Non-medullary thyroid carcinoma has a low incidence and an overall favorable prognosis. Nevertheless important diagnostic and therapeutic challenges are present. In the Part 1 (Hot Thyroidology, March 2003), new developments in initial diagnosis and therapy have been reviewed. In the present article, recent research on therapeutic targets for recurrent and metastatic disease will be presented.
 
Therapeutic challenges
 
Differentiated thyroid carcinoma has an overall 10-years survival rate of 90% (1). This favorable outcome is the combined result of the biological properties of the tumor as well as the effective initial therapy, consisting of near-total thyroidectomy followed by radioiodide ablation therapy.
However, when distant metastases have developed, the prognosis drops dramatically, with a 5 year survival in bone-metastases of follicular thyroid carcinoma of only 5%. Even if death is not imminent, the burden of metastatic decease may hamper quality of life for years. The main problem in metastasized thyroid carcinoma is that the current conventional therapeutic arsenal is limited to radioiodide therapy. When tumors have lost their ability to accumulate radioiodide, which is the case in approximately 50% of the patients with metastases, virtually no therapeutic alternatives are left. The development of new therapies is therefore vital. In the following, recent developments in therapy for differentiated thyroid carcinoma are discussed. These developments can be divided in (a) approaches aimed at improving or re-establishing the potential for radioiodide therapy and (b) targeting other, often non-thyroid specific pathways.
  
Improving radioiodide therapy
 
Because radioiodide therapy has such an important role in thyroid carcinoma, many attempts have been undertaken to improve the uptake of radioiodide. The discovery and molecular cloning of the rat and later the human sodium iodide symporter (hNIS) have contributed greatly to the understanding of the physiology and pathophysiology of iodide uptake by the thyroid gland (2; 3).
However, the ultimate dose of radioactivity in thyroid tumors (expressed in Gray (Gy)) is not only determined by iodide uptake but also by the effective half-life, which on its turn is influenced by iodide efflux from the cell. The exact mechanism of iodide efflux remains elusive. Although candidate molecules for apical iodide efflux, pendrin (4) and the apical iodide transporter AIT (5) have been discovered, their exact role in apical iodide transport has not been determined yet.

TSH

The TSH dependency of NIS activity is the base for the long established clinical practice to realize high TSH plasma levels by thyroid hormone withdrawal. The introduction of recombinant human TSH (rhTSH) has offered the possibility to avoid the cumbersome thyroid hormone withdrawal. The value of rhTSH has been demonstrated for diagnostic purposes, as discussed in Part 1 (Hot Thyroidology, March 2003). Although rhTSH has not yet been approved for the preparation of radioiodide therapy, several reports suggest the feasibility of rhTSH as adjuvant to radioiodide therapy (6). It will be difficult however to compare the therapeutic endpoints of radioiodide with rhTSH with classical thyroid hormone withdrawal in patients with metastatic thyroid carcinoma, as the conductance of randomized trials in these patients is hardly impossible.

Iodide deprivation

A well known mechanism to increase radioiodide uptake is to increase the specific activity of iodide, e.g. to decrease the dilution factor of radioiodide with 'cold' inorganic iodide. Although this practice has been established for long by prescribing low-iodide diets, it has only recently been demonstrated that low-iodide diets indeed have benefits for radioiodide therapy (7).

Lithium

The net effect of lithium salts on the thyroid appears to be a decrease in the efflux of thyroid hormone, leading to retention of iodide within the thyroid. Although the mechanism is not clear, this effect led to the application of lithium in hyperthyroidism, both as therapy or as adjuvant for radioiodide (8). It has been used to the same purpose in differentiated thyroid cancer (9). This latter study however is compromised by methodological problems and to date no convincing studies on improved efficacy of radioiodide therapy together with lithium have been published. In addition, the mechanism of radioiodide retention by lithium in thyroid cancer is poorly understood, leading to controversies on optimal dosages and therapy schedules.

NIS

The relation between decreased radioiodide uptake in thyroid carcinoma and decreased NIS activity has been well established. However, controversy exists on the mechanism: Some studies report decreased NIS mRNA and protein in thyroid carcinoma, suggesting that the origin of the problem is at the transcriptional level (10). In other studies however, a defect in targeting of NIS to the cell membrane is reported, which is even accompanied by an intracytoplasmatic overexpression of NIS in about 80% of thyroid tumors (11). These differences have important consequences for interventions aimed at increasing NIS expression.

