Combination of RET siRNA and irinotecan inhibited the growth of medullary thyroid carcinoma TT cells and xenografts via apoptosis

Medullary thyroid carcinoma (MTC) is a rare endocrine tumor originating from calcitonin-secreting C cells. MTC may be sporadic or hereditary, including multiple endocrine neoplasia (MEN) type 2A, MEN type 2B and familial medullary thyroid carcinoma (FMTC).⁽¹⁾ MTC has an overall 10-year cause-specific survival of 60–70%, with a particularly poor prognosis for patients with MEN2B and sporadic MTC, who have a 5-year mortality of 30–50%.⁽²⁾ Hereditary MTC is caused by a germline mutation in the Rearranged during transfection (RET) gene. About 40% of sporadic MTCs harbor a somatic RET mutation.⁽¹⁾ The RET gene encodes a receptor tyrosine kinase with an extracellular ligand-binding domain and a cysteine-rich domain, a signal transmembrane domain and an intracellular domain containing the catalytic tyrosine kinase domain.⁽³⁾ RET has a glial cell line-derived neurotrophic factor as a ligand,⁽⁴⁾ but mutated RET leads to a constitutive active RET tyrosine kinase, causing malignant behavior of C cells.⁽⁵⁾

Surgery is currently the only effective treatment for primary MTC.⁽⁶⁾ Radioactive iodine has no benefit since C cells do not take up iodine. The role of chemotherapeutic regimens is also limited.⁽⁷⁾ Imatinib specifically inhibits the tyrosine kinase activity of Abl, Kit and platelet-derived growth factor receptor (PDGFR).⁽⁸⁾ However, imatinib therapy for MTC yielded no objective responses and induced considerable toxicity in patients.⁽⁹⁾ CPT-11 injected intraperioneally was relatively effective for TT tumor xenografts.⁽¹⁰⁾ There is, therefore, no curative therapy for patients with metastatic MTC, which is responsible for many of the deaths caused by MTC. Gene therapy is a potentially useful alternative treatment for MTC. Specific inhibition of RET signaling using the dominant-negative RET mutant and ribozyme resulted in both growth suppression and subsequently the death of MTC cells.^(11–13) Expressions of thymidine kinase, interleukin (IL-2) and IL-12 by adenoviral vectors have resulted in tumor suppression in MTC animal models;⁽¹⁴⁾ however, the observed antitumor effect in vivo was mostly transient.

New technology based on specific inhibition of the RET gene may be useful for MTC treatment to improve safety. RNA interference (RNAi) is a powerful gene-silencing process that holds great...