Current Oncology Reports

, Volume 14, Issue 2, pp 97–104 | Cite as

RET TKI: Potential Role in Thyroid Cancers

  • Alessandro Antonelli
  • Poupak Fallahi
  • Silvia Martina Ferrari
  • Caterina Mancusi
  • Michele Colaci
  • Libero Santarpia
  • Clodoveo Ferri
Evolving Therapies (RM Bukowski, Section Editor)

Abstract

The increasing incidence of thyroid cancer is associated with a higher number of advanced disease characterized by the loss of cancer differentiation and metastatic spread. The knowledge of the molecular pathways involved in the pathogenesis of thyroid cancer has made possible the development of new therapeutic drugs able to blockade the oncogenic kinases (RET/PTC) or signaling kinases (vascular endothelial growth factor receptor [VEGFR]) involved in cellular growth and proliferation. Some clinical trials have been conducted showing the ability of targeted therapies able to inhibit RET (sorafenib, imatinib, vandetanib) in stabilizing the course of the disease. The aim of the introduction of these targeted therapies is to extend life duration assuring a good quality of life; however, further studies are needed to reach these goals.

Keywords

Papillary thyroid cancer Medullary thyroid cancer Targeted molecular therapies Tyrosine kinase inhibitors RET VEGFR 

Notes

Disclosure

No potential conflicts of interest relevant to this article were reported.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973–2002. JAMA. 2006;295(18):2164–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Ries LAG, et al (eds). SEER cancer statistics review, 1975–2001, National Cancer Institute, Bethesda, MD, 2004. Available at: seer.cancer.gov/csr/1975–2001.Google Scholar
  3. 3.
    Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA Cancer J Clin. 2007;57(1):43–66.PubMedCrossRefGoogle Scholar
  4. 4.
    Hundahl SA, Fleming ID, Fremgen AM, et al. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985–1995 [see commetns]. Cancer. 1998;83(12):2638–48.PubMedCrossRefGoogle Scholar
  5. 5.
    Antonelli A, Miccoli P, Derzhitski VE, et al. Epidemiologic and clinical evaluation of thyroid cancer in children from the Gomel region (Belarus). World J Surg. 1996;20(7):867–71.PubMedCrossRefGoogle Scholar
  6. 6.
    Antonelli A, Fallahi P, Grosso M, et al. Lobectomy versus total thyroidectomy in children with post-Chernobyl thyroid cancer: a 15 year follow-up. Endocrine. 2011 Jun 23.Google Scholar
  7. 7.
    Wartofsky L. Increasing world incidence of thyroid cancer: increased detection or higher radiation exposure? Hormones (Athens). 2010;9(2):103–8.Google Scholar
  8. 8.
    Nikiforov YE, Nikiforova MN. Molecular genetics and diagnosis of thyroid cancer. Nat Rev Endocrinol. 2011;7(10):569–80.PubMedCrossRefGoogle Scholar
  9. 9.
    de Groot JW, Links TP, Plukker JT, et al. RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumors. Endocr Rev. 2006;5:535–60.CrossRefGoogle Scholar
  10. 10.
    Pasini B, Hofstra RM, Yin L, et al. The physical map of the human RET proto-oncogene. Oncogene. 1995;11(9):1737–43.PubMedGoogle Scholar
  11. 11.
    Anders J, Kjar S, Ibanez CF. Molecular modeling of the extracellular domain of the RET receptor tyrosine kinase reveals multiple cadherin-like domains and calcium-binding site. J Biol Chem. 2001;276(38):35808–17.PubMedCrossRefGoogle Scholar
  12. 12.
    Plaza-Menacho I, Burzynski GM, De Groot JW, et al. Current concepts in RET-related genetics, signaling and therapeutics. Trends Genet. 2006;22(11):627–36.PubMedCrossRefGoogle Scholar
  13. 13.