Gene transfer

Given the importance of NIS, experimental studies have been conducted to enhance NIS expression in thyroid tumors. NIS gene transfer has been performed in a NIS defective thyroid carcinoma cell line. Tumors established with this cellline in mice responded to radioiodide therapy, proving that the concept of reinduction of NIS expression ultimately restores the susceptibility to radioiodide therapy (12).
However, NIS protein expression is the end-point of complex regulatory mechanisms. It may therefore be assumed that the origin of defective NIS expression is located 'higher up' in the cellular hierarchy.
One of the causal chromosomal rearrangements in papillary thyroid carcinoma involves the ret oncogene, leading to constitutive ret activation. Introducing this chromosomal rearrangement into a benign thyroid cellline leads to decreased gene expression of the thyroid transcription factors TTF-1 and PAX-8 (13). TTF-1 and PAX-8 are involved in the gene expression of important thyroid proteins, including NIS. As a result, the chromosomal ret rearrangement ultimately leads to decreased NIS expression. To underline the importance of this mechanism, it has been reported that experimental gene transfer with PAX-8 leads to re-expression of NIS in a dedifferentiated thyroid cell-line (14). Although these approaches are fascinating from a conceptual viewpoint, a potential clinical application appears not to be with in reach.

Pharmacological approaches

Therefore, medical approaches aimed at redifferentiation, or re-induction of thyroid specific proteins have gained much interest. Compounds that have been reported to reinduce NIS expression are retinoids, demethylation inducing substances and histone-deacetylase inhibitors.

Retinoids

Retinoids are vitamin-A derivatives. They influence the transcription of tissue specific gene repertoires, and as such play an important role in embryonic development. The archetypal example of disruption of retinoid signaling leading to cancer is promyelocytic myeloid leukemia, where therapy with retinoids has been highly effective (15). Retinoid therapy has been attempted in other types of cancer with limited success. In thyroid carcinoma, retinoids have been reported to reinduce NIS mRNA expression in cell-lines, although not leading to NIS protein re-expression (16). A clinical study has suggested that 13-cis retinoic acid therapy leads to restoration of sensitivity to radioiodide therapy and tumor regression (17). However, effectiveness parameters in this non-randomized, unblinded study were not uniformly studied. Therefore, the question on clinical validity of retinoids in differentiated thyroid carcinoma still awaits confirmation.

Demethylation and histone-deacetylase inhibitors

One of the mechanisms by which cells can block the expression of certain genes is by enzymes that methylate these genes or de-acetylate the histones that envelope a particular gene. These mechanisms also play a role in the silencing of genes in cancer. Therefore, compounds that can reverse methylation or inhibit histone deacetylation may lead to the reexpression of genes that are silenced in cancer.
Demethylation therapy has been proven successful in leukemia. In an in-vitro study in thyroid carcinoma, the demethylating agent 5-azacytidine led to reinduction of NIS expression, accompanied by radioiodine uptake in thyroid cancer cell lines (18). In parallel, the histone deacetylase inhibitor depsipetide has been reported to reinduce NIS mRNA expression and radioiodine uptake in thyroid carcinoma cell-lines (19). A clinical trial with depsipeptide is now underway (http://www.nci.nih.gov/clinicaltrials).

In conclusion, research directed at re-inducing NIS expression has revealed important insights into NIS regulation in thyroid carcinoma. Gene-therapeutic and pharmacological approaches have had anecdotal success in experimental systems. However, their value has been limited in clinical trials or still needs to be confirmed in patients.

Non-thyroid specific targets

Over the last decade, exciting developments have taken place in the identification and molecular dissection of novel pathways involved in cancer. The avalanche of new approaches has lead to a considerable number of promising compounds. One of the disadvantages of differentiated thyroid carcinoma is that this low prevalent tumor is usually not included in initial clinical trials with these therapies. However, successful strategies that have survived these initial trials may well become available for thyroid carcinoma. It is not possible to review all candidates for therapy in this article. Ongoing trials in the United States can be viewed at http://www.nci.nih.gov/clinicaltrials. The most promising approaches are discussed below.

Cell proliferation

Although differentiated thyroid carcinoma is a low prevalent malignancy, many chemotherapeutic protocols that have been developed over the last decades for more common malignancies have been tried in progressive thyroid carcinoma. Overall, these approaches have been disappointing. Of the classical chemotherapeutic agents, adriamycin, alone or combined with cisplatin and bleomycin may induce temporary remissions or stationary disease in about 30-50% of the patients (20; 21). The same has been reported for paclitaxel (22). Most remissions however, last only a few months and at the cost of a considerable reduction in quality of life.

