Targeted Therapy in Refractory Thyroid Cancer

Current Achievements and Limitations

Lucia Brilli; Furio Pacini

Disclosures

Future Oncol. 2011;7(5):657-668. 

In This Article

Abstract and Introduction

Abstract

Thyroid cancer refractory to conventional treatments lacks effective treatment. Targeted therapy is an emerging therapeutic strategy for these cancers, based on preliminary promising results. Tyrosine kinase inhibitors target both specific oncogenic pathways involved in thyroid cancer progression and aspecific mechanisms such as neoangiogenesis. They are generally well tolerated and most adverse events have low-to-moderate severity. Other classes of drugs have been tested, alone or in combination with tyrosine kinase inhibitors, but so far the results have been limited. The aim of this article is to describe the benefits and limitations of innovative drugs that are currently under investigation in patients with refractory thyroid cancer.

Introduction

Thyroid cancer is the most frequent tumor of the endocrine system and in the last few decades it has been the tumor with the largest increase in incidence among all human cancers.[1]

Thyroid cancer is represented by differentiated thyroid carcinoma (a large majority), medullary thyroid cancer (arising from the parafollicular C-cells) and anaplastic thyroid cancer (ATC). Differentiated thyroid carcinoma (DTC), papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma, arise from the thyroid follicular epithelium; PTC represents the most frequent histotype, accounting for 80% of DTCs.[2] Most patients with DTC have limited disease and display an excellent prognosis with standard treatment, consisting of surgical resection, radioactive iodine (131I) and L-tyroxine suppressive therapy. Distant metastases at the time of diagnosis are very rare (5% of the patients) and recurrent disease occurs in another 10–15% of the cases. Approximately half of these cases can be cured with conventional radioiodine therapy or additional surgical procedures, but another half of these tumors became poorly differentiated, lose the ability to take up radioiodine and have a poor survival (15% at 10 years).[2–4] No effective treatment is currently available for this subgroup of patients; chemotherapy with cytotoxic drugs (doxorubicin alone or in combination with other drugs) has shown limited effects and its use is almost universally abandoned.

Medullary thyroid cancer (MTC) accounts for approximately 5% of all thyroid cancer cases, its prognosis is intermediate between DTC and ATC, demonstrating a cumulative 10-year survival of approximately 75%, but it is strongly dependent from the initial stage.[5] Recurrent disease develops in approximately 50% of the patients and distant metastases are present, at first diagnosis, in 7–23% of MTC patients. For metastatic MTC, the overall survival rate is only 25% at 5 years and surgery is the only treatment option since radioactive iodine and thyroid-stimulating hormone suppressive therapy have no role. In addition in MTC, chemotherapy is not effective in MTC. MTC is sporadic in 80% of the cases and hereditary in the remainder. Hereditary MTC is associated with the multiple endocrine neoplasia type II syndrome transmitted with an autosomal dominant pattern.[6]

Anaplastic thyroid cancer represents less than 5% of all thyroid cancer but it is one of the most aggressive human tumors and its prognosis is very poor, with survival rate rarely exceeding 6–12 months.[7] It can arise de novo or from pre-existing DTC. Therapy is based on surgery (whenever it is possible), external beam radiotherapy and chemotherapy but with palliative effects.

Treatment of radioactive iodine-refractory DTC, metastatic MTC and ATC is a serious challenge for practioners. In the absence of consolidated treatments, patients with these tumors are candidates for innovative therapy.

The molecular pathogenesis of thyroid cancer has largely been defined in the last 20 years and it has been shown that thyroid cancers, like many other cancers, often evolve through a multistep process involving oncogenes (Figure 1).[8,9] Genetic alterations in the RET–RAS–RAF–MAPK or PI3K–AKT/mTOR pathways are associated with the development of most PTCs. In particular, activating mutations in BRAF or RAS genes, and rearrangement of the RET proto-oncogene (rearranged during transfection/PTC [RET/PTC]), all belonging to the MAPK pathway and leading to a constitutive activation of the MAPK pathway are found in 80% of PTCs.

Figure 1.

Molecular pathways involved in thyroid tumorigenesis and molecular targets for new drugs.
EGFR: EGF receptor; RET: Rearranged during transfection; TK: Tyrosine kinase; VEGFR: VEGF receptor.
Reproduced with permission from Smit JWA.

The BRAF V600E mutation is the most prevalent somatic event in PTC, accounting for 40–60% of cases, and it is correlated with a more aggressive phenotype. On the contrary, RAS point mutations are not specific to thyroid cancer and may also be found in follicular adenomas. They account for approximately 20% of PTCs, particularly the follicular variant of PTC and are found in nearly 20% of follicular thyroid carcinomas. In the latter, another rearrangement (PAX8/PPARγ) is identified in approximately 30% of the cases.

Genetic alteration of PI3K–AKT–mTOR pathway also has a key role in thyroid carcinogenesis and is correlated with a more aggressive histotype.[10]

Rearrangement of the RET proto-oncogene (RET/PTC) are found in approximately 20% of PTCs. Alterations of the same proto-oncogene, in the form of point mutations, are implicated in the development of MTC. Activating RET mutations have been observed in nearly 95% of hereditary MTC, and in 50% of sporadic cases.

Late events in thyroid tumorigenesis play a role in the transition from well-differentiated to undifferentiated or poorly differentiated thyroid cancer, and are represented by mutations in p53, which regulates the cell cycle, inducing growth cell arrest, senescence and/or apoptosis, and CTNNB1, which encodes the β-catenin protein, involved in cell adhesion and transcription. Mutations in p53 and β-catenin are common in poorly differentiated thyroid cancer (both in 20% of cases) and particularly in anaplastic thyroid cancer (~70 and 60%, respectively).[7]

Evidence has been accumulated through experimental models and clinical trials that, among several aberrant molecular mechanisms, one specific oncogene or a particular pathway may be sufficient to maintain the malignant phenotype. This concept has been defined as 'oncogene addiction'.[11] The reversal of this abnormality can lead to inhibition of cancer growth and/or apoptosis, and it is the rationale for targeted therapy. An example of this phenomenon is the inactivation of angiogenetic genes, leading to inhibition of tumor invasion, angiogenesis and recurrence.

Increased vascularity has been reported in thyroid cancer. VEGF plays a key role in angiogenesis, promoting endothelial cell growth and migration. Thyroid cancer cell lines are characterized by high expression of both VEGF and its receptors; key factors in neoangiogenesis.[12,13] VEGF levels also correlate with tumor stage, size, distant metastases and the presence of the BRAF V600E mutation.[14–16]

The logical application of the above discoveries has been the development of new drugs targeting specific thyroid oncogenes and/or growth factors promoting angiogenesis. Such drugs are usually referred to as tyrosine kinase inhibitors (TKIs) from the moment that the target of these drugs are genes belonging to the family of tyrosine kinase (TK) receptors.

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