Thyroid Cancer—Risks and Causes

The incidence of thyroid cancer has almost doubled in recent years and over 60,000 people will be diagnosed in the US in 2015. While the prognosis for most such patients is excellent, a significant proportion die of thyroid cancer from local tumor progression and above all from metastases. Here we review the different types of thyroid cancers and their molecular changes with a special emphasis on the currently known susceptibility and precipitating factors. With the recent clinical introduction of tyrosine kinase inhibitors for the treatment of metastatic thyroid cancer it is clear that a simple cure is not at hand and further understanding of the molecular mechanisms of these tumors is urgently needed.

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Targeted Therapy for Advanced Thyroid Cancer: Kinase Inhibitors and Beyond

Endocrine Reviews ◽

10.1210/er.2019-00007 ◽

2019 ◽

Vol 40 (6) ◽

pp. 1573-1604 ◽

Cited By ~ 25

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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When will the cancer start? Elucidating the correlations between cancer initiation times and lifetime cancer risks

10.1101/640284 ◽

2019 ◽

Author(s):

Hamid Teimouri ◽

Maria Kochugaeva ◽

Anatoly B. Kolomeisky

Keyword(s):

Molecular Mechanisms ◽

Theoretical Method ◽

Cancer Risks ◽

Discrete State ◽

Stochastic Description ◽

Cancer Initiation ◽

Different Types ◽

Fixation Probabilities ◽

The Times ◽

Neutral Mutations

AbstractCancer is a genetic disease that results from accumulation of unfavorable mutations. As soon as genetic and epigenetic modifications associated with these mutations become strong enough, the uncontrolled tumor cell growth is initiated, eventually spreading through healthy tissues. Clarifying the dynamics of cancer initiation is thus critically important for understanding the molecular mechanisms of tumorigenesis. Here we present a new theoretical method to evaluate the dynamic processes associated with the cancer initiation. It is based on a discrete-state stochastic description of the formation of tumors as a fixation of unfavorable mutations in tissues. Using a first-passage analysis the probabilities for the cancer to appear and the times before it happens, which are viewed as fixation probabilities and fixation times, respectively, are explicitly calculated. It is predicted that the slowest cancer initiation dynamics is observed for neutral mutations, while it is fast for both advantageous and, surprisingly, disadvantageous mutations. The method is applied for estimating the cancer initiation times from experimentally available lifetime cancer risks for different types of cancer. It is found that the higher probability of the cancer to occur does not necessary lead to the fast times of starting the cancer. Our theoretical analysis helps to clarify microscopic aspects of cancer initiation processes.

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Elucidating the correlations between cancer initiation times and lifetime cancer risks

Scientific Reports ◽

10.1038/s41598-019-55300-w ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Hamid Teimouri ◽

Maria P. Kochugaeva ◽

Anatoly B. Kolomeisky

Keyword(s):

Molecular Mechanisms ◽

Theoretical Method ◽

Cancer Risks ◽

Discrete State ◽

Stochastic Description ◽

Cancer Initiation ◽

Different Types ◽

Fixation Probabilities ◽

The Times ◽

Neutral Mutations

AbstractCancer is a genetic disease that results from accumulation of unfavorable mutations. As soon as genetic and epigenetic modifications associated with these mutations become strong enough, the uncontrolled tumor cell growth is initiated, eventually spreading through healthy tissues. Clarifying the dynamics of cancer initiation is thus critically important for understanding the molecular mechanisms of tumorigenesis. Here we present a new theoretical method to evaluate the dynamic processes associated with the cancer initiation. It is based on a discrete-state stochastic description of the formation of tumors as a fixation of cancerous mutations in tissues. Using a first-passage analysis the probabilities for the cancer to appear and the times before it happens, which are viewed as fixation probabilities and fixation times, respectively, are explicitly calculated. It is predicted that the slowest cancer initiation dynamics is observed for neutral mutations, while it is fast for both advantageous and, surprisingly, disadvantageous mutations. The method is applied for estimating the cancer initiation times from experimentally available lifetime cancer risks for different types of cancer. It is found that the higher probability of the cancer to occur does not necessary lead to the faster times of starting the cancer. Our theoretical analysis helps to clarify microscopic aspects of cancer initiation processes.

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Tyrosine kinase inhibitors for advanced or metastatic thyroid cancer: a meta-analysis of randomized controlled trials

Current Medical Research and Opinion ◽

10.1080/03007995.2017.1368466 ◽

2017 ◽

Vol 34 (5) ◽

pp. 795-803 ◽

Cited By ~ 11

Author(s):

Jen-Wei Liu ◽

Chiehfeng Chen ◽

El-Wui Loh ◽

Chun-Cheng Chu ◽

Mu-Yi Wang ◽

...