Neovascularization

Molecular pathways involved in neovascularization have been demonstrated in thyroid carcinoma (23). The cascade of approaches to target tumor-induced neovascularization has led to a number of promising compounds that are now being tested in clinical trials in prevalent tumors. Reports have been published on beneficial effects of anti-VEGF antibodies in thyroid carcinoma cell-lines (24) and endostatin in animal experiments (25). A clinical trial with thalidomide is underway in the United States.

Tyrosine kinase inhibitors

Another intriguing development is the advent of tyrosine kinase inhibitors. The development of imatinib mesylate (Glivec) is prototypical for the innovative design of modern drugs with the molecular pathogenic defect as a starting point. Following imatinib, other small molecules have been developed, aimed at other tyrosine kinase activated pathways such as the eptithelial growth factor receptor activated pathway. Activation of tyrosine kinase pathways is relevant for thyroid carcinoma. The earlier discussed ret chromosomal translocation leads to constitutive activation of ret, which is a tyrosine kinase activating receptor. Tumors established with cell lines in which the ret translocation has been introduced have been successfully treated with the tyrosine kinase inhibitor PP1 (26).

PPAR-g agonists

An interesting new class of drugs are agonists of peroxisome-proliferator activated receptor gamma. (PPAR-g). These drugs have been introduced as anti-diabetic agents. Their proposed mechanism is the differentiation of pre-adipocytes into adipocytes, thereby increasing the fatty-acid storing capacity of adipose tissue. The involvement of PPAR-g in differentiation processes extents beyond the area of adipose tissue. Indeed, altered expression of PPAR-g and in vitro beneficial effects of PPAR-g agonists have been described in a number of malignancies, and recently also in pituitary tumors (27). In thyroid carcinoma, thiazolidinedione treatment induced apoptosis in thyroid tumors and prevented their growth in nude mice (28). Interestingly, a unique chromosomal rearrangement has been described in benign and malignant thyroid neoplasms, involving PPAR-g and PAX-8 (29). This rearrangement acts as a dominant competitive inhibitor of PPAR-gamma and from a theoretical point of view would render these tumors insensitive for PPARgamma agonists.

Radionuclide therapy

Somatostatin Receptor Scintigraphy (SRS)

In part 1, (Hot Thyroidology, March 2003) it has been discussed that the expression of somatostatin receptors (SSTR3 and SSTR5) by differentiated thyroid carcinoma is the base for SRS imaging and therapy. Interestingly, in a considerable number of carcinoma's irresponsive to radioiodide, SRS imaging shows pathological lesions, which has diagnostic and therapeutic consequences (30; 31). A therapeutic trial is currently performed in Rotterdam, the Netherlands, which includes patients with poorly differentiated thyroid carcinoma (32). An interim analysis showed a considerable response rate (seeFig), but definite conclusions have to be awaited until the conclusion of the trial.

Courtesy Prof Dr. E.P. Krenning, Rotterdam, NL

Palliative therapy

Surgery, external irradiation, and to a lesser extent radioiodine therapy, are the conventional palliative treatment modalities in patients with metastases of thyroid carcinoma. However, as most metastases do not accumulate iodide and the effect of radioiodide therapy is not rapid, radioiodide therapy is of limited use as a palliative treatment option. Surgery may lead to rapid relief of symptoms, but is only possible when the metastasis is approachable. External irradiation is the most frequently applied palliative therapy in bone metastases of thyroid carcinoma. Although this therapy can be effective, limiting factors may be the radiosensitivity of the tumor and the site of the tumor: in vertebral metastases, the maximal radiation dose is limited by the proximity of the spinal cord. Selective embolization of tumor metastases is another option, which is effective in about 60% of the patients to induce an immediate relief of pain and neurological symptoms (33).

The search for new targets

The recent introduction of high-yield genomic and proteomic techniques has provided enormous perspectives to identify diagnostic and potential therapeutic targets in disease, as indicated by recent high-impact studies in breast carcinoma (34). Gene expression arrays in thyroid carcinoma have revealed differential expression of genes in papillary carcinoma as compared with follicular thyroid carcinoma and normal thyroid tissue, including genes so far not associated with thyroid carcinoma (35; 36). These approaches will without doubt provide new insights into thyroid tumor biology and thereby new candidates for therapy.

Conclusion (2)

The clinical and therapeutic dilemmas as well as the intriguing biological features of differentiated thyroid carcinoma offer unique challenges for both clinicians and basic researchers. Although thyroid carcinoma research will profit from insights gained in other fields of cancer, in reverse, thyroid carcinoma research has contributed importantly to the understanding of processes of dedifferentiation and malignant transformation. Given the low prevalence, coordination and coupling of research efforts are vital.

Summary

 

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