scholarly journals RET as a Diagnostic and Therapeutic Target in Sporadic and Hereditary Endocrine Tumors

2006 ◽  
Vol 27 (5) ◽  
pp. 535-560 ◽  
Author(s):  
Jan Willem B. de Groot ◽  
Thera P. Links ◽  
John T. M. Plukker ◽  
Cornelis J. M. Lips ◽  
Robert M. W. Hofstra
Keyword(s):  
Thyroid Carcinoma ◽  
Tyrosine Kinase ◽  
Medullary Thyroid Carcinoma ◽  
Therapeutic Option ◽  
Dominant Negative ◽  
Tyrosine Kinase Domain ◽  
Endocrine Tumors ◽  
Medullary Thyroid ◽  
Familial Medullary Thyroid Carcinoma ◽  
Men 2

The RET gene encodes a receptor tyrosine kinase that is expressed in neural crest-derived cell lineages. The RET receptor plays a crucial role in regulating cell proliferation, migration, differentiation, and survival through embryogenesis. Activating mutations in RET lead to the development of several inherited and noninherited diseases. Germline point mutations are found in the cancer syndromes multiple endocrine neoplasia (MEN) type 2, including MEN 2A and 2B, and familial medullary thyroid carcinoma. These syndromes are autosomal dominantly inherited. The identification of mutations associated with these syndromes has led to genetic testing to identify patients at risk for MEN 2 and familial medullary thyroid carcinoma and subsequent implementation of prophylactic thyroidectomy in mutation carriers. In addition, more than 10 somatic rearrangements of RET have been identified from papillary thyroid carcinomas. These mutations, as those found in MEN 2, induce oncogenic activation of the RET tyrosine kinase domain via different mechanisms, making RET an excellent candidate for the design of molecular targeted therapy. Recently, various kinds of therapeutic approaches, such as tyrosine kinase inhibition, gene therapy with dominant negative RET mutants, monoclonal antibodies against oncogene products, and nuclease-resistant aptamers that recognize and inhibit RET have been developed. The use of these strategies in preclinical models has provided evidence that RET is indeed a potential target for selective cancer therapy. However, a clinically useful therapeutic option for treating patients with RET-associated cancer is still not available.

scholarly journals HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: The state of science in medullary thyroid carcinoma: current challenges and unmet needs

2020 ◽  
Vol 27 (8) ◽  
pp. T27-T39
Author(s):  
Ramona Dadu ◽  
Rozita Bagheri-Yarmand ◽  
Matthew D Ringel ◽  
Elizabeth G Grubbs ◽  
Mark Zafereo ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Unmet Needs ◽  
The State ◽  
Endocrine Tumors ◽  
Medullary Thyroid ◽  
Men 2 ◽  
Current State ◽  
Workshop Model ◽  
Working Groups

The 16th International Multiple Endocrine Neoplasia Workshop (MEN2019) held in Houston, TX, USA, focused on emerging topics in the pathogenesis and therapy of malignant endocrine tumors associated with MEN syndromes. With MEN-2 syndromes, the most common malignancy is medullary thyroid carcinoma (MTC). In the spirit of the original MEN meeting workshop model, the conference included didactic lectures and interactive working groups of clinicians and researchers focused on the state of science in MTC and ongoing challenges or unmet needs in the understanding of MTC and to develop strategies to address these issues.

scholarly journals Medullary thyroid carcinoma beyond surgery: advances, challenges, and perspectives

2019 ◽  
Vol 26 (9) ◽  
pp. R499-R518 ◽  
Author(s):  
Lucieli Ceolin ◽  
Marta Amaro da Silveira Duval ◽  
Antônio Felippe Benini ◽  
Carla Vaz Ferreira ◽  
Ana Luiza Maia
Keyword(s):  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Intracellular Signaling ◽  
Progression Free Survival ◽  
Thyroid Neoplasms ◽  
Rare Type ◽  
Medullary Thyroid ◽  
Men 2 ◽  
Thyroid C Cells ◽  
Molecular Therapies

Medullary thyroid carcinoma (MTC) is a rare type of tumor that originates from thyroid C cells and accounts for 2–4% of all malignant thyroid neoplasms. MTC may occur sporadically or be inherited, as part of the MEN 2 syndrome. Germline mutations of the RET (REarranged during Transfection) proto-oncogene cause hereditary cancer, whereas somatic RET mutations and, less frequently, RAS mutations have been described in sporadic MTC samples. Since early surgery with complete resection of tumor mostly determines the likelihood of attaining cure for MTC, the broader use of RET genetic screening has dramatically changed the prognostic of gene carriers in hereditary MTC. Nevertheless, despite recent advances, the management of advanced, progressive MTC remains challenging. The multikinase inhibitors (MKI), vandetanib and cabozantinib, were approved for the treatment of progressive or symptomatic MTC, and several other compounds have exhibited variable efficacy. Although these drugs have been shown to improve progression-free survival, no MKI has been shown to increase the overall survival. As these drugs are nonselective, significant off-target toxicities may occur, limiting achievement of the required TK-specific inhibition. Recently, next-generation small-molecule TKI has been developed. These TKI are specifically designed for highly potent and selective targeting of oncogenic RET alterations, making them promising drugs for the treatment of advanced MTC. Here, we summarize the current understanding of the intracellular signaling pathways involved in MTC pathogenesis as well as the therapeutic approaches and challenges for the management of advanced MTC, focusing on targeted molecular therapies.

scholarly journals Molecular genetic diagnostic program of multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma syndromes in Hungary

2001 ◽  
Vol 170 (3) ◽  
pp. 661-666 ◽  
Author(s):  
I Klein ◽  
O Esik ◽  
V Homolya ◽  
F Szeri ◽  
A Varadi
Keyword(s):  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Multiple Endocrine Neoplasia ◽  
Multiple Endocrine Neoplasia Type ◽  
Medullary Thyroid ◽  
Familial Medullary Thyroid Carcinoma ◽  
Clinical Criteria ◽  
Ret Protooncogene ◽  
Endocrine Neoplasia ◽  
Endocrine Neoplasia Type

Medullary thyroid carcinoma (MTC) occurs usually in sporadic form, but about a quarter of the cases are hereditary and appear as part of one of the multiple endocrine neoplasia type 2 (MEN2) syndromes. Mutations in the RET protooncogene are known to be the cause of the MEN2A and familial medullary thyroid carcinoma (FMTC) syndromes in the majority of the families. Direct DNA testing allows prophylactic thyroidectomy to be offered to individuals carrying a mutation in the above codons, and in mutation-negative cases it reduces the yearly screening-related burden on family members at risk of the disease. By DNA sequencing and PCR-restriction fragment length polymorphisms, 65 MTC probands were examined for mutations in residues 609, 611, 618, 620 of exon 10, and in residues 634, 768, 804 of exons 11, 13, and 14 respectively of the RET protooncogene. In our study, mutations in the above codons were detected in all of the 14 clinically MEN2A and FMTC families. One of these mutations, TGC609 TCC has not been reported previously. Of the 14 probands with the mutation, 25 relatives also had the identified mutation and 18 relatives proved to be non-carriers. Among the 51 probands with clinically sporadic MTC, none was found to carry a mutation in the above positions even if indirect signs of MTC, pheochromocytoma or hyperparathyroidism could be detected in some families. The frequency of the TGC634AGC mutation is unexpectedly high in our samples, which can probably be attributed to a founder effect. We conclude that screening for mutations in these codons is effective in families fulfilling the strict clinical criteria of MEN2A or FMTC.

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