TY - JOUR
T1 - Beyond RET
T2 - Potential therapeutic approaches for advanced and metastatic medullary thyroid carcinoma
AU - Santarpia, L.
AU - Ye, L.
AU - Gagel, R. F.
PY - 2009/7
Y1 - 2009/7
N2 - Medullary thyroid carcinoma (MTC) is a rare calcitonin-producing neuroendocrine tumour that originates from the parafollicular C-cells of the thyroid gland. The RET proto-oncogene encodes the RET receptor tyrosine kinase, which has essential roles in cell survival, differentiation and proliferation. Activating mutations of RET are associated with the pathogenesis of MTC and have been demonstrated in nearly all hereditary and in 30-50% of sporadic MTC cases, making this receptor an excellent target for small-molecule inhibitors for this tumour. Clinical trials of small organic inhibitors of tyrosine kinase receptors (TKIs) targeting the RET receptor have shown efficacy for treatment of metastatic MTC with 30-50% of patients responding to these agents. Despite the importance of the RET receptor in MTC, it is clear that other signal transduction pathways, tyrosine kinase receptors, and tumour suppressor genes are involved in MTC tumourigenesis and progression. A better understanding of molecular cross-talk between these signal pathways and the RET receptor may lead to combinatorial therapy that will improve outcomes beyond what is currently possible with RET-directed TKIs. Finally, there is evidence that immunological-based therapy using dendritic cell vaccination strategies have been effective for reducing tumour mass in a small number of patients. The identification of additional MTC-specific tumour antigens and a better understanding of specific epitopes in these tumour antigens may lead to improvement of response rates.
AB - Medullary thyroid carcinoma (MTC) is a rare calcitonin-producing neuroendocrine tumour that originates from the parafollicular C-cells of the thyroid gland. The RET proto-oncogene encodes the RET receptor tyrosine kinase, which has essential roles in cell survival, differentiation and proliferation. Activating mutations of RET are associated with the pathogenesis of MTC and have been demonstrated in nearly all hereditary and in 30-50% of sporadic MTC cases, making this receptor an excellent target for small-molecule inhibitors for this tumour. Clinical trials of small organic inhibitors of tyrosine kinase receptors (TKIs) targeting the RET receptor have shown efficacy for treatment of metastatic MTC with 30-50% of patients responding to these agents. Despite the importance of the RET receptor in MTC, it is clear that other signal transduction pathways, tyrosine kinase receptors, and tumour suppressor genes are involved in MTC tumourigenesis and progression. A better understanding of molecular cross-talk between these signal pathways and the RET receptor may lead to combinatorial therapy that will improve outcomes beyond what is currently possible with RET-directed TKIs. Finally, there is evidence that immunological-based therapy using dendritic cell vaccination strategies have been effective for reducing tumour mass in a small number of patients. The identification of additional MTC-specific tumour antigens and a better understanding of specific epitopes in these tumour antigens may lead to improvement of response rates.
KW - Medullary thyroid carcinoma
KW - RET proto-oncogene
KW - Signalling transduction pathways
KW - Target therapies
KW - Tumour suppressor genes
KW - Tyrosine kinases inhibitors
UR - http://www.scopus.com/inward/record.url?scp=66849128386&partnerID=8YFLogxK
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U2 - 10.1111/j.1365-2796.2009.02112.x
DO - 10.1111/j.1365-2796.2009.02112.x
M3 - Article
C2 - 19522829
AN - SCOPUS:66849128386
SN - 0954-6820
VL - 266
SP - 99
EP - 113
JO - Journal of Internal Medicine
JF - Journal of Internal Medicine
IS - 1
ER -