    Pandey A, Duan H, Di Fiore PP, et al. The Ret receptor protein tyrosine kinase associates with the SH2-containing adapter protein Grb10. J Biol Chem. 1995;270(37):21461–3.PubMedCrossRefGoogle Scholar
  14. 14.
    Salvatore D, Barone MV, Salvatore G, et al. Tyrosines 1015 and 1062 are in vivo autophosphorylation sites in ret and ret-derived oncoproteins. J Clin Endocrinol Metab. 2000;85(10):3898–907.PubMedCrossRefGoogle Scholar
  15. 15.
    Kato M, Takeda K, Kawamoto Y, et al. Repair by Src kinase of function-impaired RET with multiple endocrine neoplasia type 2A mutation with substitutions of tyrosines in the COOH-terminal kinase domain for phenylalanine. Cancer Res. 2002;62(8):2414–22.PubMedGoogle Scholar
  16. 16.
    Santarpia L, Myers JN, Sherman SI, et al. Genetic alterations in the RAS/RAF/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt signaling pathways in the follicular variant of papillary thyroid carcinoma. Cancer. 2010;116(12):2974–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Santoro M, Chiappetta G, Cerrato A, et al. Development of thyroid papillary carcinomas secondary to tissue-specific expression of the RET/PTC1 oncogene in transgenic mice. Oncogene. 1996;12(8):1821–6.PubMedGoogle Scholar
  18. 18.
    Mitsutake N, Miyagishi M, Mitsutake S, et al. BRAF mediates RET/PTC-induced mitogen-activated protein kinase activation in thyroid cells: functional support for requirement of the RET/PTC-RAS-BRAF pathway in papillary thyroid carcinogenesis. Endocrinology. 2006;147(2):1014–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med. 2005;353(2):172–87.PubMedCrossRefGoogle Scholar
  20. 20.
    Antonelli A, Fallahi P, Ferrari SM, et al. Dedifferentiated thyroid cancer: a therapeutic challenge. Biomed Pharmacother. 2008;62(8):559–63.PubMedCrossRefGoogle Scholar
  21. 21.
    Fenton CL, Lukes Y, Nicholson D, et al. The ret/PTC mutations are common in sporadic papillary thyroid carcinoma of children and young adults. J Clin Endocrinol Metab. 2000;85(3):1170–5.PubMedCrossRefGoogle Scholar
  22. 22.
    Santoro M, Dathan NA, Berlingieri MT, et al. Molecular characterization of RET/PTC3; a novel rearranged version of the RETproto-oncogene in a human thyroid papillary carcinoma. Oncogene. 1994;9(2):509–16.PubMedGoogle Scholar
  23. 23.
    Powell Jr DJ, Russell J, Nibu K, et al. The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids. Cancer Res. 1998;58(23):5523–8.PubMedGoogle Scholar
  24. 24.
    Nikiforov YE, Rowland JM, Bove KE, et al. Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children. Cancer Res. 1997;57(9):1690–4.PubMedGoogle Scholar
  25. 25.
    Antonelli A, Ferrari SM, Fallahi P, et al. Medullary thyroid cancer: new targeted molecular therapies. Recent Pat Endocr Metab Immune Drug Discov. 2010;4(1):10–4. 5.CrossRefGoogle Scholar
  26. 26.
    Ball DW, Baylin SB, De Butros AC. Medullary thyroid carcinoma. In: BravermanLE UtigerRD, editor. Werner and Ingbar’s the thyroid. 8th ed. Philadelphia: Lippincott Williams and Wilkins; 2000. p. 930–43.Google Scholar
  27. 27.
    Kebebew E, Clark OH. Medullary thyroid cancer. Curr Treat Options Oncol. 2000;1(14):359–67.PubMedCrossRefGoogle Scholar
  28. 28.
    Weber T, Shilling T, Buchler MW. Thyroid carcinoma. Curr Opin Oncol. 2006;18(1):30–5.PubMedGoogle Scholar
  29. 29.
    Drosten M, Pützer BM. Mechanisms of Disease: cancer targeting and the impact of oncogenic RET for medullary thyroid carcinoma therapy. Nat Clin Pract Oncol. 2006;3(10):564–74.PubMedCrossRefGoogle Scholar
  30. 30.
    Verdy M, Weber AM, Roy CC, et al. Hirschsprung’s disease in a family with multiple endocrine neoplasia type 2. J Pediatric Gastroenterol Nutr. 1982;1(14):603–7.Google Scholar
  31. 31.
