Head and Neck TumorsHead and Neck TumorsОпухоли головы и шеи2222-14682411-4634Publishing House ABV Press15610.17650/2222-1468-2015-5-2-30-34LITERATURE REVIEWОБЗОР ЛИТЕРАТУРЫNew-generation mutitargeted tyrosine kinase inhibitors in the treatment of radioactive iodine-refractory differentiated thyroid cancerНовое поколение мультитаргетных ингибиторов тирозинкиназ в лечении радиойодрефрактерного дифференцированного рака щитовидной железыMudunovA. M.МудуновАли Мурадович
Russian Federation

23 Kashirskoe Shosse, Moscow, 115478, Russia

Россия, 115478, Москва, Каширское шоссе, 23

ali.mudunov@info.ruN.N. Blokhin Russian Cancer Research CenterФГБНУ «РОНЦ им. Н.Н. Блохина»080620155230340806201508062015Copyright ©; 2015, Mudunov A.M.Copyright ©; 2015, Мудунов А.М.2015Mudunov A.M.Мудунов А.М.https://creativecommons.org/licenses/by/4.0https://ogsh.abvpress.ru/jour/article/view/156

Background. Thyroid cancer (TC) is one of the common oncological disease of the head and neck. However, its treatment is sharply restricted in a locally advanced and metastatic cancer process. In the past decade, there have been fundamental changes in the understanding of the molecular bases of thyroid carcinogenesis, resulting in the design of novel targeted drugs aimed at disseminated and refractory TC control. Multikinase inhibitors that are able to block the processes of proliferation, invasion, and neoangiogenesis are being intensively studied worldwide. Performed placebo-controlled trials have culminated in the registration of the antitumor drugs that is highly active against disseminated medullary and differentiated TC, which will make a change in the situation in treating radioactive iodine-refractory differentiated TC in the near future.

Objective: to review recent advances in the targeted therapy of TC with particular emphasis on lenvatinib, a multikinase inhibitor.

Введение. Рак щитовидной железы (РЩЖ) – одна из самых распространенных онкологических патологий в области головы и шеи. Однако его лечение резко ограничивается при местно-распространенном и метастатическом опухолевом процессе. За последнее 10-летие произошли кардинальные изменения в понимании молекулярных основ канцерогенеза РЩЖ, которые привели к созданию новых таргетных препаратов, направленных на борьбу с диссеминированным и рефрактерным РЩЖ. Мультикиназные ингибиторы, способные блокировать процессы пролиферации, инвазии и неоангиогенеза, активно изучаются во всем мире. Проведенные плацебо-контролируемые исследования привели к регистрации противоопухолевых препаратов для терапии диссеминированного медуллярного и дифференцированного РЩЖ, что в недалеком будущем может способствовать изменению ситуации в лечении радиойодрефрактерного дифференцированного РЩЖ.

Целью настоящей публикации является обзор литературы о современных достижениях таргетной терапии РЩЖ с особенным вниманием к ленватинибу – мультикиназному ингибитору

