostic applications. Several minigastrin-derived analogs, such as DOTA-MGS5 and DOTA-CCK-66, have demonstrated favorable tumor targeting and imaging performance. Building on these advances, we developed and evaluated a novel dimeric CCK2R-targeted radiotracer, and further investigated its radiosensitization potential in combination with mTOR inhibition. Experimental Design: We designed a dimeric CCK2R-targeted agent, DOTA-CCK2R-dimer, labeled with 68Ga for PET imaging and 177Lu for radionuclide therapy. Furthermore, we combined [177Lu]Lu-DOTA-CCK2R-dimer with the mTOR inhibitor RAD001 and used single-cell RNA sequencing (scRNA-seq) to investigate the mechanisms of radiosensitization. Results: Compared with its monomeric counterpart [68Ga]Ga-DOTA-CCK-66, [68Ga]Ga-DOTA-CCK2R-dimer demonstrated superior tumor targeting in vivo. Tumor uptake reached 26.13 ± 6.21 %ID/g at 2 h post-injection, which was significantly greater than that of the monomeric tracer (19.63 ± 3.35 %ID/g, p < 0.05). Additionally, [177Lu]Lu-DOTA-CCK2R-dimer selectively eliminated highly proliferative and poorly differentiated tumor cell subpopulations. Combination treatment with RAD001 improved therapeutic efficacy by suppressing glutathione-mediated detoxification and increasing oxidative stress. Furthermore, glutathione S-transferase kappa 1 (GSTK1) was identified as a key regulator that modulates radiosensitivity. Conclusions: DOTA-CCK2R-dimer exhibits favorable in vivo stability, notable tumor retention, and excellent imaging performance. Combining this agent with mTOR inhibition offers a synergistic strategy to sensitize tumors to radiotherapy, providing a promising approach for treating refractory CCK2R-positive malignancies.
small molecules
2026-09-08 | Novel nastorazepide-based radioligands demonstrate effective cholecystokinin-2 receptor targeting with potential for theranostic applications.
Radiolabeled gastrin antagonists are emerging as a new tool for the diagnosis and treatment of cholecystokinin-2 receptor (CCK2R) expressing tumors such as medullary thyroid carcinoma and small cell lung cancer, overcoming limitations of agonist-based ligands. In this study, the CCK2R antagonist nastorazepide (Z-360) was used as a targeting scaffold in combination with either a peptidic (NPP) or a hydrophilic polysaccharide (NPS) linker and the chelators DOTA and DOTAGA, yielding four novel radioligands. These were evaluated alongside the reference minigastrin analogs DOTA-PP-F11 and DOTA-MGS5. All ligands were synthetized via solid-phase peptide synthesis and labeled with In-111 and Lu-177. In vitro characterization included receptor affinity, hydrophilicity and cellular uptake in A431-CCK2R. In vivo biodistribution and imaging were performed in A431-CCK2R xenografts. [177Lu]Lu-DOTAGA-NPP was further assessed in a proof-of-concept therapy study and metabolic stability assays. 111In-labeled antagonists showed 3-4-fold higher site recognition than [111In]In-DOTA-PP-F11 and nanomolar affinities comparable to the reference ligand. Among the tested ligands, [111In]In-DOTAGA-NPP demonstrated the highest cellular uptake (22.0 ± 0.2%), approximately twice that of the other ligands and moderately higher than [111In]In-DOTA-PP-F11 (16.2 ± 1.8%) after 4 h at 37 °C. In vivo, all 177Lu-labeled antagonists demonstrated high tumor uptake (range: 22.98 ± 7.04 - 29.00 ± 3.30% I.A./g tissue) with [177Lu]Lu-DOTAGA-NPP exhibiting the most favorable tumor-to-tissue ratios. Compared with [177Lu]Lu-DOTA-MGS5, [177Lu]Lu-DOTAGA-NPP showed rapid tumor accumulation with faster washout but reduced stomach exposure and high in vivo stability. [¹⁷⁷Lu]Lu-DOTAGA-NPP emerged as the most promising lead compound, combining high tumor uptake, favorable tumor-to-organ ratios, and excellent in vivo stability. Although no significant therapeutic efficacy was observed in the tested xenograft model, the results support [177Lu]Lu-DOTAGA-NPP as a promising lead for optimization. Overall, these findings highlight the potential of Z-360-based CCK2R antagonists as scaffolds for next-generation theranostic radioligands and support their development as alternatives to minigastrin-based tracers.
2026-09-01 | Mechanistic and Clinical Perspectives on Traditional Chinese Medicine in Thyroid Cancer Management.
Thyroid cancer is one of the most prevalent malignancies of the endocrine system, comprising various subtypes such as papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), medullary thyroid carcinoma (MTC), and the aggressive anaplastic thyroid carcinoma (ATC). Despite a generally favorable prognosis for PTC, recurrence, metastasis, and resistance to conventional therapies continue to pose significant challenges. The pathogenesis of thyroid cancer involves genetic mutations in BRAF, RAS, and RET, as well as dysregulated molecular pathways such as MAPK, PI3K/Akt/mTOR, and NF-κB, all of which contribute to cancer progression and therapeutic resistance. This review highlights how Traditional Chinese Medicine (TCM), with its extensive history and a diverse range of bioactive compounds derived from natural sources, offers a complementary approach to thyroid cancer treatment. TCM has been shown to modulate various cellular mechanisms, including inhibiting tumor proliferation, inducing apoptosis, and regulating immune responses. Additionally, TCM can influence the tumor microenvironment (TME), reducing immune evasion and improving therapeutic sensitivity. Many TCM compounds have been identified for their ability to target critical oncogenic signaling pathways, offering a holistic approach to cancer treatment with fewer side effects than traditional chemotherapy. Furthermore, integrating TCM with modern medicine, including novel formulations and nanotechnology, offers the potential to improve efficacy and reduce side effects. The convergence of Artificial Intelligence (AI) and Systems Biology also holds great promise for optimizing personalized treatment regimens and advancing targeted therapies, ultimately improving patient outcomes in thyroid cancer management.
2026-08-14 | Signaling pathways and targeted therapy in high‑risk refractory thyroid cancer: From bench to bedside (Review).
Thyroid cancer is the most common endocrine malignancy worldwide, with its incidence increasing markedly over the past several decades, while mortality trends have shown complex patterns. High‑risk refractory thyroid cancers (including radioactive iodine‑refractory differentiated thyroid cancer, poorly differentiated thyroid cancer, anaplastic thyroid carcinoma, progressive medullary thyroid carcinoma and locally advanced disease) pose major challenges in clinical management. The present review systematically reviewed recent epidemiological trends in thyroid cancer and provided an in‑depth exploration of the molecular regulatory mechanisms of key signaling pathways, including MAPK, PI3K/AKT, Janus kinase/STAT, WNT/β‑catenin and NF‑κB, along with their roles in the pathogenesis and progression of thyroid cancer. Based on this, the latest clinical research advances in targeted therapies for high‑risk, refractory thyroid cancer are elaborated on, covering multikinase inhibitors, B‑Raf proto‑oncogene, serine/threonine kinase/mitogen‑activated protein kinase kinase inhibitors, immunotherapy combinations, innovative targeted strategies and redifferentiation approaches. Finally, future directions are discussed based on the 'total treatment' paradigm and strategies to overcome drug resistance, aiming to provide a systematic reference for basic research and clinical translation in thyroid cancer.
2026-07-29 | Targeted therapies in the management of advanced medullary thyroid cancer.
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor that contributes disproportionately to thyroid cancer-related mortality. Historically, systemic treatment options for advanced MTC were limited due to poor responsiveness to radioactive iodine and conventional chemotherapy. The development of targeted therapies has significantly transformed disease management. This narrative review summarizes current evidence on targeted therapies for advanced MTC, including multikinase inhibitors (MKIs), selective RET inhibitors, and emerging treatment strategies. Literature on efficacy, safety, resistance mechanisms, and novel therapeutic approaches was evaluated. First-generation MKIs, including vandetanib and cabozantinib, demonstrated clinical benefit by targeting RET and angiogenic pathways, though off-target toxicities limited tolerability. More recently, selective RET inhibitors, such as selpercatinib and pralsetinib, have shown high response rates and improved safety profiles, establishing them as preferred first-line therapies for RET-mutant MTC. However, pralsetinib's recent market withdrawal due to regulatory challenges highlights the need for additional options. Emerging therapies, including BOS172738, SY-5007, and peptide receptor radionuclide therapy, show promising early results. Resistance mechanisms, including gatekeeper and solvent front mutations, remain a challenge. Advances in clinical biomarkers and novel approaches, such as CAR-T cell therapy, may further support personalized treatment. Targeted therapies have reshaped the management of advanced MTC, with selective RET inhibitors offering improved efficacy and tolerability. Continued research is essential to overcome resistance, expand therapeutic options, and improve patient outcomes.
2026-07-01 | Clinical performance of [68Ga]Ga-DOTA-FAPI-04 PET/CT in detecting recurrent disease in medullary thyroid carcinoma: a comparative analysis with [18F]F-FDG and [68Ga]Ga-DOTATATE PET/CT, alongside identification of suitable candidates for targeted radionuclide therapy.
