Molecular targets of tyrosine kinase inhibitors in thyroid cancer

Abstract

Thyroid cancer (TC) is the eighth most frequently diagnosed cancer worldwide with a rising incidence in the past 20 years. Surgery is the primary strategy of therapy for patients with medullary TC (MTC) and differentiated TC (DTC). In DTC patients, radioactive iodine (RAI) is administered after thyroidectomy. Neck ultrasound, basal and thyroid-stimulating hormone-stimulated thyroglobulin are generally performed every three to six months for the first year, with subsequent intervals depending on initial risk assessment, for the detection of possible persistent/recurrent disease during the follow up. Distant metastases are present at the diagnosis in ∼5 % of DTC patients; up to 15 % of patients have recurrences during the follow up, with a survival reduction (70 %–50 %) at 10-year. During tumor progression, the iodide uptake capability of DTC cancer cells can be lost, making them refractory to RAI, with a negative impact on the prognosis.

Significant advances have been done recently in our understanding of the molecular pathways implicated in the progression of TCs. Several drugs have been developed, which inhibit signaling kinases or oncogenic kinases (BRAF^V600E, RET/PTC), such as those associated with Platelet-Derived Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor.

Tyrosine kinase receptors are involved in cancer cell proliferation, angiogenesis, and lymphangiogenesis. Several tyrosine kinase inhibitors (TKIs) are emerging as new treatments for DTC, MTC and anaplastic TC (ATC), and can induce a clinical response and stabilize the disease. Lenvatinib and sorafenib reached the approval for RAI-refractory DTC, whereas cabozantinib and vandetanib for MTC. These TKIs extend median progression-free survival, but do not increase the overall survival. Severe side effects and drug resistance can develop in TC patients treated with TKIs. Additional studies are needed to identify a potential effective targeted therapy for aggressive TCs, according to their molecular characterization.

Introduction

Among endocrine tumors, thyroid cancer (TC) is the eighth most frequently diagnosed cancer worldwide [1], with a rising incidence in the past 20 years [[2], [3], [4], [5], [6], [7]]. Thyroid follicular epithelial-derived cancers, also known as differentiated thyroid carcinomas (DTC), represent over 90 % of TC and are divided into papillary TC (PTC; about 90 %), follicular TC (FTC; about 10 %) and anaplastic TC (ATC, less than 2 %). Medullary TC (MTC) represents less than 5 % of TCs. MTC can be hereditary (25 %), including familial MTC and multiple endocrine neoplasia type 2 (MEN) 2A, MEN 2B, or sporadic (75 %) [8].

The primary therapeutic strategy for patients with DTC and MTC is surgery [9]. In patients with DTC, radioactive iodine (RAI) is administered after thyroidectomy to ablate residual normal thyroid tissue, can be an adjuvant treatment of subclinical micrometastatic disease, and/or treat evident residual or metastatic TC [10]. For the detection of possible persistent/recurrent disease in the follow up, neck ultrasound and basal and thyroid-stimulating hormone (TSH)-stimulated thyroglobulin (Tg) are generally performed every three to six months for the first year, with subsequent intervals depending on initial risk assessment [[11], [12], [13]].

TCs have different clinical behaviors, from indolent tumors with low mortality in most of the cases, to very aggressive forms, i.e. ATC [14]. Over 90 % of DTC patients has a normal life expectancy [15]. At the diagnosis, distant metastases (lung, bone, or other sites) are reported in ∼5 % of DTC patients. In the follow up, about 15 % of patients develop recurrences (in lymph nodes or in thyroid bed), with a survival decrease at 10-years from 70 % to 50 % [16,17]. When DTC progesses, the iodide uptake by thyroid cells is abolished. Consequently, the cells become refractory to RAI, and this impacts negatively the prognosis [[15], [16], [17]]. For patients with metastatic DTC that progresses regardless of systemic treatment, such as RAI and TSH-suppressive thyroid hormone treatment [18], therapeutic options [e.g., surgery, chemotherapy and external beam radiation therapy (EBRT)], are associated with significant side effects and a palliative role (10–20 % transient efficacy), with no prolongation of survival either used alone or in combination [19]. It may be difficult to differentiate ATC from poorly differentiated thyroid cancer (PDTC), which represents an aggressive subtype of TC, but less than ATC [20].

Significant advances have been done recently in the knowledge of the molecular pathways implicated in TC progression. Novel classes of drugs that inhibit oncogenic kinases [e.g., v-Raf murine sarcoma viral oncogene homolog B (BRAF^V600E), REarranged during Transfection (RET)/PTC], or signaling kinases [e.g., Vascular Endothelial Growth Factor Receptor (VEGFR), Platelet-Derived Growth Factor Receptor (PDGFR), etc.] associated with TC cell proliferation have been described [[21], [22], [23], [24]]. Most of these molecular alterations are prognostic and diagnostic markers and therapeutical targets [[21], [22], [23]].

During the last years, several small molecule inhibitors that target the intracellular tyrosine kinase (TK) associated with various receptors [i.e., VEGFR2/3, PDGFR, RET, KIT, epidermal growth factor receptor (EGFR), c-Met, fibroblast growth factor receptors (FGFR), and Tie2] have been approved by US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for treating aggressive and refractory TCs [21,22,24]. As expected considering agents that target the ATP-binding site of the intracellular TK, different small molecule TK inhibitors (TKIs) affect multiple TKs beside their initially intended target [25].

In this paper, we review the molecular targets of TKIs, and the results that have emerged from clinical studies that aimed to evaluate the safety and efficacy of these drugs in aggressive TCs.