The prognosis of differentiated thyroidal tumors is generally favorable mainly because there are different and effective tools in the early diagnosis and treatment of these tumors [
28]. In fact, the use of US and FNC in the diagnosis of thyroid nodules usually leads to an early and accurate diagnosis of small and differentiated tumors, as well as less frequent thyroidal neoplasms [
3,
5,
6]. In particular FNC, coupled with immunocytochemistry (ICC), flow cytometry (FC) and molecular techniques [
3‐
6,
29‐
31] has dramatically enhanced the sensitivity and the accuracy of preoperative diagnosis of thyroidal nodules [
3,
5,
29]. The bad prognosis of advanced thyroid carcinoma, prompted researchers to evaluate the efficacy of new pharmaceutical compounds with enzymatic inhibitory properties (Table
4). The prevalence of
RET/PTC rearrangements in ATC was much lower than in papillary thyroid cancer reported in most of the studies (4% vs. 36%) [
25,
32]. Noteworthy, benign thyroid nodules exhibiting
RET/PTC rearrangements do not evolve in cancer [
33,
34]. This data suggest that this oncogene has a minor role in the progression from well-differentiated to undifferentiated thyroid cancer. It also indicate that tyrosine kinase inhibitors such as sorafenib, sunitinib, and vandetanib have little chance to function through the inhibition of this oncogene in ATC. The encouraging results obtained by these drugs in non RAI-responsive differentiated thyroid carcinomas in some clinical trials where the
RET rearrangement was not evaluated, were more likely due to the effects on neo-angiogenesis [
35]. The high prevalence of
BRAF
V600E
mutation in ATC supports the hypothesis that many ATCs actually represent a progressive malignant degeneration of
BRAF-mutated, well-differentiated thyroid carcinomas [
36]. This gene is a pivotal component of the MAPK pathway and reduces the activity of p21
kip1 in thyroid tumors, stimulating the cell cycle machinery [
37]. Vemurafenib (PLX4032), a BRAF selective kinase inhibitor and sorafenib, a multi-target inhibitor, find application in selected BRAF-mutation positive melanomas [
38]. Although clinical studies of BRAF inhibitors in advanced non RAI-responsive differentiated thyroid carcinomas have shown encouraging results with frequent early responses, in a relevant fraction of patients this effect was of limited duration, with frequent relapse or no response. In addition, intratumoral heterogeneity with respect to
BRAF mutation makes the evaluation of these clinical trials even more complex [
39,
40]. Poor results were obtained with sorafenib in ATC, although positive results reported with vemurafenib in one ATC with
BRAF
V600E
mutation are worthy to be mentioned [
27,
35]. A relevant obstacle to the efficacy of treatments based on the inhibition of BRAF
V600E is the presence of activating mutations of
RAS. This proto-oncogene is a small GTP binding protein located upstream RAF in the MAPK cascade. Activating mutations of this protein reactivate the MAPK pathway, making
BRAF
V600E
inhibition inefficient [
41]. The high prevalence of
RAS activating mutations in ATC (60%) makes the inhibition of the MAPK pathway by kinase inhibitors a strategy whose success is unlikely. Moreover, papillary thyroid carcinoma and ATC exhibit concomitant
BRAF
V600E
and
RAS mutations, although a rare occurrence [
42‐
44]. In light of these considerations, the pharmacological inhibition of the MAPK pathway looks less promising than the inhibition of the PI3K/Akt/mTOR pathway. This pathway is constitutively activated by inactivating mutations of PTEN and by activating mutations of PI3KCA. Both mutations are frequent in ATC (10% and 24% respectively). Ongoing studies in cells, both in culture and
in vivo, are investigating the anticancer effect of the novel allosteric Akt inhibitor, MK2206, in combination with several anticancer agents [
45]. This agent selectively inhibits thyroid cancer cells harboring mutations that can activate the PI3K/Akt pathway [
46,
47]. An appealing feature of Akt/mTOR inhibitors is the possibility of treating advanced thyroid cancer also when resistance to single targeted therapy is conferred by multiple genetic alterations. Most of the kinase inhibitors currently under investigation are multitargeted inhibitors, with a beneficial double effect impairing the viability of tumor cells and tumor vascularization [
13,
14,
20,
48]. The TP53 tumor suppressor gene increases the cyclin kinase inhibitor p21
kip1, promoting cell cycle arrest at G1/S. Its inactivation by a mutation impairs the correct modulation of cell proliferation and apoptosis. This gene is mutated in 48% of ATC. The loss of the TP53 mediated control of the apoptotic machinery is probably the most difficult obstacle to overcome for a pharmacological agent to be active in ATC. Beneficial effects in ATC cell lines have been observed with an adenovirus TP53-regulated Cre/loxP system and with a E1B gene-defective adenovirus (ONYX-015) in TP53 mutant cells [
49,
50].
Table 4
Major pharmaceutical compounds in clinical development for the treatment of thyroid cancer
Axitinib | + | | - | + | - |
Cabozantinib | +/- | | - | - | - |
Lenvatinib | + | | - | + | - |
Motesanib | + | | - | + | - |
Pazopanib | + | | - | + | - |
Sorafenib | + | + | + | + | - |
Sunitinib | + | + | - | + | - |
Vandetanib | + | + | - | - | - |
Vemurafenib | - | - | + | - | - |
Everolimus | - | - | - | - | + |