To evaluate and compare the diagnostic performance of [68Ga]Ga-DOTA-FAPI-04 with [18F]F-FDG and [68Ga]Ga-DOTATATE PET/CT for detecting recurrent disease in patients with medullary thyroid carcinoma (MTC) and additionally evaluate their role for prognostication and theranostics in management of MTC. In this prospective single-centre study, 56 patients with suspected recurrent MTC underwent [68Ga]Ga-DOTA-Fibroblast activation protein inhibitor (FAPI)-04, [18F]F-FDG, and [68Ga]Ga-DOTATATE PET/CT. The primary endpoint was patient-based diagnostic accuracy for recurrent disease. Secondary endpoints included lesion-based detection rates across pre-defined anatomical regions, correlation with biochemical and clinicopathological parameters, prognostic assessment for progression-free survival, and a novel exploratory FAPI-SSTR Theranostic (FAST) score was developed to guide personalized radiopharmaceutical therapy (RPT). [68Ga]Ga-DOTA-FAPI-04 PET/CT demonstrated higher sensitivity 95.92% and accuracy 94.64% compared to [18F]F-FDG-PET/CT (sensitivity: 89.80%, accuracy: 89.29%) and [68Ga]Ga-DOTATATE (sensitivity: 77.55%, accuracy: 76.79%) on patient-based analysis for detecting recurrent disease. [68Ga]Ga-DOTA-FAPI-04 was showed high detection rates for disease recurrence in mediastinal nodal (91.9%), liver (91.7%), and skeletal (86.5%) metastases.[68Ga]Ga-DOTA-FAPI-04 uptake was associated with a modestly shorter mean progression-free survival and altered clinical management in 35.7% of total patients. Additionally, the pre-defined exploratory FAST scoring system stratified 34 patients (60.7%) for [177Lu]Lu-FAPI-RPT, 8 (14.3%) for [177Lu]Lu-DOTATATE PRRT, and 9 (16.1%) for either or combined RPT. [68Ga]Ga-DOTA-FAPI-04 PET/CT showed higher diagnostic accuracy for the identification of recurrent MTC over standard [18F]F-FDG and [68Ga]Ga-DOTATATE PET/CT, with higher regional detection rates for liver and osteoblastic skeletal metastases. Furthermore, while the exploratory FAST score provides a framework for patient stratification and personalizing targeted theranostic strategies, it requires future validation through larger multicentre trials prior to clinical adoption.
oligonucleotides
2024-07-01 | LncRNA ZFAS1 promotes invasion of medullary thyroid carcinoma by enhancing EPAS1 expression via miR-214-3p/UCHL1 axis.
lncRNA ZFAS1 was identified to facilitate thyroid cancer, but its role in medullary thyroid carcinoma (MTC) remains unknown. This study aimed to unravel the potential function of this lncRNA in MTC by investigating the involvement of the lncRNA ZFAS1 in a ceRNA network that regulates MTC invasion. Proliferation, invasion, and migration of cells were evaluated using EdU staining and Transwell assays. Immunoprecipitation (IP) assays, dual-fluorescence reporter, and RNA IP assays were employed to examine the binding interaction among genes. Nude mice were used to explore the role of lncRNA ZFAS1 in MTC in vivo. ZFAS1 and EPAS1 were upregulated in MTC. Silencing ZFAS1 inhibited MTC cell proliferation and invasion under hypoxic conditions, which reduced EPAS1 protein levels. UCHL1 knockdown increased EPAS1 ubiquitination. ZFAS1 positively regulated UCHL1 expression by binding to miR-214-3p. Finally, silencing ZFAS1 significantly repressed tumor formation and metastasis in MTC. LncRNA ZFAS1 promotes invasion of MTC by upregulating EPAS1 expression via the miR-214-3p/UCHL1 axis.
2024-06-03 | MicroRNAs in thyroid cancer with focus on medullary thyroid carcinoma: potential therapeutic targets and diagnostic/prognostic markers and web based tools.
This review aimed to describe the inculpation of microRNAs (miRNAs) in thyroid cancer (TC) and its subtypes, mainly medullary thyroid carcinoma (MTC), and to outline web-based tools and databases for bioinformatics analysis of miRNAs in TC. Additionally, the capacity of miRNAs to serve as therapeutic targets and biomarkers in TC management will be discussed. This review is based on a literature search of relevant articles on the role of miRNAs in TC and its subtypes, mainly MTC. Additionally, web-based tools and databases for bioinformatics analysis of miRNAs in TC were identified and described. MiRNAs can perform as oncomiRs or antioncoges, relying on the target mRNAs they regulate. MiRNA replacement therapy using miRNA mimics or antimiRs that aim to suppress the function of certain miRNAs can be applied to correct miRNAs aberrantly expressed in diseases, particularly in cancer. MiRNAs are involved in the modulation of fundamental pathways related to cancer, resembling cell cycle checkpoints and DNA repair pathways. MiRNAs are also rather stable and can reliably be detected in different types of biological materials, rendering them favorable diagnosis and prognosis biomarkers as well. MiRNAs have emerged as promising tools for evaluating medical outcomes in TC and as possible therapeutic targets. The contribution of miRNAs in thyroid cancer, particularly MTC, is an active area of research, and the utility of web applications and databases for the biological data analysis of miRNAs in TC is becoming increasingly important.
2024-05-28 | LINC00887 Acts as an Enhancer RNA to Promote Medullary Thyroid Carcinoma Progression by Binding with FOXQ1.
Medullary thyroid carcinoma (MTC) is a rare but aggressive endocrine malignancy that originates from the parafollicular C cells of the thyroid gland. Enhancer RNAs (eRNAs) are non-coding RNAs transcribed from enhancer regions, which are critical regulators of tumorigenesis. However, the roles and regulatory mechanisms of eRNAs in MTC remain poorly understood. This study aims to identify key eRNAs regulating the malignant phenotype of MTC and to uncover transcription factors involved in the regulation of key eRNAs. GSE32662 and GSE114068 were used for the identification of differentially expressed genes, eRNAs, enhancers and enhancer-regulated genes in MTC. Metascape and the transcription factor affinity prediction method were used for gene function enrichment and transcription factor prediction, respectively. qRT-PCR was used to detect gene transcription levels. ChIP-qPCR was used to assess the binding of histone H3 lysine 27 acetylation (H3K27ac)-enriched regions to anti- H3K27ac. RIP-qPCR was used to detect the binding between FOXQ1 and LINC00887. CCK8 and Transwell were performed to measure the proliferation and invasion of MTC cells, respectively. Intracellular reactive oxygen species (ROS) levels were quantified using a ROS assay kit. Four eRNAs (H1FX-AS1, LINC00887, MCM3AP-AS1 and A1BG-AS1) were screened, among which LINC00887 was the key eRNA promoting the proliferation and invasion of MTC cells. A total of 135 genes controlled by LINC00887-regulated enhancers were identified; among them, BCL2, PRDX1, SFTPD, TPO, GSS, RAD52, ZNF580, and ZFP36L1 were significantly enriched in the "ROS metabolic process" term. As a transcription factor regulating genes enriched in the "ROS metabolic process" term, FOXQ1 could recruit LINC00887. Overexpression of FOXQ1 restored LINC00887 knockdown-induced downregulation of GSS and ZFP36L1 transcription in MTC cells. Additionally, FOXQ1 overexpression counteracted the inhibitory effects of LINC00887 knockdown on the proliferation and invasion of MTC cells and the promotion of intracellular ROS accumulation induced by LINC00887 knockdown. LINC00887 was identified as a key eRNA promoting the malignant phenotype of MTC cells. The involvement of FOXQ1 was essential for LINC00887 to play a pro-tumorigenic role in MTC. Our findings suggest that the FOXQ1/LINC00887 axis is a potential therapeutic target for MTC.
2023-06-28 | Validation of miRNAs as diagnostic and prognostic biomarkers, and possible therapeutic targets in medullary thyroid cancers.
Medullary thyroid cancer (MTC) is a rare type of neuroendocrine tumor that produces a hormone called calcitonin (CT). Thyroidectomy is the preferred treatment for MTC, as chemotherapy has been shown to have limited effectiveness. Targeted therapy approaches are currently being used for patients with advanced, metastatic MTC. Several studies have identified microRNAs, including miR-21, as playing a role in the development of MTC. Programmed cell death 4 (PDCD4) is a tumor suppressor gene that is an important target of miR-21. Our previous research has shown that high levels of miR-21 are associated with low PDCD4 nuclear scores and high CT levels. The aim of this study was to investigate the potential of this pathway as a novel therapeutic target for MTC. We used a specific process to silence miR-21 in two human MTC cell lines. We studied the effect of this anti-miRNA process alone and in combination with cabozantinib and vandetanib, two drugs used in targeted therapy for MTC. We analyzed the effect of miR-21 silencing on cell viability, PDCD4 and CT expression, phosphorylation pathways, cell migration, cell cycle, and apoptosis. Silencing miR-21 alone resulted in a reduction of cell viability and an increase in PDCD4 levels at both mRNA and protein levels. It also led to a reduction in CT expression at both mRNA and secretion levels. When combined with cabozantinib and vandetanib, miR-21 silencing did not affect cell cycle or migration but was able to enhance apoptosis. Silencing miR-21, although not showing synergistic activity with TKIs (tyrosine kinase inhibitors), represents a potential alternative worth exploring as a therapeutic target for MTC.
2022-07-19 | Tumor-related Molecular Regulatory Mechanisms of Long Non-coding RNA RMST: Recent Evidence.
Long non-coding RNA rhabdomyosarcoma 2-associated transcript (LncRNA RMST) can affect every aspect of tumor progressions, such as proliferation, translocation, and apoptosis. As a result, RMST can be used as an attractive biomarker for early diagnosis and clinical therapies of different disease states. This article aims to review pathophysiological functions, molecular mechanisms as well as promising biotherapies of RMST in multiple tumors. Through the systematic induction and summary of 46 papers published in PubMed concerning this study, the molecular mechanisms of RMST in all kinds of tumors have been reviewed. LncRNA RMST is a tumor-related regulatory mediator, aberrantly expressed in diverse tumors, including medullary thyroid cancer, hepatocellular carcinoma, endometrial carcinoma, colon cancer, pancreatic cancer, glioma, Wilm's tumor, and breast cancer. Furthermore, as a mechanismbased player, RMST probably guides the translation and post-translation modification, containing DNA methylation and SUMOylation. It is capable of regulating distinct tumor cells and stem cells of biological behaviors via various molecular pathways. LncRNA RMST, potentially as an original therapeutic target, is valuable in the occurrence, development, and apoptosis of different tumors.
antibodies
2026-09-03 | Compartment-Specific Recurrence in Medullary Thyroid Cancer.