Keyword(s):

Thyroid Cancer ◽

Tyrosine Kinase ◽

Randomized Controlled Trials ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Meta Analysis ◽

Controlled Trials ◽

Randomized Controlled ◽

Metastatic Thyroid Cancer

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Challenges Associated with Tyrosine Kinase Inhibitor Therapy for Metastatic Thyroid Cancer

Journal of Thyroid Research ◽

10.4061/2011/985780 ◽

2011 ◽

Vol 2011 ◽

pp. 1-9 ◽

Cited By ~ 31

Author(s):

Maria E. Cabanillas ◽

Mimi I. Hu ◽

Jean-Bernard Durand ◽

Naifa L. Busaidy

Keyword(s):

Thyroid Cancer ◽

Tyrosine Kinase ◽

Medullary Thyroid Cancer ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

The United States ◽

Adverse Event Profile ◽

Tyrosine Kinase Inhibitor Therapy ◽

Differentiated Thyroid Cancers ◽

Metastatic Thyroid Cancer

Tyrosine kinase inhibitors (TKIs) which target angiogenesis are promising treatments for patients with metastatic medullary and differentiated thyroid cancers. Sorafenib, sunitinib, and pazopanib are commercially available drugs which have been studied in these diseases. Vandetanib is the first drug approved in the United States for treatment of medullary thyroid cancer. These TKIs are used as chronic therapies, and therefore it is imperative to understand the adverse event profile in order to avoid excessive toxicity and maintain patients on therapy as long as it proves beneficial. Here we review common toxicities, management of these, and other challenging situations that arise when using TKIs in patients with thyroid cancer.

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Pyrrolopyrimidine, A Multifaceted Scaffold in Cancer Targeted Therapy

Drug Research ◽

10.1055/s-0044-101256 ◽

2018 ◽

Vol 68 (09) ◽

pp. 485-498 ◽

Cited By ~ 1

Author(s):

Mai Adel ◽

Rabah Serya ◽

Deena Lasheen ◽

Khaled Abouzid

Keyword(s):

Clinical Trials ◽

Heterocyclic Compounds ◽

Kinase Inhibitors ◽

Recent Literature ◽

Biological Activities ◽

Biologically Active ◽

The Us ◽

Different Types ◽

Us Fda ◽

Cancer Targeted Therapy

AbstractPyrrolopyrimidine derivatives represent a class of biologically active heterocyclic compounds which can serve as promising scaffolds that display remarkable biological activities, such as anti-inflammatory, antimicrobial, antiviral and anticancer. In the last few years, several pyrrolopyrimidine derivatives have been approved by the US FDA and in other countries for the treatment of different diseases or are currently in phase I/II clinical trials. Due to their inimitable antioxidant and anti-tumor properties, researchers were inspired to develop novel derivatives for the treatment of different types of cancer. The present review summarizes recent literature up to 2017 on the most recent development in the medicinal chemistry of pyrrolopyrimidine derivatives and their potential as anticancer therapeutics, especially compounds acting as kinase inhibitors.

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Molecular Alterations in Thyroid Cancer: From Bench to Clinical Practice

Genes ◽

10.3390/genes10090709 ◽

2019 ◽

Vol 10 (9) ◽

pp. 709 ◽

Cited By ~ 12

Author(s):

Elena Tirrò ◽

Federica Martorana ◽

Chiara Romano ◽

Silvia Rita Vitale ◽

Gianmarco Motta ◽

...

Keyword(s):

Thyroid Cancer ◽

Molecular Mechanisms ◽

Kinase Inhibitors ◽

Tumor Biology ◽

Cancer Development ◽

Disease Evolution ◽

Molecular Alterations ◽

Genomic Landscape ◽

Thyroid Malignancies

Thyroid cancer comprises different clinical and histological entities. Whereas differentiated (DTCs) malignancies are sensitive to radioiodine therapy, anaplastic (ATCs) and medullary (MTCs) tumors do not uptake radioactive iodine and display aggressive features associated with a poor prognosis. Moreover, in a majority of DTCs, disease evolution leads to the progressive loss of iodine sensitivity. Hence, iodine-refractory DTCs, along with ATCs and MTCs, require alternative treatments reflective of their different tumor biology. In the last decade, the molecular mechanisms promoting thyroid cancer development and progression have been extensively studied. This has led to a better understanding of the genomic landscape, displayed by thyroid malignancies, and to the identification of novel therapeutic targets. Indeed, several pharmacological compounds have been developed for iodine-refractory tumors, with four multi-target tyrosine kinase inhibitors already available for DTCs (sorafenib and lenvatinib) and MTCs (cabozantib and vandetanib), and a plethora of drugs currently being evaluated in clinical trials. In this review, we will describe the genomic alterations and biological processes intertwined with thyroid cancer development, also providing a thorough overview of targeted drugs already tested or under investigation for these tumors. Furthermore, given the existing preclinical evidence, we will briefly discuss the potential role of immunotherapy as an additional therapeutic strategy for the treatment of thyroid cancer.