thyroid cancerlenvatinibtyrosine kinase inhibitorsmultikinase inhibitorstargeted therapyradioactive iodine-refractory differentiated cancerрак щитовидной железыленватинибингибиторы тирозинкиназмультикиназные ингибиторытаргетная терапиярадиойодрефрактерный дифференцированный рак1. Durante C., Haddy N., Baudin E. et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab 2006;91(8):2892–9.Durante C., Haddy N., Baudin E. et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab 2006;91(8):2892–9.2. Sgouros G., Kolbert K.S., Sheikh A. et al. Patient-specific dosimetry for I131 thyroid cancer therapy using I124 PET and 3-dimensional-internal dosimetry (3D–ID) software. J Nucl Med 2004;45(8):1366–72.Sgouros G., Kolbert K.S., Sheikh A. et al. Patient-specific dosimetry for I131 thyroid cancer therapy using I124 PET and 3-dimensional-internal dosimetry (3D–ID) software. J Nucl Med 2004;45(8):1366–72.3. Leboulleux S., El Bez I., Borget I. et al. Postradioiodine treatment whole-body scan in the era of 18-fluorodesoxyglucose positron emission tomography for differentiated thyroid carcinoma with elevated serum thyroglobulin levels. Thyroid 2012;22(8): 832–8.Leboulleux S., El Bez I., Borget I. et al. Postradioiodine treatment whole-body scan in the era of 18-fluorodesoxyglucose positron emission tomography for differentiated thyroid carcinoma with elevated serum thyroglobulin levels. Thyroid 2012;22(8): 832–8.4. Vaisman F., Tala H., Grewal R., Tuttle R.M. In differentiated thyroid cancer, an incomplete structural response to therapy is associated with significantly worse clinical outcomes than only an incomplete thyroglobulin response. Thyroid 2011;21(12):1317–22.Vaisman F., Tala H., Grewal R., Tuttle R.M. In differentiated thyroid cancer, an incomplete structural response to therapy is associated with significantly worse clinical outcomes than only an incomplete thyroglobulin response. Thyroid 2011;21(12):1317–22.5. Deandreis D., Al Ghuzlan A., Leboulleux S., et al. Do histological, immunohistochemical, and metabolic (radioiodine and fluorodeoxyglucose uptake) patterns of metastatic thyroid cancer correlate with patient outcome? Endocr Relat Cancer 2011;18(1):159–69.Deandreis D., Al Ghuzlan A., Leboulleux S., et al. Do histological, immunohistochemical, and metabolic (radioiodine and fluorodeoxyglucose uptake) patterns of metastatic thyroid cancer correlate with patient outcome? Endocr Relat Cancer 2011;18(1):159–69.6. Schlumberger M., Brose M., Elisei R. et al. Definition and management of radioactive iodine-refractory differentiated thyroid cancer. Lancet Diabetes Endocrinol 2014;2(5):356–8.Schlumberger M., Brose M., Elisei R. et al. Definition and management of radioactive iodine-refractory differentiated thyroid cancer. Lancet Diabetes Endocrinol 2014;2(5):356–8.7. Sabra M.M., Grewal R.K., Tala H. et al. Clinical outcomes following empiric radioiodine therapy in patients with structurally identifiable metastatic follicular cell-derived thyroid carcinoma with negative diagnostic but positive post-therapy I131 whole-body scans. Thyroid 2012; 22(9): 877–83.Sabra M.M., Grewal R.K., Tala H. et al. Clinical outcomes following empiric radioiodine therapy in patients with structurally identifiable metastatic follicular cell-derived thyroid carcinoma with negative diagnostic but positive post-therapy I131 whole-body scans. Thyroid 2012; 22(9): 877–83.8. Robbins R.J., Wan Q., Grewal R.K. et al. Real-time prognosis for metastatic thyroid carcinoma based on 2- [18F] fluoro-2-deoxyD-glucose-positron emission tomography scanning. J Clin Endocrinol Metab 2006;91(2):498–505.Robbins R.J., Wan Q., Grewal R.K. et al. Real-time prognosis for metastatic thyroid carcinoma based on 2- [18F] fluoro-2-deoxyD-glucose-positron emission tomography scanning. J Clin Endocrinol Metab 2006;91(2):498–505.9. Rubino C., De Vathaire F., Dottorini M.E. et al. Second primary malignancies in thyroid cancer patients. Br J Cancer 2003;89(9):1638–44.Rubino C., De Vathaire F., Dottorini M.E. et al. Second primary malignancies in thyroid cancer patients. Br J Cancer 2003;89(9):1638–44.10. Wells S.A. Jr., Robinson B.G., Gagel R.F. et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind