scholarly journals Activation of the IGF Axis in Thyroid Cancer: Implications for Tumorigenesis and Treatment

2019 ◽  
Vol 20 (13) ◽  
pp. 3258 ◽  
Author(s):  
Livia Manzella ◽  
Michele Massimino ◽  
Stefania Stella ◽  
Elena Tirrò ◽  
Maria Stella Pennisi ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Kinase Inhibitors ◽  
Current Knowledge ◽  
Thyroid Neoplasms ◽  
Thyroid Carcinomas ◽  
Signaling Inhibitors ◽  
Poorly Differentiated ◽  
Biological Entities ◽  
Complex Signaling ◽  
Igf Signaling

The Insulin-like growth factor (IGF) axis is one of the best-established drivers of thyroid transformation, as thyroid cancer cells overexpress both IGF ligands and their receptors. Thyroid neoplasms encompass distinct clinical and biological entities as differentiated thyroid carcinomas (DTC)—comprising papillary (PTC) and follicular (FTC) tumors—respond to radioiodine therapy, while undifferentiated tumors—including poorly-differentiated (PDTC) or anaplastic thyroid carcinomas (ATCs)—are refractory to radioactive iodine and exhibit limited responses to chemotherapy. Thus, safe and effective treatments for the latter aggressive thyroid tumors are urgently needed. Despite a strong preclinical rationale for targeting the IGF axis in thyroid cancer, the results of the available clinical studies have been disappointing, possibly because of the crosstalk between IGF signaling and other pathways that may result in resistance to targeted agents aimed against individual components of these complex signaling networks. Based on these observations, the combinations between IGF-signaling inhibitors and other anti-tumor drugs, such as DNA damaging agents or kinase inhibitors, may represent a promising therapeutic strategy for undifferentiated thyroid carcinomas. In this review, we discuss the role of the IGF axis in thyroid tumorigenesis and also provide an update on the current knowledge of IGF-targeted combination therapies for thyroid cancer.

scholarly journals Characterization of thyroid cancer driven by known and novel ALK fusions

2019 ◽  
Vol 26 (11) ◽  
pp. 803-814 ◽  
Author(s):  
Federica Panebianco ◽  
Alyaksandr V Nikitski ◽  
Marina N Nikiforova ◽  
Cihan Kaya ◽  
Linwah Yip ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Nodules ◽  
Thyroid Neoplasms ◽  
Thyroid Carcinomas ◽  
Fine Needle Aspirates ◽  
Target Spectrum ◽  
Radiation History ◽  
Rare Gene ◽  
Poorly Differentiated ◽  
Well Differentiated

ALK fusions are found in various tumors, including thyroid cancer, and serve as a diagnostic marker and therapeutic target. Spectrum and outcomes of ALK fusions found in thyroid nodules and cancer are not fully characterized. We report a series of 44 ALK-translocated thyroid neoplasms, including 31 identified preoperatively in thyroid fine-needle aspirates (FNA). The average patients’ age was 43 years (range, 8–76 years); only one with radiation history. All 19 resected thyroid nodules with ALK fusion identified preoperatively were malignant. Among nodules with known surgical pathology (n = 32), 84% were papillary thyroid carcinomas (PTCs) and 16% poorly differentiated thyroid carcinomas (PDTCs). PTCs showed infiltrative growth with follicular architecture seen exclusively (30%) or in combination with papillary and/or solid growth (37%). Tumor multifocality was seen in 10 (31%) PTC cases. Most PDTC had a well-differentiated PTC component. Lymph node metastases were identified in 10/18 (56%) patients with neck dissection. The most common ALK fusion partners were STRN (n = 22) and EML4 (n = 17). In five cases, novel ALK fusion partners were discovered. All five PDTCs carried STRN-ALK fusion. On follow-up, ten patients were free of disease at 2–108 months, whereas two patients with PDTC died of disease. In summary, ALK fusion-positive thyroid carcinomas are typically infiltrative PTC with common follicular growth, which may show tumor dedifferentiation associated with increased mortality. Compared to EML4-ALK, STRN-ALK may be more common in PDTC, and ~10% of ALK fusions occur to rare gene partners. When ALK fusion is detected preoperatively in FNA samples, malignancy should be expected.