Total thyroidectomy with bilateral central neck dissection is recommended for medullary thyroid carcinoma (MTC), even in patients without clinical nodal involvement. However, the role of contralateral prophylactic central neck dissection (pCND) remains debated, leading to variations in practice. To evaluate the outcomes of nodal dissection in compartment-specific recurrence in patients undergoing surgical treatment for MTC, including a subgroup analysis of patients with preoperative clinically node-negative (cN0) disease stratified by whether they underwent contralateral pCND. This was a multicenter retrospective cohort study of adult patients with MTC who underwent thyroidectomy between 1998 and 2021 in 4 academic referral centers. Data were analyzed from February to July 2026. Patients with missing operative data, including initial thyroidectomy information and central neck dissection laterality, were excluded. Contralateral pCND at the time of initial surgical treatment. Recurrence categorized as biochemical (calcitonin >2 pg/mL without radiographic findings); ipsilateral central, ipsilateral lateral, contralateral central, and contralateral lateral neck; and distant metastatic. Effect size was reported as Rosenthal r (r) for continuous variables and as risk difference (RD) with 95% CIs for categorical variables. Multivariable Cox regression was used to evaluate risk factors for contralateral neck recurrence and overall recurrence. This study in a total of 235 patients who underwent surgical treatment for MTC (132 [56%] female; median age, 56 years [IQR, 43-66 years]) found that, preoperatively, 105 patients (45%) had cN0 disease, of whom 58 (55%) underwent contralateral pCND. Genetic testing was performed in 127 (54%) patients, with a 25% rate of germline RET variant. Overall, 73 patients (31%) developed disease recurrence: 15% in the ipsilateral central, 15% ipsilateral lateral, 5% contralateral central, and 8% contralateral lateral neck; 11% distant metastatic; and 4% biochemical. Among patients with cN0 disease, differences in the rates of overall recurrence (22% vs 15%; RD, 0.07; 95% CI, -0.07 to 0.22) and contralateral central neck recurrence (5% vs 2%; RD, 0.03; 95% CI, -0.04 to 0.10) were small and imprecisely estimated between those who did and did not undergo contralateral pCND. On multivariable analysis adjusting for sex, tumor size, and nodal involvement, contralateral pCND was not associated with reduced overall recurrence (hazard ratio [HR], 0.59; 95% CI, 0.21-1.62) or contralateral neck recurrence (HR, 0.23; 95% CI, 0.02-3.08). This study found that, in MTC, the most frequent sites of recurrence were the ipsilateral central and lateral neck. Contralateral central neck recurrence was uncommon; however, our wide CIs preclude definitive conclusions about the benefit of contralateral pCND, and larger studies are warranted.
2026-07-25 | Tumor expression of CGRP confers sensitivity to growth inhibition by the anti-CGRP antibody fremanezumab.
Calcitonin gene related peptide (CGRP) is a neuropeptide exerting key neuromodulatory, vasoactive and immune functions within the periphery and central nervous system. Drugs targeting CGRP such as anti-CGRP mAbs or small molecule CGRP receptor antagonists have been recently approved for prevention and acute treatment of migraine. A growing body of evidence, however, indicates that CGRP plays key roles in tumor growth. Specifically, the neuropeptide promotes tumor angiogenesis, counteracts antitumor immune responses, and supports cancer proliferation in nutrient-poor environment via autophagic activation. There is general agreement that tumor-infiltrating sensory nerve fibers represent the source of CGRP within neoplasms. In keeping with the tumorigenic role of CGRP, several studies report anticancer effects of rimegepant, a CGRP receptor antagonist. In the present study, by means of in vitro and xenograft models we build upon these findings showing that CGRP can be released within the tumor microenvironment directly by cancer cells. Of note, the migraine preventative anti-CGRP mAb fremanezumab selectively counteracted growth to CGRP-proficient tumors. The antitumoral effect occurred in spite of lack of evidence for intratumoral sensory fiber infiltration, angiogenesis inhibition, or promotion of autophagy. The antibody, however, by altering ERK signaling, might counteract MAPK-dependent growth signaling in CGRP-expressing tumors. Collectively, our findings disclose for the first time the tumorigenic effects of CGRP released from cancer cells and suggest the translational potential of clinically available anti-CGRP monoclonal antibodies as a therapeutic strategy for cancer.
2026-06-08 | DLL3 Expression in a Genotyped Cohort of Sporadic Medullary Thyroid Carcinomas.
Delta-like ligand 3 (DLL3) has been identified as a therapeutic target in high-grade neuroendocrine carcinomas, particularly small cell lung carcinoma. Data on DLL3 expression in medullary thyroid carcinoma (MTC) are limited; moreover, the relationship between DLL3 expression and MTC genotype has not been explored. We evaluated DLL3 expression (based on staining intensity and percentage of positive cells) in a genotyped cohort of sporadic MTC. In our cohort of 39 cases, 27 (69%) tumors were positive for DLL3, including 1 (4%) with low DLL3 expression, 10 (26%) with moderate expression, and 16 (41%) with high expression. DLL3 expression was significantly associated with grade (P=0.036), presence of a RET mutation (P=0.014), presence of lymph node metastases at diagnosis (P<0.005), and disease progression (P<0.005). All 9 (100%) high-grade tumors were positive for DLL3. In contrast, 18 (60%) of 30 low-grade tumors were DLL3 positive. DLL3 was positive in 17 (89%) of 19 RET-mutated tumors, 4 (50%) of 8 RAS-mutated tumors, and 6 (50%) of 12 RET/RAS wild-type tumors. All 24 primary tumors with associated lymph node metastases at diagnosis were positive for DLL3. Among cases with follow-up data (n=35), all 17 tumors with disease progression were DLL3 positive (13 RET-mutated tumors, 1 RAS-mutated tumor, and 3 RET/RAS wild-type tumors), including 5 with moderate expression and 12 with high expression. Most MTCs express DLL3; moreover, DLL3 expression is associated with lymph node metastases at diagnosis and disease progression, indicating that DLL3 may be an effective therapeutic target in MTC.
2026-06-02 | B7-H3 (CD276) as a candidate therapeutic target in medullary thyroid cancer.
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignancy with limited therapeutic options in advanced disease. While selective RET inhibitors have expanded systemic treatment strategies, disease progression frequently occurs over time. Antibody-drug conjugates (ADCs) have shown efficacy in the treatment of solid tumors but require suitable cell-surface targets, which have not yet been systemically characterized in MTC. This study aimed to identify therapeutically relevant surface antigens in MTC using immunohistochemical profiling. In this retrospective exploratory study, tumor specimens of 41 patients with histologically confirmed MTC were analyzed. Formalin-fixed paraffin-embedded tissues from primary tumors were subjected to immunohistochemical staining for six therapeutically relevant cell-surface antigens. Surface expression was assessed and categorized as strong, weak, or absent. Statistical analyses were conducted using descriptive statistics and Fisher's exact test. The study included 41 patients with MTC, representing different tumor stages and clinicopathological characteristics with lymph node involvement in 45%. B7-H3 showed membranous expression in 91% of the included cases with strong expression in 82%, which was consistent across tumor stages and clinical subgroups. In contrast, no expression was detected for Nectin-4, Trop-2, c-Met, PD-L2, and Claudin 18.2 in any evaluable samples. B7-H3 was identified as the only consistently and strongly expressed surface antigen in a clinically heterogeneous MTC cohort. These findings identify B7-H3 as a potential therapeutic opportunity for advanced MTC and underscore the limited number of targetable surface antigens in this disease.
2026-05-12 | A Novel Approach to Targeting DLL3 with Tarlatamab in a Patient with Medullary Thyroid Carcinoma after Progression on Selpercatinib.
After progression on selpercatinib, patients with RET-altered medullary thyroid carcinoma (MTC) face a poor prognosis. Tarlatamab-a Delta-like ligand 3-targeted bispecific T-cell engager-is a promising therapeutic option for patients with MTC, but a prior case series raised safety concerns in this population. A patient with RET-altered MTC who progressed on selpercatinib received tarlatamab using a three-step step-up dosing regimen with modified protocols for monitoring and managing cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). This patient experienced grade 2 CRS and grade 2 ICANS after cycle 1, day 1. He did not experience any grade ≥3 treatment-related adverse events. The patient had rapid improvement of the disease-associated symptoms. After 8 weeks of treatment, the patient experienced a biochemical and radiographic complete response that is ongoing. A modified dosing and monitoring protocol may improve the safety of tarlatamab in patients with MTC while maintaining efficacy. Further research is needed to evaluate the role of tarlatamab in MTC.
other
2026-01-29 | Induction of trained immunity in myeloid cells and their progenitors from thyroid cancer patients.
The prognosis of patients with cancer in which tumor-associated macrophages with a pro-tumoral phenotype are abundant is poor. This includes aggressive forms of non-medullary thyroid carcinoma (NMTC). Trained immunity describes long-term epigenetic and metabolic reprogramming in innate immune cells and their bone marrow progenitors, leading to improved responsiveness, which is currently being explored as a potential new treatment approach in cancer. We aimed to assess whether trained immunity can be induced in myeloid cells of patients with NMTC to enhance the anti-tumor immune response, and whether this effect is tumor-specific or can be elicited in other forms of cancers sharing the immune-mediated pathophysiology, such as colorectal carcinoma (CRC). Peripheral blood and bone marrow were obtained from 53 NMTC patients (39 differentiated and 14 poorly differentiated/anaplastic NMTC) and 13 healthy controls. Peripheral monocytes and bone marrow progenitors were isolated ex vivo, and trained immunity was induced using different stimuli. Cytokine production upon restimulation and expression of cell membrane activation markers were used as biomarkers of cellular activation. In addition, trained immunity was assessed in peripheral monocytes from seven CRC patients. Training of circulating monocytes with β-glucan or interleukin-4 resulted in amplified cytokine production upon restimulation, a hallmark of trained immunity responses. Fold changes of increase in cytokine production were comparable between the NMTC subtypes, CRC, and healthy controls. Flow cytometry showed that training of bone marrow progenitors resulted in macrophages with lower CD206 and CD163 and higher CD86 expression, a profile associated with a less immunosuppressive and more anti-tumoral phenotype. Ex vivo training of monocytes and bone marrow progenitors from patients with NMTC and CRC results in macrophages with increased proinflammatory cytokine production and differentiation toward an anti-tumoral phenotype. This suggests that trained immunity may be exploited as a potential novel treatment strategy for cancer.
2025-12-30 | A phase 2 study of GI-6207 in patients with recurrent medullary thyroid cancer.
