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 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 What's New in Molecular Targeted Therapies for Thyroid Cancer?

2021 ◽  
Vol 37 (2) ◽  
pp. 1-9
Author(s):  
Seonyoung Min ◽  
Hyunseok Kang
Keyword(s):  
Thyroid Cancer ◽  
Targeted Therapies ◽  
Radioactive Iodine ◽  
Checkpoint Inhibitors ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Thyroid Cancers ◽  
Ret Mutation ◽  
Poorly Differentiated ◽  
Differentiated Thyroid Cancers

Thyroid cancer refers to various cancers arising from thyroid gland. Differentiated thyroid cancers (DTCs) include papillary, follicular, and Hurthle cell carcinomas and represent cancers retain normal thyroid functions such as iodine uptake. Radioactive iodine (RAI) is generally used for upfront treatment of metastatic DTCs, but RAI refractory DTCs remain to be clinical challenges. Sorafenib and lenvatinib were approved for the treatment of RAI refractory DTCs and more recently, genomics-based targeted therapies have been developed for NTRK and RET gene fusion-positive DTCs. Poorly differentiated and anaplastic thyroid cancers (ATCs) are extremely challenging diseases with aggressive courses. BRAF/MEK inhibition has been proven to be highly effective in BRAF V600E mutation-positive ATCs and immune checkpoint inhibitors have shown promising activities. Medullary thyroid cancers, which arise from parafollicular cells of thyroid, represent a unique subset of thyroid cancer and mainly driven by RET mutation. In addition to vandetanib and cabozantinib, highly specific RET inhibitors such as selpercatinib and pralsetinib have demonstrated impressive activity and are in clinical use.

scholarly journals MON-LB76 Impact of Age on Survival and Prognostic Factors in Radioiodine Refractory Differentiated Thyroid Cancer Patients

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Camille Buffet
Keyword(s):  
Thyroid Cancer ◽  
Prognostic Factors ◽  
Differentiated Thyroid Cancer ◽  
Kinase Inhibitors ◽  
Progression Free Survival ◽  
Therapeutic Management ◽  
Duration Of Treatment ◽  
Free Survival ◽  
Secondary Endpoints ◽  
Systemic Therapies

Abstract BACKGROUND Age has been identified as a major prognostic factor in differentiated thyroid cancer (DTC). Prognostic factors of radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) are poorly described. The objectives of our study were to analyze the influence of age on the survival of patients with RAIR-DTC and to determine their prognostic factors according to age. PATIENTS AND METHOD This single centre, retrospective study enrolled 155 patients diagnosed with a RAIR-DTC between 1991 and 2017. The primary end point was overall survival (OS). Secondary endpoints were progression free survival (PFS) and prognostic factors. RESULTS Median OS was 8.2 years (95% IC: 5.3-9.6). There was no difference according to age (P = 0.47) with median OS at 8.3 years in patients < 65 (95% IC: 4.9-10), and 7.5 years in patients > 65 (IC: 4,9-11,3). PFS after RAIR-diagnosis was 2.1 years (95% IC: 0.8-3) in patients < 65, and 1 year in patients > 65 (95% IC: 0.34-0.68). In both groups, progressive disease despite 131I reduced OS, in comparison with other RAIR criteria. In patients < 65, an interval between the initial diagnosis of DTC and the diagnosis of RAIR metastatic disease more than 3 years was protective from poor OS (HR: 2.12; 95% CI: 1.05-4.27). In patients > 65, presence of a mediastinum metastasis at RAIR-diagnosis was a significant factor for decreased OS (HR: 0.22; 95% CI: 0.11-0.44). No difference was found between groups regarding therapeutic management. One third of patients received tyrosine kinase inhibitors in both groups (< 65 years: 20 patients (28%), ≥ 65 years: 28 (33%), P = 0.49). They were also similar regarding the number of lines received or the median duration of treatment (< 65 years: 19.5 months (2-59), ≥ 65 years: 19 months (1-64), p= 0.35). At least one line of TKI was transitorily or definitively withdrawn due to toxicity in 40% of patients (< 65 years: 8/20 patients (40%), ≥ 65 years: 13/28 (46%), p= 0,037). CONCLUSION In RAIR-DTC patients, age was not predictive of the outcome. In our study, older patients seem to have benefited from intensive therapeutic management. Continual progress made in the management of RAIR-DTC, especially with the implementation of systemic therapies should probably make reconsider the natural history and conventional prognostic factors of RAIR-DTC.