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SCFβ-TRCP suppresses angiogenesis and thyroid cancer cell migration by promoting ubiquitination and destruction of VEGF receptor 2

Journal of Experimental Medicine ◽

10.1084/jem.20112446 ◽

2012 ◽

Vol 209 (7) ◽

pp. 1289-1307 ◽

Cited By ~ 47

Author(s):

Shavali Shaik ◽

Carmelo Nucera ◽

Hiroyuki Inuzuka ◽

Daming Gao ◽

Maija Garnaas ◽

...

Keyword(s):

Cell Migration ◽

Thyroid Cancer ◽

Molecular Mechanisms ◽

Kinase Inhibitors ◽

Inverse Correlation ◽

Endothelial Cell Proliferation ◽

Vegf Receptor ◽

Dependent Manner

The incidence of human papillary thyroid cancer (PTC) is increasing and an aggressive subtype of this disease is resistant to treatment with vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor. VEGFR2 promotes angiogenesis by triggering endothelial cell proliferation and migration. However, the molecular mechanisms governing VEGFR2 stability in vivo remain unknown. Additionally, whether VEGFR2 influences PTC cell migration is not clear. We show that the ubiquitin E3 ligase SCFβ-TRCP promotes ubiquitination and destruction of VEGFR2 in a casein kinase I (CKI)–dependent manner. β-TRCP knockdown or CKI inhibition causes accumulation of VEGFR2, resulting in increased activity of signaling pathways downstream of VEGFR2. β-TRCP–depleted endothelial cells exhibit enhanced migration and angiogenesis in vitro. Furthermore, β-TRCP knockdown increased angiogenesis and vessel branching in zebrafish. Importantly, we found an inverse correlation between β-TRCP protein levels and angiogenesis in PTC. We also show that β-TRCP inhibits cell migration and decreases sensitivity to the VEGFR2 inhibitor sorafenib in poorly differentiated PTC cells. These results provide a new biomarker that may aid a rational use of tyrosine kinase inhibitors to treat refractory PTC.

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Sorafenib in metastatic thyroid cancer

Endocrine Related Cancer ◽

10.1530/erc-11-0351 ◽

2012 ◽

Vol 19 (2) ◽

pp. 209-216 ◽

Cited By ~ 61

Author(s):

Jaume Capdevila ◽

Lara Iglesias ◽

Irene Halperin ◽

Ángel Segura ◽

Javier Martínez-Trufero ◽

...

Keyword(s):

Thyroid Cancer ◽

Tumor Marker ◽

Kinase Inhibitors ◽

Objective Response ◽

Progression Free Survival ◽

Curative Surgery ◽

Phase Ii Studies ◽

Further Development ◽

Metastatic Thyroid Cancer

Although thyroid cancer usually has an excellent prognosis, few therapeutic options are available in the refractory setting. Based on the recent results of phase II studies with tyrosine kinase inhibitors, we designed a retrospective analysis of patients with metastatic thyroid cancer treated with sorafenib in seven Spanish referral centers. Consecutive patients with progressive metastatic thyroid cancer (papillary, follicular, medullary, and anaplastic) not suitable for curative surgery, radioactive-iodine therapy, or radiotherapy were treated with sorafenib 400 mg twice a day. The primary end point was objective response rate (RR). Secondary end points included toxicity, median progression-free survival (mPFS), median overall survival (mOS), and correlation between tumor marker levels (thyroglobulin, calcitonin, and carcinoembryonic antigen) and efficacy. Between June 2006 and January 2010, 34 patients were included in the study. Sixteen patients presented differentiated thyroid carcinomas (DTC) of which seven (21%) were papillary, nine (26%) follicular, 15 (44%) medullary (MTC), and three (9%) were anaplastic (ATC). Eleven (32%) patients achieved partial response and 14 (41%) had stable disease beyond 6 months. Regarding histological subtype, RRs were 47% (seven of 15) for MTC, 19% (three of 16) for DTC, and 33% (one of three) for ATC. With a median follow-up of 11.5 months, mPFS were 13.5, 10.5, and 4.4 months for DTC, MTC, and ATC respectively. Tumor markers were evaluated in 22 patients, and a statistically significant association was observed between RR and decrease in tumor marker levels >50% (P=0.033). In this retrospective trial, sorafenib showed antitumor efficacy in all histological subtypes of thyroid cancer, warranting further development in this setting.

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