    Gagel RF, Levy ML, Donovan DT, et al. Multiple endocrine neoplasia type 2a associated with cutaneous lichen amyloidosis. Ann Intern Med. 1989;111(10):802–6.PubMedGoogle Scholar
  32. 32.
    Farndon JR, Leight GS, Dilley WG, et al. Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity. Br J Surg. 1986;73(4):278–81.PubMedCrossRefGoogle Scholar
  33. 33.
    Williams ED, Pollock DJ. Multiple mucosal neuromata with endocrine tumours: a syndrome allied to von Recklinghausen’s disease. J Pathol Bacteriol. 1966;91(1):71–80.PubMedCrossRefGoogle Scholar
  34. 34.
    Arighi E, Borrello MG, Sariola H. RET tyrosine kinase signaling in development and cancer. Cytokine Growth Factor Rev. 2005;16(4–5):441–67.PubMedCrossRefGoogle Scholar
  35. 35.
    Castellone MD, Santoro M. Dysregulated RET signaling in thyroid cancer. Endocrinol Metab Clin North Am. 2008;37(2):363–74.PubMedCrossRefGoogle Scholar
  36. 36.
    Croyle M, Akeno N, Knauf JA, et al. RET/PTC-induced cell growth is mediated in part by epidermal growth factor receptor (EGFR) activation: evidence for molecular and functional interactions between RET and EGFR. Cancer Res. 2008;68(11):4183–91.PubMedCrossRefGoogle Scholar
  37. 37.
    Lorusso PM, Eder JP. Therapeutic potential of novel selective-spectrum kinase inhibitors in oncology. Expert Opin Investig Drugs. 2008;17(7):1013–28.PubMedCrossRefGoogle Scholar
  38. 38.
    Antonelli A, Ferri C, Ferrari SM, et al. New targeted molecular therapies for dedifferentiated thyroid cancer. J Oncol. 2010;2010:921682.PubMedGoogle Scholar
  39. 39.
    Carlomagno F, Vitagliano D, Guida T, et al. ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res. 2002;62(24):7284–90.PubMedGoogle Scholar
  40. 40.
    Vieira JM, Santos SC, Espadinha C, et al. Expression of vascular endothelial growth factor (VEGF) and its receptors in thyroid carcinomas of follicular origin: a potential autocrine loop. Eur J Endocrinol. 2005;153(5):701–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Elliott DD, Sherman SI, Busaidy NL, et al. Growth factor receptors expression in anaplastic thyroid carcinoma: potential markers for therapeutic stratification. Hum Pathol. 2008;39(1):15–20.PubMedCrossRefGoogle Scholar
  42. 42.
    McGregor LM, McCune BK, Graff JR, et al. Roles of trk family neurotrophin receptors in medullary thyroid carcinoma development and progression. Proc Natl Acad Sci USA. 1999;96(13):4540–5.PubMedCrossRefGoogle Scholar
  43. 43.
    Mitsiades CS, Kotoula V, Poulaki V, et al. Epidermal growth factor receptor as a therapeutic target in human thyroid carcinoma: mutational and functional analysis. J Clin Endocrinol Metab. 2006;91(9):3662–6.PubMedCrossRefGoogle Scholar
  44. 44.
    Cuccuru G, Lanzi C, Cassinelli G, et al. Cellular effects and antitumor activity of RET inhibitor RPI-1 on MEN2A-associated medullary thyroid carcinoma. J Natl Cancer Inst. 2004;96(13):1006–14.PubMedCrossRefGoogle Scholar
  45. 45.
    Strock CJ, Park JI, Rosen M, et al. CEP-701 and CEP-751 inhibit constitutively activated RET tyrosine kinase activity and block medullary thyroid carcinoma cell growth. Cancer Res. 2003;63(17):5559–63.PubMedGoogle Scholar
  46. 46.
    Carniti C, Perego C, Mondellini P, et al. PP1 inhibitor induces degradation of RETMEN2A and RETMEN2B oncoproteins through proteosomal targeting. Cancer Res. 2003;63(9):2234–43.PubMedGoogle Scholar
  47. 47.
    Carlomagno F, Vitagliano D, Guida T, et al. Efficient inhibition of RET/papillary thyroid carcinoma oncogenic kinases by 4-amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2). J Clin Endocrinol Metab. 2003;88(4):1897–902.PubMedCrossRefGoogle Scholar