Medullary thyroid cancer (MTC) accounts for approximately 4% of thyroid carcinomas. Patients with unresectable, metastatic disease are candidates for approved agent-targeted therapies such as vandetanib, cabozantinib, or selpercatinib, but toxicity is often an issue. Preclinical data supported the potential use of immunotherapy targeting carcinoembryonic antigen (CEA) in this indolent disease. Patients with advanced/recurrent MTC were randomly assigned in a 1:1 ratio to receive a Saccharomyces cerevisiae (yeast)-based immunotherapy (GI-6207) targeting CEA starting at the time of enrollment or 6 months after surveillance. The primary endpoint was to compare the calcitonin growth rate in the GI-6207 arm at 6 months with patients in the surveillance arm at 6 months. Between March 2013 and May 2018, 34 patients were randomly assigned to receive the yeast-CEA vaccine (GI-6207) starting at the time of enrollment or 6 months after surveillance. The mean age was 51 years, and 82% of patients were diagnosed with sporadic MTC. There was no significant change in the calcitonin growth rates at 6 months when the immunotherapy group was compared with the surveillance group (-2.490042 vs -2.526385; P = .3760). Treatment with GI-6207 was associated with increased peripheral CEA-specific CD4 and/or CD8 T cells, with 15/26 (58%) patients displaying increases after 3 months of treatment. One patient had a significant inflammatory event 17 months after the last vaccine at a known lymph node, perhaps related to a delayed immune response. There were no grade 3 or 4 adverse events. Grade 1 injection site reactions were most common. The immunotherapy was well tolerated but did not have an impact on tumor growth rate at 6 months as measured by calcitonin kinetics. NCT01856920.
2025-08-20 | Unraveling the Complexity of Medullary Thyroid Cancer
This thesis aims to improve diagnosis and treatment of medullary thyroid carcinoma (MTC), a rare thyroid cancer. A nationwide study of MTC patients in the Netherlands (1989–2018) showed a stable incidence. The extent of primary surgery increasingly followed national guidelines, and treatments were more often performed in academic hospitals, reflecting better guideline adherence and care centralization.
A major focus is the role of PET/CT imaging. Preoperative PET/CT was valuable for detecting metastases in locoregional lymph nodes and distant sites, helping to personalize surgical plans. A new imaging method, 18F-PSMA PET/CT, showed similar sensitivity and potential for targeted therapies. The link between PET/CT results and systemic treatment response was also explored in a small patient group.
The newly developed international MTC classification system was validated, enabling more reliable risk stratification into low- and high-risk groups. The protein EZH2, linked to poorer prognosis, emerged as a potential therapeutic target.
A unique contribution is the creation of patient-specific organoids from MTC tissue. These mini-tumors maintained key biological features of the original tumors and may allow personalized testing of imaging agents and treatments.
Finally, the thesis examined side effects of external beam radiotherapy. Acute and late toxicities were common and could impact patients’ long-term quality of life.
2025-04-30 | Precision treatment guided by patient-derived organoids-based drug testing for locally advanced thyroid cancer: a single arm, phase 2 study.
Locally advanced thyroid cancer (LATC) presents significant surgical challenges, with a high risk of incomplete resection and poor prognosis. Patient-derived organoids (PDOs) are a powerful tool to assess drug sensitivity at an individual level and to suggest new treatment options or re-challenge. This study aimed to evaluate the method's feasibility and efficacy as applied to patients with LATC. In this single arm, phase 2 study, we enrolled 75 patients with LATC. Biopsies from the primary tumor or metastatic site were cultured using organoid models. Sensitivity testing was performed by using PDOs with a panel of drugs with proven activity in phase II or III trials. At the discretion of the investigator considering toxicity, the drug with the highest relative activity was offered. The primary endpoint was the objective response rate (ORR). Fifty-five patients received at least one dose of recommended drug and the primary endpoint, objective response was met in 18 patients with an overall ORR as 32.7% (95% CI 20.7-46.7). Based on the pre-defined subgroups of different histological subtypes, the ORR for patients with differentiated thyroid cancer, medullary thyroid cancer, anaplastic thyroid cancer were 32.6%, (95% CI 19.1-48.5), 16.7% (95% CI 0.4-64.1) and 50% (95% CI 11.8-88.2), respectively. The R0/R1 resection rate was 34.5% (19/55). This study is the first to validate the feasibility of PDOs and in vitro sensitivity testing for LATC. PDO-based neoadjuvant therapy holds promise in improving prognosis and providing surgical opportunities for these patients. The study was registered at ClinicalTrials.gov (NCT06482086) on 06/25/2024.
2025-01-10 | Remission of Insulin-Dependent Diabetes Mellitus in Multiple Endocrine Neoplasia Type 2A After Adrenalectomy.
A 37-year-old man presented with symptoms of polyuria and weight loss over the past year. Initial laboratory examination showed elevated blood glucose level (468 mg/dL [25.9 mmol/L]; normal reference range [RR], 75-109 mg/dL [4.1-6.0 mmol/L]), high glycated hemoglobin A1c (13.2% [120 mmol/mol]; RR, 4.6-6.2% [26-44 mmol/mol]), low urinary C-peptide excretion (17.4 μg/day [5.76 nmol/day]; RR, 18.3-124.4 μg/day [6.0-41.1 nmol/day]), and ketosis, leading to a diagnosis of insulin-dependent diabetes mellitus. Subsequent investigations identified medullary thyroid carcinoma and bilateral pheochromocytomas. Given the detected RET gene variant and the patient's family history of multiple endocrine neoplasia type 2A (MEN2A), the diagnosis of MEN2A was confirmed. Upon hospital admission, intensive insulin therapy was commenced, which resolved the symptoms and normalized blood glucose levels. Subsequently, laparoscopic bilateral adrenalectomy was performed, after which the patient's glucose tolerance normalized, eliminating the need for diabetes treatment and avoiding hypoglycemia. This case highlights the potential for catecholamine-induced suppression of insulin secretion via α2 action on pancreatic β-cells to be remission and rapidly improved by adrenalectomy in individuals with MEN2A experiencing insulin-dependent diabetes mellitus.
proteins
2026-07-31 | Application of Theranostics in Thyroid Cancer Management.
The incidental thyroid uptake of radiolabeled ligands used in positron emission tomography/computed tomography (PET/CT) targeting cell-surface proteins is observed in up to 6% of all scans. While diffuse thyroid uptake of ligands targeting somatostatin receptor type 2 (SSTR2), prostate-specific membrane antigen (PSMA), fibroblast activation protein (FAPI), or choline, is observed in normal thyroid or usually signifies a benign thyroid abnormality, a heterogenous or focal uptake is associated with malignant lesions in up to 19.7% of patients. The PET/CTs utilizing these ligands are characterized by decreased diagnostic sensitivity for detection of thyroid cancer metastases than cross-sectional imaging or 18-fluorodeoxyglucose (18FDG)-PET/CT but are highly specific for detection of a subset of thyroid cancers characterized by a high target protein expression. Increased uptake of radiolabeled ligands targeting SSTR2, PSMA, FAPI, integrin αvβ3 and minigastrin can be used for patients' selection for peptide receptor radionuclide therapy (PRRT). PRRT can be applied in clinical trials and/or off label for patients with advanced radioactive iodine-refractory thyroid cancer who have limited treatment options or for medullary thyroid carcinoma of neuroendocrine origin. The PRRT-induced disease control rate approaches 60% and PRRT is well tolerated with limited side effects. Efficacy could be improved with careful patients' selection based on the expression of molecular targets and their function, quantified by standard uptake values (SUVmax) in diagnostic PET/CT imaging. Adopting an individualized dosimetry-based approach and synthesizing ligands with better tumor retention and residence time may help optimize treatment response.
2026-02-19 | Safety and efficacy of peptide receptor radionuclide therapy for advanced medullary thyroid cancer: a systematic review and meta-analysis.
This systematic review and meta-analysis evaluated the safety and efficacy of somatostatin receptor (SSTR) peptide receptor radionuclide therapy (PRRT) in patients with metastatic or progressive medullary thyroid cancer (MTC). PubMed, Scopus, and Web of Science databases were systematically searched from inception to April 22, 2025, to identify relevant clinical studies. Methodological quality was assessed via the National Institutes of Health Quality Assessment Tool. Pooled estimates of the disease control rate (DCR), overall response rate (ORR), and adverse events (AEs) following SSTR PRRT administration were calculated for both the imaging and biochemical endpoints via Stata software version 17. The analysis revealed pooled DCRs of 52% (95% CI: 43–61%) and 58% (95% CI: 46–70%) for the biochemical and imaging endpoints, respectively. The pooled ORRs were 32% (95% CI: 23–42%) for the biochemical endpoints and 17% (95% CI: 7–26%) for the imaging endpoints. Compared with [90Y]Y-DOTATOC, [177Lu]Lu-DOTATATE had a slightly greater pooled imaging DCR (64% vs. 50%) and a lower overall toxicity rate (7% vs. 24%). The biochemical DCRs were comparable (51–52%), although [177Lu]Lu-DOTATATE achieved a higher biochemical ORR (37% vs. 29%). The [90Y]Y-DOTATOC group reported relatively higher rates of gastrointestinal and hematologic toxicities, with only limited cases of high-grade events reported in three studies. [177Lu]Lu-DOTATATE showed no renal toxicity, unlike [90Y]Y-DOTATOC, which mainly caused low-grade nephrotoxicity events at a pooled rate of 6%. Overall, this meta-analysis suggests that SSTR PRRT is a promising therapeutic option for metastatic or progressive MTC, achieving reliable disease control with a favorable safety profile.
2026-02-14 | Peptide receptor radionuclide therapy in neuroendocrine tumours: advances, combination strategies, and future directions.