scholarly journals Thyroid Cancers: From Surgery to Current and Future Systemic Therapies through Their Molecular Identities

2021 ◽  
Vol 22 (6) ◽  
pp. 3117
Author(s):  
Loredana Lorusso ◽  
Virginia Cappagli ◽  
Laura Valerio ◽  
Carlotta Giani ◽  
David Viola ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Kinase Inhibitors ◽  
Therapeutic Option ◽  
Progression Free Survival ◽  
Thyroid Cancers ◽  
Poorly Differentiated ◽  
Differentiated Thyroid Cancers ◽  
Approved Drugs ◽  
New Generation ◽  
Systemic Therapies

Differentiated thyroid cancers (DTC) are commonly and successfully treated with total thyroidectomy plus/minus radioiodine therapy (RAI). Medullary thyroid cancer (MTC) is only treated with surgery but only intrathyroidal tumors are cured. The worst prognosis is for anaplastic (ATC) and poorly differentiated thyroid cancer (PDTC). Whenever a local or metastatic advanced disease is present, other treatments are required, varying from local to systemic therapies. In the last decade, the efficacy of the targeted therapies and, in particular, tyrosine kinase inhibitors (TKIs) has been demonstrated. They can prolong the disease progression-free survival and represent the most important therapeutic option for the treatment of advanced and progressive thyroid cancer. Currently, lenvatinib and sorafenib are the approved drugs for the treatment of RAI-refractory DTC and PDTC while advanced MTC can be treated with either cabozantinib or vandetanib. Dabrafenib plus trametinib is the only approved treatment by FDA for BRAFV600E mutated ATC. A new generation of TKIs, specifically for single altered oncogenes, is under evaluation in phase 2 and 3 clinical trials. The aim of this review was to provide an overview of the current and future treatments of thyroid cancer with regards to the advanced and progressive cases that require systemic therapies that are becoming more and more targeted on the molecular identity of the tumor.

scholarly journals Lenvatinib Administered via Nasogastric Tube in Poorly Differentiated Thyroid Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-4 ◽  
Author(s):  
Eleonora Molinaro ◽  
David Viola ◽  
Nicola Viola ◽  
Pierpaolo Falcetta ◽  
Francesca Orsolini ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Carcinoma ◽  
Gastric Tube ◽  
Kinase Inhibitors ◽  
Locally Advanced ◽  
Differentiated Thyroid Carcinoma ◽  
Cervical Esophagus ◽  
Extrinsic Compression ◽  
Poorly Differentiated ◽  
Iodine 131

Background. The tyrosine kinase inhibitors (TKIs) are indicated for the treatment of locally advanced or metastatic progressive thyroid carcinoma (CDT), refractory to radioactive iodine. The following report describes the efficacy of lenvatinib administered through a nose-gastric tube (SNG) in a patient affected with a poorly differentiated thyroid carcinoma (PDTC) which determined a stenosis of the esophagus. Material and Methods. A patient was followed up for papillary thyroid carcinoma follicular variant (T3NxMx), subjected to total thyroidectomy and treated with iodine-131 radio metabolic therapy. Two years after surgery, following the onset of dysphonia and dysphagia, patient was submitted to a computed tomography (CT) scan of the neck that showed the presence of a lesion of 6 × 2.5 × 3.5 cm, which determined trachea deviation and cervical esophagus compression. The biopsy indicated the presence of PDTC, triggering tracheal lumen reduction and sub-stenosis of the cervical esophagus for an ab-extrinsic compression. A nose-gastric tube (SNG) was placed and lenvatinib was started at a dose of 20 mg/day, administered via this probe after opening the capsules and diluting the drug in 10 ml of saline solution. Results. One month later, CT showed a significant cervical lesion reduction. Bronchoscopy confirmed tracheal infiltration, but the residual caliber was improved from 50% to 75%. At the esophagogastroduodenoscopy (EGDS), the sub stenosis of the cervical esophagus was no longer appreciated; however, a double perforation of the esophagus was found, without fistula. Conclusion. Lenvatinib therapy is effective also when administered via SNG. Our result is of particular relevance in the management of thyroid cancer patients, especially in the presence of subjects unable to swallow. Further studies are needed to validate the administration of lenvatinib by SNG, in order to extend the indications to this alternative administration way, beside the oral one.