Phase III trial. J Clin Oncol 2012;30(2):134–41.Wells S.A. Jr., Robinson B.G., Gagel R.F. et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind Phase III trial. J Clin Oncol 2012;30(2):134–41.11. Elisei R., Schlumberger M.J., Müller S.P. et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol 2013;31(29):3639–46.Elisei R., Schlumberger M.J., Müller S.P. et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol 2013;31(29):3639–46.12. Kroll T.G., Sarraf P., Pecciarini L. et al. PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected]. Science 2000;289(5483):1357–60.Kroll T.G., Sarraf P., Pecciarini L. et al. PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected]. Science 2000;289(5483):1357–60.13. Hou P., Liu D., Xing M. Functional characterization of the T1799-1801del and A1799-1816ins BRAF mutations in papillary thyroid cancer. Cell Cycle 2007;6(3):377–9.Hou P., Liu D., Xing M. Functional characterization of the T1799-1801del and A1799-1816ins BRAF mutations in papillary thyroid cancer. Cell Cycle 2007;6(3):377–9.14. Saji M., Ringel M.D. The PI3K-AktmTOR pathway in initiation and progression of thyroid tumors. Mol Cell Endocrinol2010;321(1):20–8.Saji M., Ringel M.D. The PI3K-AktmTOR pathway in initiation and progression of thyroid tumors. Mol Cell Endocrinol2010;321(1):20–8.15. Mulligan L.M., Kwok J.B., Healey C.S. et al. Germ-line mutations of the RET protooncogene in multiple endocrine neoplasia type 2A. Nature 1993;363(6428):458–60.Mulligan L.M., Kwok J.B., Healey C.S. et al. Germ-line mutations of the RET protooncogene in multiple endocrine neoplasia type 2A. Nature 1993;363(6428):458–60.16. Learoyd D.L., Messina M., Zedenius J., Robinson B.G. Molecular genetics of thyroid tumors and surgical decision-making. World J Surg 2000;24(8):923–33.Learoyd D.L., Messina M., Zedenius J., Robinson B.G. Molecular genetics of thyroid tumors and surgical decision-making. World J Surg 2000;24(8):923–33.17. Holbro T., Civenni G., Hynes N.E. The ErbB receptors and their role in cancer progression. Exp Cell Res 2003; 284(1):99–110.Holbro T., Civenni G., Hynes N.E. The ErbB receptors and their role in cancer progression. Exp Cell Res 2003; 284(1):99–110.18. Matsui J., Funahashi Y., Uenaka T. et al. Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer Res 2008; 14(17):5459–65.Matsui J., Funahashi Y., Uenaka T. et al. Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer Res 2008; 14(17):5459–65.19. Krause D.S., Van Etten R.A. Tyrosine kinases as targets for cancer therapy. N Engl J Med 2005;353(2):172–87.Krause D.S., Van Etten R.A. Tyrosine kinases as targets for cancer therapy. N Engl J Med 2005;353(2):172–87.20. Antonelli A., Fallahi P., Ferrari S.M. et al. Dedifferentiated thyroid cancer: a therapeutic challenge. Biomed Pharmacother 2008; 62(8):559–63.Antonelli A., Fallahi P., Ferrari S.M. et al. Dedifferentiated thyroid cancer: a therapeutic challenge. Biomed Pharmacother 2008; 62(8):559–63.21. Grande E., Diez J.J., Zafon C., Capdevila J. Thyroid cancer: molecular aspects and new therapeutic strategies. J Thyroid Res 2012;2012:847108.Grande E., Diez J.J., Zafon C., Capdevila J. Thyroid cancer: molecular aspects and new therapeutic strategies. J Thyroid Res 2012;2012:847108.22. Stjepanovic N., Capdevila J. Multikinase inhibitors in the treatment of thyroid cancer: specific role of lenvatinib. Biologics 2014;8:129–39.Stjepanovic N., Capdevila J. Multikinase inhibitors in the treatment of thyroid cancer: specific role of lenvatinib. Biologics 2014;8:129–39.23. Sherman S.I., Jarzab B., Cabanillas M.E. et al. A phase 2 trial of lenvatinib (E7080) in advanced, progressive, radioiodinerefractory, differentiated thyroid cancer: A clinical outcomes and biomarker assessment. Cancer 2015.Sherman S.I., Jarzab B., Cabanillas M.E. et al. A phase 2 trial of lenvatinib (E7080) in advanced, progressive, radioiodinerefractory, differentiated thyroid cancer: A clinical outcomes and biomarker assessment. Cancer 2015.24. Schlumberger M., Tahara M., Wirth L.J. et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 2015;372:621–30.Schlumberger M., Tahara M., Wirth L.J. et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 2015;372:621–30.