Peptide receptor radionuclide therapy (PRRT) has established itself as a pivotal component in the management of advanced, somatostatin receptor (SSTR)-positive neuroendocrine tumours (NETs). The NETTER-1 phase III trial demonstrated that [177Lu]Lu-DOTATATE significantly prolongs progression-free survival (PFS) and improves quality of life in patients with midgut NETs refractory to somatostatin analogues, leading to regulatory approval by both EMA (2017) and FDA (2018). The recent NETTER-2 phase III trial further extended these findings by supporting the first-line use of PRRT in Grade 2 and 3 gastroentero-pancreatic (GEP)-NETs (Ki-67 ≥ 10 ≤ 55%). Beyond standard β-emitting therapy, several developments are reshaping the field: the clinical adoption of SSTR antagonists such as radiolabelled JR-11 and LM3, targeted α-particle-emitting therapies (225Ac, 212Pb, 213Bi) for resistant disease, and rational combination strategies with chemotherapy, DNA-repair inhibitors, and immunotherapy. Parallel innovation in radiopharmaceutical chemistry has yielded new peptide ligands, including cholecystokinin-2 receptor (CCK2R)-targeted compounds such as DOTA-MGS5, which show promise for rare NETs such as medullary thyroid carcinoma (MTC) and small-cell lung cancer (SCLC). This review summarises clinical evidence, translational advances, and future perspectives for PRRT as a cornerstone of precision nuclear oncology. Emphasis is placed on expanding indications, integrating α-emitters, improving safety and dosimetry, and developing novel theragnostic ligands that enable personalised treatment strategies for NETs patients.
2025-10-26 | Incretin signaling at the crossroads of metabolism, inflammation, and tumorigenesis: implications for obesity patients.
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for type 2 diabetes and obesity, delivering robust metabolic and cardiovascular benefits. However, their potential impact on tumorigenesis remains debated. Preclinical findings in rodents have suggested that GLP-1R activation may influence thyroid C-cells and pancreatic ducts, while human studies have yielded inconsistent cancer risk signals. This review synthesizes current evidence on GLP-1R and glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling in cancer biology, emphasizing the role of biased agonism and context-dependent effects. GLP-1R activation, predominantly via cAMP/PKA signaling, has shown antiproliferative effects in gastrointestinal adenocarcinomas and pancreatic ductal adenocarcinoma models, whereas GIPR activation frequently engages PI3K/Akt (PI3K, phosphoinositide 3-kinase; Akt, protein kinase B) and ERK/MAPK cascades (ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase), enhancing proliferation in colorectal and neuroendocrine tumors. Conversely, GLP-1R stimulation can promote growth in GLP-1R-high neuroendocrine tumors, reflecting ligand- and tissue-specific signaling biases. Beyond direct tumor cell effects, GLP-1RAs modulate the tumor microenvironment by reducing NF-κB-driven inflammation, altering stromal activity, and potentially enhancing immune surveillance. Current clinical evidence does not support a generalized increase in cancer risk with GLP-1RA therapy; benefits in metabolic control may even reduce obesity-related cancer incidence. Nonetheless, caution is advised in patients with medullary thyroid carcinoma, MEN2, or GLP-1R-high neuroendocrine tumors. The emerging paradigm suggests precision approaches, integrating receptor profiling, biased agonist design, and risk stratification, will be key to safely leveraging incretin-based therapies in oncology.
2025-09-18 | Dimeric CCK2R radiotheranostic tracers synergize with mTOR inhibition for enhanced tumor therapy.
Purpose: The cholecystokinin-2 receptor (CCK2R) is highly expressed in several neuroendocrine cancers, particularly in medullary thyroid carcinoma (MTC) and small cell lung cancer (SCLC) and represents a promising target for radiotheranostic applications. Several minigastrin-derived analogs, such as DOTA-MGS5 and DOTA-CCK-66, have demonstrated favorable tumor targeting and imaging performance. Building on these advances, we developed and evaluated a novel dimeric CCK2R-targeted radiotracer, and further investigated its radiosensitization potential in combination with mTOR inhibition. Experimental Design: We designed a dimeric CCK2R-targeted agent, DOTA-CCK2R-dimer, labeled with 68Ga for PET imaging and 177Lu for radionuclide therapy. Furthermore, we combined [177Lu]Lu-DOTA-CCK2R-dimer with the mTOR inhibitor RAD001 and used single-cell RNA sequencing (scRNA-seq) to investigate the mechanisms of radiosensitization. Results: Compared with its monomeric counterpart [68Ga]Ga-DOTA-CCK-66, [68Ga]Ga-DOTA-CCK2R-dimer demonstrated superior tumor targeting in vivo. Tumor uptake reached 26.13 ± 6.21 %ID/g at 2 h post-injection, which was significantly greater than that of the monomeric tracer (19.63 ± 3.35 %ID/g, p < 0.05). Additionally, [177Lu]Lu-DOTA-CCK2R-dimer selectively eliminated highly proliferative and poorly differentiated tumor cell subpopulations. Combination treatment with RAD001 improved therapeutic efficacy by suppressing glutathione-mediated detoxification and increasing oxidative stress. Furthermore, glutathione S-transferase kappa 1 (GSTK1) was identified as a key regulator that modulates radiosensitivity. Conclusions: DOTA-CCK2R-dimer exhibits favorable in vivo stability, notable tumor retention, and excellent imaging performance. Combining this agent with mTOR inhibition offers a synergistic strategy to sensitize tumors to radiotherapy, providing a promising approach for treating refractory CCK2R-positive malignancies.
small molecules
2026-09-08 | Novel nastorazepide-based radioligands demonstrate effective cholecystokinin-2 receptor targeting with potential for theranostic applications.
Radiolabeled gastrin antagonists are emerging as a new tool for the diagnosis and treatment of cholecystokinin-2 receptor (CCK2R) expressing tumors such as medullary thyroid carcinoma and small cell lung cancer, overcoming limitations of agonist-based ligands. In this study, the CCK2R antagonist nastorazepide (Z-360) was used as a targeting scaffold in combination with either a peptidic (NPP) or a hydrophilic polysaccharide (NPS) linker and the chelators DOTA and DOTAGA, yielding four novel radioligands. These were evaluated alongside the reference minigastrin analogs DOTA-PP-F11 and DOTA-MGS5. All ligands were synthetized via solid-phase peptide synthesis and labeled with In-111 and Lu-177. In vitro characterization included receptor affinity, hydrophilicity and cellular uptake in A431-CCK2R. In vivo biodistribution and imaging were performed in A431-CCK2R xenografts. [177Lu]Lu-DOTAGA-NPP was further assessed in a proof-of-concept therapy study and metabolic stability assays. 111In-labeled antagonists showed 3-4-fold higher site recognition than [111In]In-DOTA-PP-F11 and nanomolar affinities comparable to the reference ligand. Among the tested ligands, [111In]In-DOTAGA-NPP demonstrated the highest cellular uptake (22.0 ± 0.2%), approximately twice that of the other ligands and moderately higher than [111In]In-DOTA-PP-F11 (16.2 ± 1.8%) after 4 h at 37 °C. In vivo, all 177Lu-labeled antagonists demonstrated high tumor uptake (range: 22.98 ± 7.04 - 29.00 ± 3.30% I.A./g tissue) with [177Lu]Lu-DOTAGA-NPP exhibiting the most favorable tumor-to-tissue ratios. Compared with [177Lu]Lu-DOTA-MGS5, [177Lu]Lu-DOTAGA-NPP showed rapid tumor accumulation with faster washout but reduced stomach exposure and high in vivo stability. [¹⁷⁷Lu]Lu-DOTAGA-NPP emerged as the most promising lead compound, combining high tumor uptake, favorable tumor-to-organ ratios, and excellent in vivo stability. Although no significant therapeutic efficacy was observed in the tested xenograft model, the results support [177Lu]Lu-DOTAGA-NPP as a promising lead for optimization. Overall, these findings highlight the potential of Z-360-based CCK2R antagonists as scaffolds for next-generation theranostic radioligands and support their development as alternatives to minigastrin-based tracers.
2026-09-01 | Mechanistic and Clinical Perspectives on Traditional Chinese Medicine in Thyroid Cancer Management.
Thyroid cancer is one of the most prevalent malignancies of the endocrine system, comprising various subtypes such as papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), medullary thyroid carcinoma (MTC), and the aggressive anaplastic thyroid carcinoma (ATC). Despite a generally favorable prognosis for PTC, recurrence, metastasis, and resistance to conventional therapies continue to pose significant challenges. The pathogenesis of thyroid cancer involves genetic mutations in BRAF, RAS, and RET, as well as dysregulated molecular pathways such as MAPK, PI3K/Akt/mTOR, and NF-κB, all of which contribute to cancer progression and therapeutic resistance. This review highlights how Traditional Chinese Medicine (TCM), with its extensive history and a diverse range of bioactive compounds derived from natural sources, offers a complementary approach to thyroid cancer treatment. TCM has been shown to modulate various cellular mechanisms, including inhibiting tumor proliferation, inducing apoptosis, and regulating immune responses. Additionally, TCM can influence the tumor microenvironment (TME), reducing immune evasion and improving therapeutic sensitivity. Many TCM compounds have been identified for their ability to target critical oncogenic signaling pathways, offering a holistic approach to cancer treatment with fewer side effects than traditional chemotherapy. Furthermore, integrating TCM with modern medicine, including novel formulations and nanotechnology, offers the potential to improve efficacy and reduce side effects. The convergence of Artificial Intelligence (AI) and Systems Biology also holds great promise for optimizing personalized treatment regimens and advancing targeted therapies, ultimately improving patient outcomes in thyroid cancer management.
2026-08-14 | Signaling pathways and targeted therapy in high‑risk refractory thyroid cancer: From bench to bedside (Review).
Thyroid cancer is the most common endocrine malignancy worldwide, with its incidence increasing markedly over the past several decades, while mortality trends have shown complex patterns. High‑risk refractory thyroid cancers (including radioactive iodine‑refractory differentiated thyroid cancer, poorly differentiated thyroid cancer, anaplastic thyroid carcinoma, progressive medullary thyroid carcinoma and locally advanced disease) pose major challenges in clinical management. The present review systematically reviewed recent epidemiological trends in thyroid cancer and provided an in‑depth exploration of the molecular regulatory mechanisms of key signaling pathways, including MAPK, PI3K/AKT, Janus kinase/STAT, WNT/β‑catenin and NF‑κB, along with their roles in the pathogenesis and progression of thyroid cancer. Based on this, the latest clinical research advances in targeted therapies for high‑risk, refractory thyroid cancer are elaborated on, covering multikinase inhibitors, B‑Raf proto‑oncogene, serine/threonine kinase/mitogen‑activated protein kinase kinase inhibitors, immunotherapy combinations, innovative targeted strategies and redifferentiation approaches. Finally, future directions are discussed based on the 'total treatment' paradigm and strategies to overcome drug resistance, aiming to provide a systematic reference for basic research and clinical translation in thyroid cancer.
