Medullary Thyroid Cancer: Molecular Biology and Novel Molecular Therapies

Abstract

Medullary thyroid cancer (MTC) arises from neural-crest-derived parafollicular C cells of the thyroid gland and accounts for approximately 4% of all thyroid cancers. Up to 25–30% of MTC cases occur as inherited disorders while the remaining cases represent the sporadic form of the disease. In this review, the structure and signalling properties of the RET proto-oncogene in its wild-type and mutant forms, and its role in hereditary and sporadic MTC, are discussed. A full data search was performed through PubMed over the years 2000–2008 with the key words ‘medullary thyroid cancer, treatment, molecular biology, RET, molecular mechanism’, and all relevant publications have been included, together with selected publications prior to that date. We also review novel therapies for metastatic MTC, especially the tyrosine kinase inhibitors which have activity at multiple receptor subtypes, and summarize the current ongoing trials in this area. While such tyrosine kinase inhibitors, particularly those affecting RET activity such as vandetanib, sorafenib and sunitinib, are promising, the low rate of partial responses and absence of complete responses in all of the various trials of monotherapy emphasize the need for new and more effective single agents or combinations of therapeutic agents with acceptable toxicity.

Interplay between Ret and Fap-1 regulates CD95-mediated apoptosis in medullary thyroid cancer cells

“…showing significant activity in patients with MTC [3]. Noteworthy, we found that one of these agents, sorafenib [38], showed effects on the Ret /Fap-1 system comparable to those described M a n u s c r i p t…”

“…Tumor regressions in treated animals were observed in association with apoptosis induction and angiogenesis inhibition [15]. Currently, several agents targeting Ret among other kinases are under clinical investigation in thyroid cancers [3,16].…”

“…MTC, which is the most common cause of death in MEN2 patients, is relatively unresponsive to radiotherapy and conventional chemotherapy. Thyroidectomy remains the standard treatment and the only curative therapy [3]. The lack of effective treatments for unresectable, recurrent, or metastatic MTC indicates the urgent need for new therapeutic options.…”

“…Most MEN2B patients harbor the M918T mutation, whereas <5% of patients have the A883F mutation. RET M918T, which is also the most frequent somatic mutation in sporadic MTCs is prognostic of aggressive disease thus indicating a strong carcinogenic potential [3,7]. Substitution of methionine 918 with threonine results in increased Ret kinase activity, release of auto-inhibition, increased ligandindependent formation of activated monomers and dimers, and change in substrate specificity contributing to the receptor oncogenic activity [8,9].…”

Autoantibody profiling of benign and malignant thyroid tumors and design of a prototype diagnostic array

“…В настоящее время идентифицировано множество биомаркеров, и многие из них продемонстрировали весьма обнадеживаю щие результаты в дифференциальной диаг ностике фолликулярных опухолей ЩЖ [4,5,7,9,10]. В то же время работы по идентифи кации циркулирующих биомаркеров начали появляться лишь в течение последних не скольких лет.…”