Genetic profile of advanced thyroid cancers in relation to distant metastasis

2020 ◽  
Vol 27 (5) ◽  
pp. 285-293 ◽  
Author(s):  
Eyun Song ◽  
Dong Eun Song ◽  
Jonghwa Ahn ◽  
Tae Yong Kim ◽  
Won Bae Kim ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Carcinoma ◽  
Distant Metastasis ◽  
Distant Metastases ◽  
Thyroid Tumors ◽  
Primary Tumors ◽  
Thyroid Cancers ◽  
Histone Methyltransferases ◽  
Thyroid Carcinomas ◽  
Poorly Differentiated

Major clinical challenges exist with differentiated thyroid cancers with distant metastases or rare but aggressive types, such as poorly differentiated thyroid carcinomas and anaplastic thyroid carcinomas. The precise characterization of the mutational profile in these advanced thyroid cancers is crucial. Samples were collected from primary tumors and distant metastases of 64 patients with distant metastases from differentiated thyroid cancer, poorly differentiated thyroid carcinoma, or anaplastic thyroid carcinoma. Targeted next-generation sequencing was performed with 50 known thyroid-cancer-related genes. Of the 82 tissues, 63 were from primary tumors and 19 from distant metastases. The most prevalent mutation observed from the primary tumors was TERT promoter mutation (56%), followed by BRAF (41%) and RAS (24%) mutations. TP3 was altered by 11%. Mutations in histone methyltransferases, SWI/SNF subunit–related genes, and PI3K/AKT/mTOR pathway-related genes were present in 42%, 12%, and 22%, respectively. When the mutational status was analyzed in 15 matched pairs of thyroid tumors and their matched distant metastases and one pair of distant metastases with two distinct sites, the concordance was high. A similar frequency of mutations in TERT promoter (58%) and BRAF (42%) as well as histone methyltransferases (37%), SWI/SNF subunits (10%), and PI3K/AKT/mTOR pathway (26%) were noted. The same main, early and late mutations were practically always present in individual primary tumor–metastasis pairs. Enrichment of TERT promoter, BRAF, and RAS mutations were detected in highly advanced thyroid cancers with distant metastasis. The genetic profiles of primary thyroid tumors and their corresponding distant metastases showed a high concordance.

scholarly journals Activation of the Sonic Hedgehog pathway in thyroid neoplasms and its potential role in tumor cell proliferation

2012 ◽  
Vol 19 (2) ◽  
pp. 167-179 ◽  
Author(s):  
Xiulong Xu ◽  
Helen Ding ◽  
Geetha Rao ◽  
Shalini Arora ◽  
Constantine P Saclarides ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Tumor Cell ◽  
Sonic Hedgehog ◽  
Thyroid Neoplasms ◽  
Thyroid Tumor ◽  
Tumor Cell Proliferation ◽  
Thyroid Carcinomas ◽  
Shh Pathway ◽  
Genes Encoding

The sonic hedgehog (SHH) pathway is activated in several types of malignancy and plays an important role in tumor cell proliferation and tumorigenesis. SHH binding to a 12-pass transmembrane receptor, Patched (PTCH), leads to freeing of Smoothened (SMO) and subsequent activation of GLI transcription factors. In the present study, we analyzed the expression of SHH, PTCH, SMO, and GLI1 in 31 follicular thyroid adenomas (FTA), 8 anaplastic thyroid carcinomas (ATC), and 51 papillary thyroid carcinomas (PTC) by immunohistochemical staining. More than 65% of FTA, PTC, and ATC specimens stained positive for SHH, PTCH, SMO, and GLI. However, the expression of the genes encoding these four molecules did not correlate with any clinicopathologic parameters, including the age, gender, the status ofBRAFgene mutation, tumor stage, local invasion, and metastasis. Three thyroid tumor cell lines (KAT-18, WRO82, and SW1736) all expressed the genes encoding these four molecules. 5-Bromo-2-deoxyuridine labeling and MTT cell proliferation assays revealed that cyclopamine (CP), an inhibitor of the SHH pathway, was able to inhibit the proliferation of KAT-18 and WRO82 cells more effectively than SW1736 cells. CP led to the arrest of cell cycle or apoptosis. Knockdown ofSHHandGLIexpression by miRNA constructs that targetSHHorGLImRNA in KAT-18 and SW1736 cells led to the inhibition of cell proliferation. Our results suggest that the SHH pathway is widely activated in thyroid neoplasms and may have potential as an early marker of thyroid cancer or as a potential therapeutic target for thyroid cancer treatment.