2026-07-29 | Targeted therapies in the management of advanced medullary thyroid cancer.
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor that contributes disproportionately to thyroid cancer-related mortality. Historically, systemic treatment options for advanced MTC were limited due to poor responsiveness to radioactive iodine and conventional chemotherapy. The development of targeted therapies has significantly transformed disease management. This narrative review summarizes current evidence on targeted therapies for advanced MTC, including multikinase inhibitors (MKIs), selective RET inhibitors, and emerging treatment strategies. Literature on efficacy, safety, resistance mechanisms, and novel therapeutic approaches was evaluated. First-generation MKIs, including vandetanib and cabozantinib, demonstrated clinical benefit by targeting RET and angiogenic pathways, though off-target toxicities limited tolerability. More recently, selective RET inhibitors, such as selpercatinib and pralsetinib, have shown high response rates and improved safety profiles, establishing them as preferred first-line therapies for RET-mutant MTC. However, pralsetinib's recent market withdrawal due to regulatory challenges highlights the need for additional options. Emerging therapies, including BOS172738, SY-5007, and peptide receptor radionuclide therapy, show promising early results. Resistance mechanisms, including gatekeeper and solvent front mutations, remain a challenge. Advances in clinical biomarkers and novel approaches, such as CAR-T cell therapy, may further support personalized treatment. Targeted therapies have reshaped the management of advanced MTC, with selective RET inhibitors offering improved efficacy and tolerability. Continued research is essential to overcome resistance, expand therapeutic options, and improve patient outcomes.
2026-07-01 | Clinical performance of [68Ga]Ga-DOTA-FAPI-04 PET/CT in detecting recurrent disease in medullary thyroid carcinoma: a comparative analysis with [18F]F-FDG and [68Ga]Ga-DOTATATE PET/CT, alongside identification of suitable candidates for targeted radionuclide therapy.
To evaluate and compare the diagnostic performance of [68Ga]Ga-DOTA-FAPI-04 with [18F]F-FDG and [68Ga]Ga-DOTATATE PET/CT for detecting recurrent disease in patients with medullary thyroid carcinoma (MTC) and additionally evaluate their role for prognostication and theranostics in management of MTC. In this prospective single-centre study, 56 patients with suspected recurrent MTC underwent [68Ga]Ga-DOTA-Fibroblast activation protein inhibitor (FAPI)-04, [18F]F-FDG, and [68Ga]Ga-DOTATATE PET/CT. The primary endpoint was patient-based diagnostic accuracy for recurrent disease. Secondary endpoints included lesion-based detection rates across pre-defined anatomical regions, correlation with biochemical and clinicopathological parameters, prognostic assessment for progression-free survival, and a novel exploratory FAPI-SSTR Theranostic (FAST) score was developed to guide personalized radiopharmaceutical therapy (RPT). [68Ga]Ga-DOTA-FAPI-04 PET/CT demonstrated higher sensitivity 95.92% and accuracy 94.64% compared to [18F]F-FDG-PET/CT (sensitivity: 89.80%, accuracy: 89.29%) and [68Ga]Ga-DOTATATE (sensitivity: 77.55%, accuracy: 76.79%) on patient-based analysis for detecting recurrent disease. [68Ga]Ga-DOTA-FAPI-04 was showed high detection rates for disease recurrence in mediastinal nodal (91.9%), liver (91.7%), and skeletal (86.5%) metastases.[68Ga]Ga-DOTA-FAPI-04 uptake was associated with a modestly shorter mean progression-free survival and altered clinical management in 35.7% of total patients. Additionally, the pre-defined exploratory FAST scoring system stratified 34 patients (60.7%) for [177Lu]Lu-FAPI-RPT, 8 (14.3%) for [177Lu]Lu-DOTATATE PRRT, and 9 (16.1%) for either or combined RPT. [68Ga]Ga-DOTA-FAPI-04 PET/CT showed higher diagnostic accuracy for the identification of recurrent MTC over standard [18F]F-FDG and [68Ga]Ga-DOTATATE PET/CT, with higher regional detection rates for liver and osteoblastic skeletal metastases. Furthermore, while the exploratory FAST score provides a framework for patient stratification and personalizing targeted theranostic strategies, it requires future validation through larger multicentre trials prior to clinical adoption.
oligonucleotides
2024-07-01 | LncRNA ZFAS1 promotes invasion of medullary thyroid carcinoma by enhancing EPAS1 expression via miR-214-3p/UCHL1 axis.
lncRNA ZFAS1 was identified to facilitate thyroid cancer, but its role in medullary thyroid carcinoma (MTC) remains unknown. This study aimed to unravel the potential function of this lncRNA in MTC by investigating the involvement of the lncRNA ZFAS1 in a ceRNA network that regulates MTC invasion. Proliferation, invasion, and migration of cells were evaluated using EdU staining and Transwell assays. Immunoprecipitation (IP) assays, dual-fluorescence reporter, and RNA IP assays were employed to examine the binding interaction among genes. Nude mice were used to explore the role of lncRNA ZFAS1 in MTC in vivo. ZFAS1 and EPAS1 were upregulated in MTC. Silencing ZFAS1 inhibited MTC cell proliferation and invasion under hypoxic conditions, which reduced EPAS1 protein levels. UCHL1 knockdown increased EPAS1 ubiquitination. ZFAS1 positively regulated UCHL1 expression by binding to miR-214-3p. Finally, silencing ZFAS1 significantly repressed tumor formation and metastasis in MTC. LncRNA ZFAS1 promotes invasion of MTC by upregulating EPAS1 expression via the miR-214-3p/UCHL1 axis.
2024-06-03 | MicroRNAs in thyroid cancer with focus on medullary thyroid carcinoma: potential therapeutic targets and diagnostic/prognostic markers and web based tools.
This review aimed to describe the inculpation of microRNAs (miRNAs) in thyroid cancer (TC) and its subtypes, mainly medullary thyroid carcinoma (MTC), and to outline web-based tools and databases for bioinformatics analysis of miRNAs in TC. Additionally, the capacity of miRNAs to serve as therapeutic targets and biomarkers in TC management will be discussed. This review is based on a literature search of relevant articles on the role of miRNAs in TC and its subtypes, mainly MTC. Additionally, web-based tools and databases for bioinformatics analysis of miRNAs in TC were identified and described. MiRNAs can perform as oncomiRs or antioncoges, relying on the target mRNAs they regulate. MiRNA replacement therapy using miRNA mimics or antimiRs that aim to suppress the function of certain miRNAs can be applied to correct miRNAs aberrantly expressed in diseases, particularly in cancer. MiRNAs are involved in the modulation of fundamental pathways related to cancer, resembling cell cycle checkpoints and DNA repair pathways. MiRNAs are also rather stable and can reliably be detected in different types of biological materials, rendering them favorable diagnosis and prognosis biomarkers as well. MiRNAs have emerged as promising tools for evaluating medical outcomes in TC and as possible therapeutic targets. The contribution of miRNAs in thyroid cancer, particularly MTC, is an active area of research, and the utility of web applications and databases for the biological data analysis of miRNAs in TC is becoming increasingly important.
2024-05-28 | LINC00887 Acts as an Enhancer RNA to Promote Medullary Thyroid Carcinoma Progression by Binding with FOXQ1.
Medullary thyroid carcinoma (MTC) is a rare but aggressive endocrine malignancy that originates from the parafollicular C cells of the thyroid gland. Enhancer RNAs (eRNAs) are non-coding RNAs transcribed from enhancer regions, which are critical regulators of tumorigenesis. However, the roles and regulatory mechanisms of eRNAs in MTC remain poorly understood. This study aims to identify key eRNAs regulating the malignant phenotype of MTC and to uncover transcription factors involved in the regulation of key eRNAs. GSE32662 and GSE114068 were used for the identification of differentially expressed genes, eRNAs, enhancers and enhancer-regulated genes in MTC. Metascape and the transcription factor affinity prediction method were used for gene function enrichment and transcription factor prediction, respectively. qRT-PCR was used to detect gene transcription levels. ChIP-qPCR was used to assess the binding of histone H3 lysine 27 acetylation (H3K27ac)-enriched regions to anti- H3K27ac. RIP-qPCR was used to detect the binding between FOXQ1 and LINC00887. CCK8 and Transwell were performed to measure the proliferation and invasion of MTC cells, respectively. Intracellular reactive oxygen species (ROS) levels were quantified using a ROS assay kit. Four eRNAs (H1FX-AS1, LINC00887, MCM3AP-AS1 and A1BG-AS1) were screened, among which LINC00887 was the key eRNA promoting the proliferation and invasion of MTC cells. A total of 135 genes controlled by LINC00887-regulated enhancers were identified; among them, BCL2, PRDX1, SFTPD, TPO, GSS, RAD52, ZNF580, and ZFP36L1 were significantly enriched in the "ROS metabolic process" term. As a transcription factor regulating genes enriched in the "ROS metabolic process" term, FOXQ1 could recruit LINC00887. Overexpression of FOXQ1 restored LINC00887 knockdown-induced downregulation of GSS and ZFP36L1 transcription in MTC cells. Additionally, FOXQ1 overexpression counteracted the inhibitory effects of LINC00887 knockdown on the proliferation and invasion of MTC cells and the promotion of intracellular ROS accumulation induced by LINC00887 knockdown. LINC00887 was identified as a key eRNA promoting the malignant phenotype of MTC cells. The involvement of FOXQ1 was essential for LINC00887 to play a pro-tumorigenic role in MTC. Our findings suggest that the FOXQ1/LINC00887 axis is a potential therapeutic target for MTC.
2023-06-28 | Validation of miRNAs as diagnostic and prognostic biomarkers, and possible therapeutic targets in medullary thyroid cancers.