  48. 48.
    Schlumberger M. Kinase inhibitors for refractory thyroid cancers. Lancet Oncol. 2010;11(10):912–3.PubMedCrossRefGoogle Scholar
  49. 49.
    Sherman SI. Targeted therapy of thyroid cancer. Biochem Pharmacol. 2010;80(5):592–601.PubMedCrossRefGoogle Scholar
  50. 50.
    •• Gupta-Abramson V, Troxel AB, Nellore A, et al. Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol. 2008;26(29):47149. Phase II clinical trial of sorafenib in thyroid cancer. Google Scholar
  51. 51.
    •• Kloos RT, Ringel MD, Knopp MV, et al. Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol. 2009;27(10):167584. Phase II clinical trial of sorafenib in thyroid cancer. Google Scholar
  52. 52.
    •• Hoftijzer H, Heemstra KA, Morreau H, et al. Beneficial effects of sorafenib on tumor progression, but not on radioiodine uptake, in patients with differentiated thyroid carcinoma. Eur J Endocrinol. 2009;161(6):92331. Phase II clinical trial of sorafenib in thyroid cancer. Google Scholar
  53. 53.
    •• Lam ET, Ringel MD, Kloos RT, et al. Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer. J Clin Oncol. 2010;28(14):232330. Phase II clinical trial of sorafenib in thyroid cancer. Google Scholar
  54. 54.
    •• Capdevila J, Iglesias L, Halperin I, et al. Sorafenib in patients (pts) with advanced thyroid carcinoma (TC): a compassionate use program. J Clin Oncol 28(Suppl. 15). 2010 (2010 ASCO Annual Meeting, Abstract 5590). Phase II clinical trial of sorafenib in thyroid cancer. Google Scholar
  55. 55.
    •• Nexavar® Versus Placebo in Locally Advanced/Metastatic RAI-Refractory Differentiated Thyroid Cancer (NCT00984282) http://clinicaltrials.gov/ct2/show/NCT00984282?term=NCT00984282&rank=1. Phase III clinical trial of sorafenib in thyroid cancer.
  56. 56.
    •• Brose MS, Nutting CM, Sherman SI, et al. Rationale and design of decision: a double-blind, randomized, placebo-controlled phase III trial evaluating the efficacy and safety of sorafenib in patients with locally advanced or metastatic radioactive iodine (RAI)-refractory, differentiated thyroid cancer. BMC Cancer. 2011;11:349. Phase III clinical trial of sorafenib in thyroid cancer. Google Scholar
  57. 57.
    •• Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer http://clinicaltrials.gov/ct2/show/NCT00704730?term=phase+III%2C+thyroid+cancer&rank=4 (NCT00704730). Phase III clinical trial of XL184 in thyroid cancer.
  58. 58.
    • Verbeek HH, Alves MM, de Groot JW, et al. The Effects of Four Different Tyrosine Kinase Inhibitors on Medullary and Papillary Thyroid Cancers Cells. J Clin Endocrinol Metab. 2011; 96(6):E9915. In vitro study of tyrosine kinase inhibitors in medullary thyroid cancer cells. Google Scholar
  59. 59.
    Cui JJ. Inhibitors targeting hepatocyte growth factor receptor and their potential therapeutic applications. Expert Opin Ther Pat. 2007;17(9):1035–45.CrossRefGoogle Scholar
  60. 60.
    •• Kurzrock R, Sherman SI, Ball DW, et al. Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol. 2011;29(19):26606. Phase II clinical trial of cabozantinib in thyroid cancer. Google Scholar
  61. 61.
    de Groot JW, Zonnenberg BA, van Ufford-Mannesse PQ, et al. A phase II trial of imatinib therapy for metastatic medullary thyroid carcinoma. J Clin Endocrinol Metab. 2007;92(9):3466–9.PubMedCrossRefGoogle Scholar
  62. 62.
    • Coxon A, Bready J, Estrada J, et al. Antintumor Activity of Motesanib in a Medullary Thyroid Cancer Model. J Endocrinol Invest. 2011 Mar 21. In vitro study of tyrosine kinase inhibitors in medullary thyroid cancer cells. Google Scholar
  63. 63.