scholarly journals Deregulation of microRNA expression in follicular cell-derived human thyroid carcinomas

2010 ◽  
Vol 17 (1) ◽  
pp. F91-F104 ◽  
Author(s):  
Pierlorenzo Pallante ◽  
Rosa Visone ◽  
Carlo Maria Croce ◽  
Alfredo Fusco
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Carcinoma ◽  
Thyroid Tissue ◽  
Endocrine System ◽  
Follicular Carcinoma ◽  
Thyroid Neoplasms ◽  
Anaplastic Thyroid Cancer ◽  
Microrna Expression ◽  
Human Thyroid ◽  
Thyroid Carcinomas

Carcinoma of the thyroid gland is an uncommon cancer, but one of the most frequent malignancies of the endocrine system. Most thyroid cancers are derived from the follicular cells. Follicular carcinoma is considered more malignant than papillary thyroid carcinoma (PTC), and anaplastic thyroid cancer (ATC) is one of the most lethal human cancers. Even though several genetic lesions have been already described in human thyroid cancer, particularly in the papillary histotype, the mechanisms underlying the development of these neoplasias are still far from being completely elucidated. Some years ago, several studies were undertaken to analyze the expression of microRNAs (miRNAs or miRs) in thyroid carcinoma to evaluate a possible role of their deregulation in the process of carcinogenesis. These studies showed an aberrant microRNA expression profile that distinguishes unequivocally among PTC, ATC, and normal thyroid tissue. Here, other than summarizing the current findings on microRNA expression in human thyroid carcinomas, we discuss the mechanisms by which microRNA deregulation may play a role in thyroid carcinogenesis, and the possible use of microRNA knowledge in the diagnosis and therapy of thyroid neoplasms.

scholarly journals Prognostic and Therapeutic Role of Angiogenic Microenvironment in Thyroid Cancer

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2775
Author(s):  
Assunta Melaccio ◽  
Lucia Ilaria Sgaramella ◽  
Alessandro Pasculli ◽  
Giovanna Di Meo ◽  
Angela Gurrado ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Kinase Inhibitors ◽  
Cell Cycle Control ◽  
Current Status ◽  
Thyroid Cancers ◽  
Angiogenic Switch ◽  
Poorly Differentiated ◽  
Differentiated Thyroid Cancers ◽  
Disease Understanding

Thyroid cancer is the most common endocrine malignancy, with a typically favorable prognosis following standard treatments, such as surgical resection and radioiodine therapy. A subset of thyroid cancers progress to refractory/metastatic disease. Understanding how the tumor microenvironment is transformed into an angiogenic microenvironment has a role of primary importance in the aggressive behavior of these neoplasms. During tumor growth and progression, angiogenesis represents a deregulated biological process, and the angiogenic switch, characterized by the formation of new vessels, induces tumor cell proliferation, local invasion, and hematogenous metastases. This evidence has propelled the scientific community’s effort to study a number of molecular pathways (proliferation, cell cycle control, and angiogenic processes), identifying mediators that may represent viable targets for new anticancer treatments. Herein, we sought to review angiogenesis in thyroid cancer and the potential role of proangiogenic cytokines for risk stratification of patients. We also present the current status of treatment of advanced differentiated, medullary, and poorly differentiated thyroid cancers with multiple tyrosine kinase inhibitors, based on the rationale of angiogenesis as a potential therapeutic target.

scholarly journals Treatment of advanced thyroid cancer with targeted therapies: ten years of experience

2016 ◽  
Vol 23 (4) ◽  
pp. R185-R205 ◽  
Author(s):  
David Viola ◽  
Laura Valerio ◽  
Eleonora Molinaro ◽  
Laura Agate ◽  
Valeria Bottici ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Targeted Therapies ◽  
Kinase Inhibitors ◽  
Survival Rates ◽  
Current Status ◽  
Thyroid Cancers ◽  
Poorly Differentiated ◽  
Advanced Thyroid Cancer ◽  
Well Differentiated ◽  
Differentiated Thyroid Cancers