scholarly journals Foundation One Genomic Interrogation of Thyroid Cancers in Patients With Metastatic Disease Requiring Systemic Therapy

2020 ◽  
Vol 105 (7) ◽  
pp. e2346-e2357 ◽  
Author(s):  
Nicole M Iñiguez-Ariza ◽  
Sina Jasim ◽  
Mabel M Ryder ◽  
Ashish V Chintakuntlawar ◽  
John C Morris ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Outcome Measures ◽  
Systemic Therapy ◽  
Radioactive Iodine ◽  
Patient Characteristics ◽  
Genomic Alterations ◽  
Epithelial Tumor ◽  
Thyroid Cancers ◽  
Poorly Differentiated ◽  
Differentiated Thyroid Cancers

Abstract Context Clinical applications of genomic assessment of thyroid cancers are rapidly evolving. Objectives, Design, and Setting We studied tumor samples from patients with imminently threatening and rare thyroid cancers to identify genomic alterations that might correlate with outcomes and/or be productively therapeutically targetable. Patient Context Progressive and metastatic, and/or rare, thyroid cancers were studied, 2012 to 2016, at Mayo Clinic sites. Intervention The intervention was Foundation One tumor interrogation. Main Outcome Measures Main outcome measures included genomic alterations, patient characteristics, and overall survival. Results Samples from 55 patients were evaluated: 20 anaplastic thyroid cancers (ATCs) (36%), 25 radioactive iodine–refractory differentiated thyroid cancers (DTCs)/poorly differentiated thyroid cancers (PDTCs) (45%; 14 papillary thyroid cancer [PTCs], 6 PDTCs, 5 Hürthle cell cancers), 8 medullary thyroid cancers (MTCs) (15%), and 2 others (a spindle epithelial tumor with thymus-like differentiation, and a primary thyroid sarcoma). Overall, 72% of DTCs, 79% of ATCs, and 75% of MTCs were deemed to have potentially productively targetable alterations. The most commonly encountered mutation was of TERT promoter (56% of DTCs, 68% of ATCs)—but this is not presently targetable. Targetable BRAFV600E mutations were found in 40% of DTCs/PDTCs (83% of PTCs) and 32% of ATCs; of MTCs, 75% had targetable RET mutations, and 25% HRAS mutations. Of patient tumors with nonmutated BRAFV600E, 53% of DTC/PDTCs and 69% of ATCs had other potentially productively targetable mutations. Genomic alterations in our series of poor prognosis metastatic DTC/PDTCs also closely resembled those seen in ATC. Conclusions Whereas genomic interrogation of favorable prognosis thyroid cancer seems ill advised, potentially productively targetable mutations were demonstrated in the majority of tumors from patients with metastatic thyroid cancers requiring systemic therapy, suggesting a rationale for the selective application of this technology.

scholarly journals EFFICACY AND SAFETY OF MULTI-TARGETED KINASE INHIBITORS IN PROGRESSIVE, RADIOIODINE-REFRACTORY DIFFERENTIATED THYROID CANCERS: A META-ANALYSIS

2016 ◽  
Vol 2 (1) ◽  
Author(s):  
Mutahir A Tunio ◽  
Mushabbab AlAsiri ◽  
Yasser Bayoumi
Keyword(s):  
Thyroid Cancer ◽  
Differentiated Thyroid Cancer ◽  
Radioactive Iodine ◽  
Kinase Inhibitors ◽  
Meta Analysis ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Cochrane Library ◽  
Differentiated Thyroid Cancers ◽  
The Impact