    • Samady AK, Mukerji R, Shah A, et al. A novel RET inhibitor with potent efficacy against medullary thyroid cancer in vivo. Surgery. 2010;148(6):122836. In vitro study of tyrosine kinase inhibitors in medullary thyroid cancer cells. Google Scholar
  64. 64.
    •• Wells SA Jr, Gosnell JE, Gagel RF, et al. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol. 2010;28(5):76772. Phase II clinical trial of vandetanib in thyroid cancer. Google Scholar
  65. 65.
    •• Robinson BG, Paz-Ares L, Krebs A, et al. Vandetanib (100 mg) in patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Endocrinol Metab. 2010;95(6):266471. Phase II clinical trial of vandetanib in thyroid cancer. Google Scholar
  66. 66.
    •• Commander H, Whiteside G, Perry C. Vandetanib: first global approval. Drugs. 2011;71(10):1355–65. Phase II clinical trial of vandetanib in thyroid cancer. Google Scholar
  67. 67.
    Blumenthal RD, Goldenberg DM. Methods and goals for the use of in vitro and in vivo chemosensitivity testing. Mol Biotechnol. 2007;35(2):185–97.PubMedCrossRefGoogle Scholar
  68. 68.
    Sawyers CL. Disabling Abl-perspectives on Abl kinase regulation and cancer therapeutics. Cancer Cell. 2002;1(1):13–5.PubMedCrossRefGoogle Scholar
  69. 69.
    • Antonelli A, Ferrari SM, Fallahi P, et al. Thiazolidinediones and antiblastics in primary human anaplastic thyroid cancer cells. Clin Endocrinol (Oxf). 2009;70(6):94653. In vitro first study evaluating sensitivity to chemotherapeutics and thiazolidinediones in cells obtained from anaplastic thyroid cancer. Google Scholar
  70. 70.
    • Antonelli A, Ferrari SM, Fallahi P, et al. Evaluation of the sensitivity to chemotherapeutics or thiazolidinediones of primary anaplastic thyroid cancer cells obtained by fine-needle aspiration. Eur J Endocrinol. 2008;159(3):28391. In vitro first study evaluating sensitivity to chemotherapeutics and thiazolidinediones in cells obtained by fine-needle aspiration. Google Scholar
  71. 71.
    • Antonelli A, Ferrari SM, Fallahi P, et al. Primary cell cultures from anaplastic thyroid cancer obtained by fine-needle aspiration used for chemosensitivity tests. Clin Endocrinol (Oxf). 2008;69(1):14852. In vitro first study evaluating sensitivity to chemotherapeutics in cells obtained by fine-needle aspiration. Google Scholar
  72. 72.
    •• Antonelli A, Bocci G, La Motta C, et al. Novel pyrazolopyrimidine derivatives as tyrosine kinase inhibitors with antitumoral activity in vitro and in vivo in papillary dedifferentiated thyroid cancer. J Clin Endocrinol Metab. 2011:96(2):E28896. First study showing the effect of tyrosine kinase inhibitors in primary cells obtained from DePTC. Google Scholar
  73. 73.
    Schlumberger MJ, Elisei R, Bastholt L, et al. Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer. J Clin Oncol. 2009;27(23):3794–801.PubMedCrossRefGoogle Scholar
  74. 74.
    Brassard M, Neraud B, Trabado S, et al. Endocrine effects of the tyrosine kinase inhibitor vandetanib in patients treated for thyroid cancer. J Clin Endocrinol Metab. 2011;96(9):2741–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Alessandro Antonelli
    • 1
  • Poupak Fallahi
    • 1
  • Silvia Martina Ferrari
    • 1
  • Caterina Mancusi
    • 1
  • Michele Colaci
    • 2
  • Libero Santarpia
    • 3
  • Clodoveo Ferri
    • 2
  1. 1.Department of Internal MedicineUniversity of Pisa, School of MedicinePisaItaly
  2. 2.Rheumatology Unit, Department of Internal MedicineUniversity of Modena & Reggio E.ModenaItaly
  3. 3.Translational Research Unit, Department of OncologyHospital of Prato and Istituto Toscana TumoriPratoItaly

Personalised recommendations