AbstractThyroid cancer is rare, but it is the most frequent endocrine malignancy. Its prognosis is generally favorable, especially in cases of well-differentiated thyroid cancers (DTCs), such as papillary and follicular cancers, which have survival rates of approximately 95% at 40 years. However, 15–20% of cases became radioiodine refractory (RAI-R), and until now, no other treatments have been effective. The same problems are found in cases of poorly differentiated (PDTC) and anaplastic (ATC) thyroid cancers and in at least 30% of medullary thyroid cancer (MTC) cases, which are very aggressive and not sensitive to radioiodine. Tyrosine kinase inhibitors (TKIs) represent a new approach to the treatment of advanced cases of RAI-R DTC, MTC, PDTC, and, possibly, ATC. In the past 10 years, several TKIs have been tested for the treatment of advanced, progressive, and RAI-R thyroid tumors, and some of them have been recently approved for use in clinical practice: sorafenib and lenvatinib for DTC and PDTC and vandetanib and cabozantinib for MTC. The objective of this review is to present the current status of the treatment of advanced thyroid cancer with the use of innovative targeted therapies by describing both the benefits and the limits of their use based on the experiences reported so far. A comprehensive analysis and description of the molecular basis of these therapies, as well as new therapeutic perspectives, are reported. Some practical suggestions are given for both the choice of patients to be treated and their management, with particular regard to the potential side effects.

scholarly journals The Use of Sorafenib in the Thyroid Cancer

2010 ◽  
Vol 9 (1) ◽  
pp. 28 ◽  
Author(s):  
Aneta L Zygulska ◽  
Krzysztof Krzemieniecki ◽  
Anna Sowa Staszczak ◽  
◽  
◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Targeted Therapy ◽  
Cancer Cells ◽  
Kinase Inhibitors ◽  
Thyroid Carcinomas

There are not effective therapies for metastatic unresectable, non-RAI-avid thyroid carcinomas. Fortunately, thyroid carcinomas represent a promising paradigm for targeted therapy due to the presence of activing mutations of genes coding the kinase tyrosines which are involved in all functions of cancer cells (such as: growth or invasion). In this paper an efficacy and toxicity of sorafenib, one of the multi-kinase inhibitors in thyroid carcinomas treatment is presented.

scholarly journals Regulators of the RAS-ERK pathway as therapeutic targets in thyroid cancer

2019 ◽  
Vol 26 (6) ◽  
pp. R319-R344 ◽  
Author(s):  
Miguel A Zaballos ◽  
Adrián Acuña-Ruiz ◽  
Marta Morante ◽  
Piero Crespo ◽  
Pilar Santisteban
Keyword(s):  
Thyroid Cancer ◽  
Human Cancer ◽  
Clinical Success ◽  
Therapeutic Targets ◽  
Relevant Information ◽  
Erk Pathway ◽  
Tumor Resistance ◽  
Thyroid Carcinomas ◽  
Complex Signaling ◽  
Spatial Specificity

Thyroid cancer is mostly an ERK-driven carcinoma, as up to 70% of thyroid carcinomas are caused by mutations that activate the RAS/ERK mitogenic signaling pathway. The incidence of thyroid cancer has been steadily increasing for the last four decades; yet, there is still no effective treatment for advanced thyroid carcinomas. Current research efforts are focused on impairing ERK signaling with small-molecule inhibitors, mainly at the level of BRAF and MEK. However, despite initial promising results in animal models, the clinical success of these inhibitors has been limited by the emergence of tumor resistance and relapse. The RAS/ERK pathway is an extremely complex signaling cascade with multiple points of control, offering many potential therapeutic targets: from the modulatory proteins regulating the activation state of RAS proteins to the scaffolding proteins of the pathway that provide spatial specificity to the signals, and finally, the negative feedbacks and phosphatases responsible for inactivating the pathway. The aim of this review is to give an overview of the biology of RAS/ERK regulators in human cancer highlighting relevant information on thyroid cancer and future areas of research.

Sign in / Sign up

Export Citation Format

Share Document