Medullary thyroid cancer (MTC) is a rare type of neuroendocrine tumor that produces a hormone called calcitonin (CT). Thyroidectomy is the preferred treatment for MTC, as chemotherapy has been shown to have limited effectiveness. Targeted therapy approaches are currently being used for patients with advanced, metastatic MTC. Several studies have identified microRNAs, including miR-21, as playing a role in the development of MTC. Programmed cell death 4 (PDCD4) is a tumor suppressor gene that is an important target of miR-21. Our previous research has shown that high levels of miR-21 are associated with low PDCD4 nuclear scores and high CT levels. The aim of this study was to investigate the potential of this pathway as a novel therapeutic target for MTC. We used a specific process to silence miR-21 in two human MTC cell lines. We studied the effect of this anti-miRNA process alone and in combination with cabozantinib and vandetanib, two drugs used in targeted therapy for MTC. We analyzed the effect of miR-21 silencing on cell viability, PDCD4 and CT expression, phosphorylation pathways, cell migration, cell cycle, and apoptosis. Silencing miR-21 alone resulted in a reduction of cell viability and an increase in PDCD4 levels at both mRNA and protein levels. It also led to a reduction in CT expression at both mRNA and secretion levels. When combined with cabozantinib and vandetanib, miR-21 silencing did not affect cell cycle or migration but was able to enhance apoptosis. Silencing miR-21, although not showing synergistic activity with TKIs (tyrosine kinase inhibitors), represents a potential alternative worth exploring as a therapeutic target for MTC.
2022-07-19 | Tumor-related Molecular Regulatory Mechanisms of Long Non-coding RNA RMST: Recent Evidence.
Long non-coding RNA rhabdomyosarcoma 2-associated transcript (LncRNA RMST) can affect every aspect of tumor progressions, such as proliferation, translocation, and apoptosis. As a result, RMST can be used as an attractive biomarker for early diagnosis and clinical therapies of different disease states. This article aims to review pathophysiological functions, molecular mechanisms as well as promising biotherapies of RMST in multiple tumors. Through the systematic induction and summary of 46 papers published in PubMed concerning this study, the molecular mechanisms of RMST in all kinds of tumors have been reviewed. LncRNA RMST is a tumor-related regulatory mediator, aberrantly expressed in diverse tumors, including medullary thyroid cancer, hepatocellular carcinoma, endometrial carcinoma, colon cancer, pancreatic cancer, glioma, Wilm's tumor, and breast cancer. Furthermore, as a mechanismbased player, RMST probably guides the translation and post-translation modification, containing DNA methylation and SUMOylation. It is capable of regulating distinct tumor cells and stem cells of biological behaviors via various molecular pathways. LncRNA RMST, potentially as an original therapeutic target, is valuable in the occurrence, development, and apoptosis of different tumors.
antibodies
2026-09-03 | Compartment-Specific Recurrence in Medullary Thyroid Cancer.
Total thyroidectomy with bilateral central neck dissection is recommended for medullary thyroid carcinoma (MTC), even in patients without clinical nodal involvement. However, the role of contralateral prophylactic central neck dissection (pCND) remains debated, leading to variations in practice. To evaluate the outcomes of nodal dissection in compartment-specific recurrence in patients undergoing surgical treatment for MTC, including a subgroup analysis of patients with preoperative clinically node-negative (cN0) disease stratified by whether they underwent contralateral pCND. This was a multicenter retrospective cohort study of adult patients with MTC who underwent thyroidectomy between 1998 and 2021 in 4 academic referral centers. Data were analyzed from February to July 2026. Patients with missing operative data, including initial thyroidectomy information and central neck dissection laterality, were excluded. Contralateral pCND at the time of initial surgical treatment. Recurrence categorized as biochemical (calcitonin >2 pg/mL without radiographic findings); ipsilateral central, ipsilateral lateral, contralateral central, and contralateral lateral neck; and distant metastatic. Effect size was reported as Rosenthal r (r) for continuous variables and as risk difference (RD) with 95% CIs for categorical variables. Multivariable Cox regression was used to evaluate risk factors for contralateral neck recurrence and overall recurrence. This study in a total of 235 patients who underwent surgical treatment for MTC (132 [56%] female; median age, 56 years [IQR, 43-66 years]) found that, preoperatively, 105 patients (45%) had cN0 disease, of whom 58 (55%) underwent contralateral pCND. Genetic testing was performed in 127 (54%) patients, with a 25% rate of germline RET variant. Overall, 73 patients (31%) developed disease recurrence: 15% in the ipsilateral central, 15% ipsilateral lateral, 5% contralateral central, and 8% contralateral lateral neck; 11% distant metastatic; and 4% biochemical. Among patients with cN0 disease, differences in the rates of overall recurrence (22% vs 15%; RD, 0.07; 95% CI, -0.07 to 0.22) and contralateral central neck recurrence (5% vs 2%; RD, 0.03; 95% CI, -0.04 to 0.10) were small and imprecisely estimated between those who did and did not undergo contralateral pCND. On multivariable analysis adjusting for sex, tumor size, and nodal involvement, contralateral pCND was not associated with reduced overall recurrence (hazard ratio [HR], 0.59; 95% CI, 0.21-1.62) or contralateral neck recurrence (HR, 0.23; 95% CI, 0.02-3.08). This study found that, in MTC, the most frequent sites of recurrence were the ipsilateral central and lateral neck. Contralateral central neck recurrence was uncommon; however, our wide CIs preclude definitive conclusions about the benefit of contralateral pCND, and larger studies are warranted.
2026-07-25 | Tumor expression of CGRP confers sensitivity to growth inhibition by the anti-CGRP antibody fremanezumab.
Calcitonin gene related peptide (CGRP) is a neuropeptide exerting key neuromodulatory, vasoactive and immune functions within the periphery and central nervous system. Drugs targeting CGRP such as anti-CGRP mAbs or small molecule CGRP receptor antagonists have been recently approved for prevention and acute treatment of migraine. A growing body of evidence, however, indicates that CGRP plays key roles in tumor growth. Specifically, the neuropeptide promotes tumor angiogenesis, counteracts antitumor immune responses, and supports cancer proliferation in nutrient-poor environment via autophagic activation. There is general agreement that tumor-infiltrating sensory nerve fibers represent the source of CGRP within neoplasms. In keeping with the tumorigenic role of CGRP, several studies report anticancer effects of rimegepant, a CGRP receptor antagonist. In the present study, by means of in vitro and xenograft models we build upon these findings showing that CGRP can be released within the tumor microenvironment directly by cancer cells. Of note, the migraine preventative anti-CGRP mAb fremanezumab selectively counteracted growth to CGRP-proficient tumors. The antitumoral effect occurred in spite of lack of evidence for intratumoral sensory fiber infiltration, angiogenesis inhibition, or promotion of autophagy. The antibody, however, by altering ERK signaling, might counteract MAPK-dependent growth signaling in CGRP-expressing tumors. Collectively, our findings disclose for the first time the tumorigenic effects of CGRP released from cancer cells and suggest the translational potential of clinically available anti-CGRP monoclonal antibodies as a therapeutic strategy for cancer.
2026-06-08 | DLL3 Expression in a Genotyped Cohort of Sporadic Medullary Thyroid Carcinomas.
Delta-like ligand 3 (DLL3) has been identified as a therapeutic target in high-grade neuroendocrine carcinomas, particularly small cell lung carcinoma. Data on DLL3 expression in medullary thyroid carcinoma (MTC) are limited; moreover, the relationship between DLL3 expression and MTC genotype has not been explored. We evaluated DLL3 expression (based on staining intensity and percentage of positive cells) in a genotyped cohort of sporadic MTC. In our cohort of 39 cases, 27 (69%) tumors were positive for DLL3, including 1 (4%) with low DLL3 expression, 10 (26%) with moderate expression, and 16 (41%) with high expression. DLL3 expression was significantly associated with grade (P=0.036), presence of a RET mutation (P=0.014), presence of lymph node metastases at diagnosis (P<0.005), and disease progression (P<0.005). All 9 (100%) high-grade tumors were positive for DLL3. In contrast, 18 (60%) of 30 low-grade tumors were DLL3 positive. DLL3 was positive in 17 (89%) of 19 RET-mutated tumors, 4 (50%) of 8 RAS-mutated tumors, and 6 (50%) of 12 RET/RAS wild-type tumors. All 24 primary tumors with associated lymph node metastases at diagnosis were positive for DLL3. Among cases with follow-up data (n=35), all 17 tumors with disease progression were DLL3 positive (13 RET-mutated tumors, 1 RAS-mutated tumor, and 3 RET/RAS wild-type tumors), including 5 with moderate expression and 12 with high expression. Most MTCs express DLL3; moreover, DLL3 expression is associated with lymph node metastases at diagnosis and disease progression, indicating that DLL3 may be an effective therapeutic target in MTC.
2026-06-02 | B7-H3 (CD276) as a candidate therapeutic target in medullary thyroid cancer.
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignancy with limited therapeutic options in advanced disease. While selective RET inhibitors have expanded systemic treatment strategies, disease progression frequently occurs over time. Antibody-drug conjugates (ADCs) have shown efficacy in the treatment of solid tumors but require suitable cell-surface targets, which have not yet been systemically characterized in MTC. This study aimed to identify therapeutically relevant surface antigens in MTC using immunohistochemical profiling. In this retrospective exploratory study, tumor specimens of 41 patients with histologically confirmed MTC were analyzed. Formalin-fixed paraffin-embedded tissues from primary tumors were subjected to immunohistochemical staining for six therapeutically relevant cell-surface antigens. Surface expression was assessed and categorized as strong, weak, or absent. Statistical analyses were conducted using descriptive statistics and Fisher's exact test. The study included 41 patients with MTC, representing different tumor stages and clinicopathological characteristics with lymph node involvement in 45%. B7-H3 showed membranous expression in 91% of the included cases with strong expression in 82%, which was consistent across tumor stages and clinical subgroups. In contrast, no expression was detected for Nectin-4, Trop-2, c-Met, PD-L2, and Claudin 18.2 in any evaluable samples. B7-H3 was identified as the only consistently and strongly expressed surface antigen in a clinically heterogeneous MTC cohort. These findings identify B7-H3 as a potential therapeutic opportunity for advanced MTC and underscore the limited number of targetable surface antigens in this disease.
2026-05-12 | A Novel Approach to Targeting DLL3 with Tarlatamab in a Patient with Medullary Thyroid Carcinoma after Progression on Selpercatinib.
