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
1,857 drug discovery papers about Medullary thyroid carcinoma, with 3 first-in-class and 10 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,857 drug discovery papers about Medullary thyroid carcinoma, with 3 first-in-class and 10 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
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.
2026-07-31 | 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.
2026-07-29 | 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.
2026-07-25 | 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.
2026-07-01 | 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.
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.
2026-07-31 | 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.
2026-07-29 | 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.
2026-07-25 | 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.
2026-07-01 | 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.
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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 | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Zeteletinib | small molecules | EMA | 2021-02-19 | — | Propharma Group The Netherlands B.V. |
pentagastrin | peptides | FDA | 2020-04-21 | — | Exela Pharma Sciences, LLC |
selpercatinib [RETEVMO] | small molecules | FDA | 2019-11-21 | 2020-05-08 | Loxo Oncology Inc., a wholly owned subsidiary of Eli Lilly and Company |
Selpercatinib | small molecules | EMA | 2018-10-26 | — | Eli Lilly Nederland B.V. |
pentagastrin | peptides | FDA | 2009-05-29 | — | AOP Orphan IP AG |
Cabozantinib S-malate [Cometriq] | small molecules | EMA | 2009-02-06 | — | Ipsen Pharma |
Metastable technetium 99 [99mTc] demogastrin 2 | peptides | EMA | 2006-08-28 | — | Biomedica Life Sciences SA |
Vandetanib [Zictifa] | small molecules | EMA | 2006-01-24 | — | AstraZeneca UK Limited |
FOSBRETABULIN TROMETHAMINE [Zybrestat] | small molecules | EMA | 2004-04-14 | — | Diamond Pharma Services Ireland Limited |
Arcitumomab | antibodies | FDA | 1996-05-10 | — | Immunomedics, Inc. |
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