Purpose: A meta-analysis was conducted to evaluate the impact of oral multitargeted kinase inhibitors (MTKIs) in radioactive-iodine refractory locally advanced, recurrent/metastatic differentiated thyroid cancer (DTC) on disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) rates. Materials and Methods: The PubMed/MEDLINE, CANCERLIT, EMBASE, Cochrane Library database and other search engines were searched to identify randomised controlled trials (RCTs) comparing MTKIs with placebo in locally advanced, recurrent/metastatic DTC. Pooled data were expressed as odds ratio (OR), with 95% con dence intervals (CIs, Mantel–Haenszel xed-effect model). Results: Three RCTs with a total patient population of 954 patients were identi ed. The use of MTKIs was associated with improved PFS (OR: 0.262, 95% CI: 0.19–0.35; heterogeneity (I2) = 22.4%; P < 0.0001), improved DCR (complete and partial responses + stable disease, P < 0.0001) and improved OS 0.66, 95% CI: 0.46–0.96 (I2 = 43%, P = 0.034). Lenvatinib (compliance = 87%) was associated with more grade ≥3 hypertension. However, its other adverse effects were much lower than sorafenib (compliance = 56%) and vandetanib. Conclusion: In radioactive iodine-refractory recurrent, metastatic DTC patients, lenvatinib and sorafenib were associated with improved PFS, DRC and OS rates, while the compliance was better with lenvatinib. Key words: Meta-analysis, multitargeted kinase inhibitors, progressive differentiated thyroid cancer, radioactive iodine- refractory 

scholarly journals Identification of tetracycline combinations as EphB1 tyrosine kinase inhibitors for treatment of neuropathic pain

2021 ◽  
Vol 118 (10) ◽  
pp. e2016265118
Author(s):  
Mahmoud S. Ahmed ◽  
Ping Wang ◽  
Ngoc Uyen Nhi Nguyen ◽  
Yuji Nakada ◽  
Ivan Menendez-Montes ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Tyrosine Kinase ◽  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Catalytic Domain ◽  
Therapeutic Option ◽  
Atp Binding ◽  
Approved Drugs ◽  
Fda Approved Drugs

Previous studies have demonstrated that the synaptic EphB1 receptor tyrosine kinase is a major mediator of neuropathic pain, suggesting that targeting the activity of this receptor might be a viable therapeutic option. Therefore, we set out to determine if any FDA-approved drugs can act as inhibitors of the EphB1 intracellular catalytic domain. An in silico screen was first used to identify a number of tetracycline antibiotics which demonstrated potential docking to the ATP-binding catalytic domain of EphB1. Kinase assays showed that demeclocycline, chlortetracycline, and minocycline inhibit EphB1 kinase activity at low micromolar concentrations. In addition, we cocrystallized chlortetracycline and EphB1 receptor, which confirmed its binding to the ATP-binding domain. Finally, in vivo administration of the three-tetracycline combination inhibited the phosphorylation of EphB1 in the brain, spinal cord, and dorsal root ganglion (DRG) and effectively blocked neuropathic pain in mice. These results indicate that demeclocycline, chlortetracycline, and minocycline can be repurposed for treatment of neuropathic pain and potentially for other indications that would benefit from inhibition of EphB1 receptor kinase activity.

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.

scholarly journals Targeted Therapy for Advanced Thyroid Cancer: Kinase Inhibitors and Beyond

2019 ◽  
Vol 40 (6) ◽  
pp. 1573-1604 ◽  
Author(s):  
Maria E Cabanillas ◽  
Mabel Ryder ◽  
Camilo Jimenez
Keyword(s):  
Thyroid Cancer ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Rapid Evolution ◽  
Anaplastic Thyroid Cancer ◽  
The Us ◽  
Advanced Thyroid Cancer ◽  
Inhibitor Drug ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract The treatment of advanced thyroid cancer has undergone rapid evolution in the last decade, with multiple kinase inhibitor drug approvals for each subtype of thyroid cancer and a number of other commercially available drugs that have been studied for this indication. Although most of the US Food and Drug Administration (FDA)–approved drugs are antiangiogenic multikinase inhibitors—vandetanib, cabozantinib, sorafenib, lenvatinib—there are two FDA indications that are mutation specific—dabrafenib/trametinib for BRAF-mutated anaplastic thyroid cancer and larotrectinib for NTRK-fusion thyroid cancer. Furthermore, other mutation-specific drugs, immunotherapies, and novel strategies for advanced thyroid cancer are under investigation. Understanding the molecular basis of thyroid cancer, the drugs of interest for treatment of advanced thyroid cancer, and how these drugs can be administered safely and in the appropriate clinical scenario are the topics of this review.

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