After progression on selpercatinib, patients with RET-altered medullary thyroid carcinoma (MTC) face a poor prognosis. Tarlatamab-a Delta-like ligand 3-targeted bispecific T-cell engager-is a promising therapeutic option for patients with MTC, but a prior case series raised safety concerns in this population. A patient with RET-altered MTC who progressed on selpercatinib received tarlatamab using a three-step step-up dosing regimen with modified protocols for monitoring and managing cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). This patient experienced grade 2 CRS and grade 2 ICANS after cycle 1, day 1. He did not experience any grade ≥3 treatment-related adverse events. The patient had rapid improvement of the disease-associated symptoms. After 8 weeks of treatment, the patient experienced a biochemical and radiographic complete response that is ongoing. A modified dosing and monitoring protocol may improve the safety of tarlatamab in patients with MTC while maintaining efficacy. Further research is needed to evaluate the role of tarlatamab in MTC.
other
2026-01-29 | Induction of trained immunity in myeloid cells and their progenitors from thyroid cancer patients.
The prognosis of patients with cancer in which tumor-associated macrophages with a pro-tumoral phenotype are abundant is poor. This includes aggressive forms of non-medullary thyroid carcinoma (NMTC). Trained immunity describes long-term epigenetic and metabolic reprogramming in innate immune cells and their bone marrow progenitors, leading to improved responsiveness, which is currently being explored as a potential new treatment approach in cancer. We aimed to assess whether trained immunity can be induced in myeloid cells of patients with NMTC to enhance the anti-tumor immune response, and whether this effect is tumor-specific or can be elicited in other forms of cancers sharing the immune-mediated pathophysiology, such as colorectal carcinoma (CRC). Peripheral blood and bone marrow were obtained from 53 NMTC patients (39 differentiated and 14 poorly differentiated/anaplastic NMTC) and 13 healthy controls. Peripheral monocytes and bone marrow progenitors were isolated ex vivo, and trained immunity was induced using different stimuli. Cytokine production upon restimulation and expression of cell membrane activation markers were used as biomarkers of cellular activation. In addition, trained immunity was assessed in peripheral monocytes from seven CRC patients. Training of circulating monocytes with β-glucan or interleukin-4 resulted in amplified cytokine production upon restimulation, a hallmark of trained immunity responses. Fold changes of increase in cytokine production were comparable between the NMTC subtypes, CRC, and healthy controls. Flow cytometry showed that training of bone marrow progenitors resulted in macrophages with lower CD206 and CD163 and higher CD86 expression, a profile associated with a less immunosuppressive and more anti-tumoral phenotype. Ex vivo training of monocytes and bone marrow progenitors from patients with NMTC and CRC results in macrophages with increased proinflammatory cytokine production and differentiation toward an anti-tumoral phenotype. This suggests that trained immunity may be exploited as a potential novel treatment strategy for cancer.
2025-12-30 | A phase 2 study of GI-6207 in patients with recurrent medullary thyroid cancer.
Medullary thyroid cancer (MTC) accounts for approximately 4% of thyroid carcinomas. Patients with unresectable, metastatic disease are candidates for approved agent-targeted therapies such as vandetanib, cabozantinib, or selpercatinib, but toxicity is often an issue. Preclinical data supported the potential use of immunotherapy targeting carcinoembryonic antigen (CEA) in this indolent disease. Patients with advanced/recurrent MTC were randomly assigned in a 1:1 ratio to receive a Saccharomyces cerevisiae (yeast)-based immunotherapy (GI-6207) targeting CEA starting at the time of enrollment or 6 months after surveillance. The primary endpoint was to compare the calcitonin growth rate in the GI-6207 arm at 6 months with patients in the surveillance arm at 6 months. Between March 2013 and May 2018, 34 patients were randomly assigned to receive the yeast-CEA vaccine (GI-6207) starting at the time of enrollment or 6 months after surveillance. The mean age was 51 years, and 82% of patients were diagnosed with sporadic MTC. There was no significant change in the calcitonin growth rates at 6 months when the immunotherapy group was compared with the surveillance group (-2.490042 vs -2.526385; P = .3760). Treatment with GI-6207 was associated with increased peripheral CEA-specific CD4 and/or CD8 T cells, with 15/26 (58%) patients displaying increases after 3 months of treatment. One patient had a significant inflammatory event 17 months after the last vaccine at a known lymph node, perhaps related to a delayed immune response. There were no grade 3 or 4 adverse events. Grade 1 injection site reactions were most common. The immunotherapy was well tolerated but did not have an impact on tumor growth rate at 6 months as measured by calcitonin kinetics. NCT01856920.
2025-08-20 | Unraveling the Complexity of Medullary Thyroid Cancer
This thesis aims to improve diagnosis and treatment of medullary thyroid carcinoma (MTC), a rare thyroid cancer. A nationwide study of MTC patients in the Netherlands (1989–2018) showed a stable incidence. The extent of primary surgery increasingly followed national guidelines, and treatments were more often performed in academic hospitals, reflecting better guideline adherence and care centralization.
A major focus is the role of PET/CT imaging. Preoperative PET/CT was valuable for detecting metastases in locoregional lymph nodes and distant sites, helping to personalize surgical plans. A new imaging method, 18F-PSMA PET/CT, showed similar sensitivity and potential for targeted therapies. The link between PET/CT results and systemic treatment response was also explored in a small patient group.
The newly developed international MTC classification system was validated, enabling more reliable risk stratification into low- and high-risk groups. The protein EZH2, linked to poorer prognosis, emerged as a potential therapeutic target.
A unique contribution is the creation of patient-specific organoids from MTC tissue. These mini-tumors maintained key biological features of the original tumors and may allow personalized testing of imaging agents and treatments.
Finally, the thesis examined side effects of external beam radiotherapy. Acute and late toxicities were common and could impact patients’ long-term quality of life.
2025-04-30 | Precision treatment guided by patient-derived organoids-based drug testing for locally advanced thyroid cancer: a single arm, phase 2 study.
Locally advanced thyroid cancer (LATC) presents significant surgical challenges, with a high risk of incomplete resection and poor prognosis. Patient-derived organoids (PDOs) are a powerful tool to assess drug sensitivity at an individual level and to suggest new treatment options or re-challenge. This study aimed to evaluate the method's feasibility and efficacy as applied to patients with LATC. In this single arm, phase 2 study, we enrolled 75 patients with LATC. Biopsies from the primary tumor or metastatic site were cultured using organoid models. Sensitivity testing was performed by using PDOs with a panel of drugs with proven activity in phase II or III trials. At the discretion of the investigator considering toxicity, the drug with the highest relative activity was offered. The primary endpoint was the objective response rate (ORR). Fifty-five patients received at least one dose of recommended drug and the primary endpoint, objective response was met in 18 patients with an overall ORR as 32.7% (95% CI 20.7-46.7). Based on the pre-defined subgroups of different histological subtypes, the ORR for patients with differentiated thyroid cancer, medullary thyroid cancer, anaplastic thyroid cancer were 32.6%, (95% CI 19.1-48.5), 16.7% (95% CI 0.4-64.1) and 50% (95% CI 11.8-88.2), respectively. The R0/R1 resection rate was 34.5% (19/55). This study is the first to validate the feasibility of PDOs and in vitro sensitivity testing for LATC. PDO-based neoadjuvant therapy holds promise in improving prognosis and providing surgical opportunities for these patients. The study was registered at ClinicalTrials.gov (NCT06482086) on 06/25/2024.
2025-01-10 | Remission of Insulin-Dependent Diabetes Mellitus in Multiple Endocrine Neoplasia Type 2A After Adrenalectomy.
A 37-year-old man presented with symptoms of polyuria and weight loss over the past year. Initial laboratory examination showed elevated blood glucose level (468 mg/dL [25.9 mmol/L]; normal reference range [RR], 75-109 mg/dL [4.1-6.0 mmol/L]), high glycated hemoglobin A1c (13.2% [120 mmol/mol]; RR, 4.6-6.2% [26-44 mmol/mol]), low urinary C-peptide excretion (17.4 μg/day [5.76 nmol/day]; RR, 18.3-124.4 μg/day [6.0-41.1 nmol/day]), and ketosis, leading to a diagnosis of insulin-dependent diabetes mellitus. Subsequent investigations identified medullary thyroid carcinoma and bilateral pheochromocytomas. Given the detected RET gene variant and the patient's family history of multiple endocrine neoplasia type 2A (MEN2A), the diagnosis of MEN2A was confirmed. Upon hospital admission, intensive insulin therapy was commenced, which resolved the symptoms and normalized blood glucose levels. Subsequently, laparoscopic bilateral adrenalectomy was performed, after which the patient's glucose tolerance normalized, eliminating the need for diabetes treatment and avoiding hypoglycemia. This case highlights the potential for catecholamine-induced suppression of insulin secretion via α2 action on pancreatic β-cells to be remission and rapidly improved by adrenalectomy in individuals with MEN2A experiencing insulin-dependent diabetes mellitus.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
10 orphan drug designations for Medullary thyroid carcinoma, including 1 approved therapy.
10 orphan drug designations for Medullary thyroid carcinoma, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Zeteletinib | small molecules | EMA | Propharma Group The Netherlands B.V. | |
pentagastrin | peptides | FDA | — | Exela Pharma Sciences, LLC |
selpercatinib [RETEVMO] | small molecules | FDA | Approved | Loxo Oncology Inc., a wholly owned subsidiary of Eli Lilly and Company |
Selpercatinib | small molecules | EMA | Eli Lilly Nederland B.V. | |
pentagastrin | peptides | FDA | — | AOP Orphan IP AG |
Cabozantinib S-malate [Cometriq] | small molecules | EMA | Ipsen Pharma | |
Metastable technetium 99 [99mTc] demogastrin 2 | peptides | EMA | — | Biomedica Life Sciences SA |
Vandetanib [Zictifa] | small molecules | EMA | AstraZeneca UK Limited | |
FOSBRETABULIN TROMETHAMINE [Zybrestat] | small molecules | EMA | Diamond Pharma Services Ireland Limited | |
Arcitumomab | antibodies | FDA | — | Immunomedics, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.