Review
Dedifferentiated thyroid cancer: A therapeutic challenge

https://doi.org/10.1016/j.biopha.2008.07.056Get rights and content

Abstract

Human papillary dedifferentiated thyroid cancer (HPDTC) represents a therapeutic dilemma. Targeted therapy (RET proto-oncogene or BRAF-targeting drugs) are promising treatments for HPDTC.

Also PPARg agonists are another exciting field for redifferentiating therapy of HPDTC.

However, even if many new approaches for the therapy of HPDTC are emerging, until now a significant clinical impact on survival by the use of these drugs is still lacking. In the future, the identification of patients who are likely to benefit from each therapeutic option will be important. In this view particular importance should be given to development of primary cells from the single patient by fine needle aspiration samples, as recently observed in anaplastic thyroid cancer. In fact, chemosensitivity tests in primary tumoral cells may help in detecting responsive patients and in preventing the administration of inactive drugs to those unresponsive.

Introduction

During thyroid tumor progression, cellular dedifferentiation occurs in up to 5% of cases and is usually accompanied by more aggressive growth, metastatic spread and loss of iodide uptake ability, making the tumor resistant to the traditional therapeutic modalities and radioiodine (dedifferentiated thyroid cancer). Conventional chemotherapy and radiotherapy have a modest, if any, effect on advanced dedifferentiated thyroid cancer [1], which is responsible for the vast majority of deaths attributed to thyroid cancer. Therefore, advanced dedifferentiated thyroid cancer represents a therapeutic dilemma and is considered a critical area of research.

Section snippets

Molecular changes in advanced thyroid cancer

Molecular abnormalities have been recorded in papillary and follicular thyroid carcinomas. In 80% of papillary carcinomas, mutations have been noted in genes that encode signaling molecules of the mitogen-activated protein kinase (MAPK) pathway [2]. In adult sporadic papillary carcinomas, RET/PTC rearrangements are found in 30–40% of cases, RAS mutations in about 10%, and BRAF mutations in around 40% of cases, with no overlap between these mutations [3]. In radiation-induced papillary

New molecular targeted therapies in advanced thyroid cancer

The clinical activity of several compounds, including AMG 706, BAY 43-9006, ZD 64–74, and AG-013736, in DTC is being studied in phase II trials [19], [20], [21], [22], [23], with preliminary studies recording disease response and stabilization [24], [25], [26]. These molecules inhibit several targets, including RET tyrosine kinase, VEGF receptor (VEGFR) 1, VEGFR2, and VEGFR3, and have an antiangiogenic effect. BAY 43-9006 also inhibits BRAF kinase. Other targets include membrane receptor

Re-inducing tumor iodide uptake

Reduced expression of NIS has been demonstrated and suggested to be responsible for the impaired iodine uptake ability; immunohistochemistry study verified that, instead, in some thyroid cancer samples NIS is overexpressed [27]. However, in these tumors NIS localization was mostly intracellular, highlighting the importance of understanding the molecular mechanism involved in targeting NIS to plasma membrane. The crucial role of radioiodine therapy in the course of thyroid carcinoma stimulated

Peroxisome proliferator-activated receptor gamma agonists

Peroxisome proliferator-activated receptors (PPAR) are members of a superfamily of nuclear hormone receptors. Activation of PPAR isoforms elicits both antineoplastic [36] and anti-inflammatory effects [37] in several types of mammalian cells. PPARs are ligand-activated transcription factors and have a subfamily of three different isoforms: PPARalfa (PPARa), PPARgamma (PPARg), and PPARbeta/delta (PPARb/d). Endogenous ligands of PPARg include long-chain polyunsaturated fatty acids, eicosanoid

Conclusions

Many new approaches for the therapy of dedifferentiated thyroid cancer are emerging, but until now a significant clinical impact on survival by the use of these drugs is still lacking. In the future, the identification of patients who are likely to benefit from each therapeutic option will be important. In this view new techniques have been developed to test the effectiveness of the various treatments in each patient. For this purpose, particular importance should be given to development of

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