J Korean Thyroid Assoc.  2015 May;8(1):26-35. 10.11106/cet.2015.8.1.26.

New Strategies for Combined Radioiodine Therapy in Refractory Thyroid Cancer

• Oh SW
• Paeng JC
• Chung JK

• KMID: 2149618
• DOI: http://doi.org/10.11106/cet.2015.8.1.26

Abstract

The prognosis of differentiated thyroid cancer (DTC) is excellent, which is mainly due to the high therapeutic efficacy of radioactive iodine (RAI) therapy as well as indolent nature of thyroid cancer itself. Although most patients with DTC are well treated with RAI therapy, a certain number of patients have been suffered from refractoriness to RAI therapy. To overcome refractoriness, many alternative treatments have been investigated, and they could be classified based on the mechanisms of action; redifferentiation drug and molecular targeted drug. Not only redifferentiated drugs but also molecular targeted drugs could induce differentiation of thyroid cancer cells. Consequently, alternative treatments allowing tumor cells of RAI avidity followed by RAI therapy could utilize a synergistic effect of both therapies. Combined RAI therapy is expected to improve therapeutic effects and prognoses of RAI refractory thyroid cancers.

Keyword

Radioiodine; Refractory thyroid cancer; Redifferentiation therapy; Molecular targeted therapy

MeSH Terms

Humans
Iodine
Molecular Targeted Therapy
Prognosis
Thyroid Gland
Thyroid Neoplasms*
Iodine

Figure

• 

  Fig. 1. Mechanisms of re-differentiation drugs. (A) In the absence of ligands, histone deacetylase (HDAC) containing complexes that are tethered through corepressors (CoR) bind to the heterodimers (RAR-RXR or PPAR-RXR) repress the transcription of target genes that are regulated by responsive elements (RARE or PRRE) in their promoters. (B) Binding of ligands (RA or PPAR γ agonist) destablizes the CoR-binding interface and induces allosteric changes in the ligand binding domain (LBD), which results in the formation of co-activators (CoA) and histone acetyltransferase (HAT) complexes. These series of conformational changes of the heterdimers activate the transcription of target genes. CoA: coactivator, CoR: corepressor, DBD: DNA binding domain, HAT: histone acetyltransferase, HDAC: histone deacetylase, LBD: ligand binding domain, PPAR: peroxisome proliferator activated receptor, PRRE: PPAR responsive element, RA: retinoic acid, RAR: retinoid acid receptor, RARE: RA responsive element, RXR: rexinoid receptor.

• 

  Fig. 2. Combined radioactive iodine therapy with retinoic acid. No radioactive iodine (RAI) uptake was seen on the previous post-therapy scan (left). After retinoic acid treatment, RAI uptake was restored in the mediastinum (black arrow) and liver (white arrow) on the post-therapy scan (right).

Reference

References

1. Jung KW, Won YJ, Kong HJ, Oh CM, Seo HG, Lee JS. Cancer statistics in Korea: incidence, mortality, survival and prevalence in 2010. Cancer Res Treat. 2013; 45(1):1–14.

2. Machens A, Holzhausen HJ, Dralle H. The prognostic value of primary tumor size in papillary and follicular thyroid carcinoma. Cancer. 2005; 103(11):2269–73.

3. Cho BY, Choi HS, Park YJ, Lim JA, Ahn HY, Lee EK. et al. Changes in the clinicopathological characteristics and outcomes of thyroid cancer in Korea over the past four decades. Thyroid. 2013; 23(7):797–804.

4. Fernandes JK, Day TA, Richardson MS, Sharma AK. Overview of the management of differentiated thyroid cancer. Curr Treat Options Oncol. 2005; 6(1):47–57.

5. Schlumberger M. Management of refractory thyroid cancers. Ann Endocrinol (Paris). 2011; 72(2):149–57.

6. Chung JK. Sodium iodide symporter: its role in nuclear medicine. J Nucl Med. 2002; 43(9):1188–200.

7. Durante C, Haddy N, Baudin E, Leboulleux S, Hartl D, Travagli JP. 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.

8. Sherman SI. Cytotoxic chemotherapy for differentiated thyroid carcinoma. Clin Oncol (R Coll Radiol). 2010; 22(6):464–8.

9. Paeng JC, Kang KW, Park do J, Oh SW, Chung JK. Alternative medical treatment for radioiodine-refractory thyroid cancers. Nucl Med Mol Imaging. 2011; 45(4):241–7.

10. Brose MS, Nutting CM, Sherman SI, Shong YK, Smit JW, Reike G. 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.

11. Ho AL, Grewal RK, Leboeuf R, Sherman EJ, Pfister DG, Deandreis D. et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med. 2013; 368(7):623–32.

12. Altucci L, Gronemeyer H. The promise of retinoids to fight against cancer. Nat Rev Cancer. 2001; 1(3):181–93.

13. Schmutzler C, Schmitt TL, Glaser F, Loos U, Kohrle J. The promoter of the human sodium/iodide-symporter gene responds to retinoic acid. Mol Cell Endocrinol. 2002; 189(1-2):145–55.

14. Jeong H, Kim YR, Kim KN, Choe JG, Chung JK, Kim MK. Effect of all-trans retinoic acid on sodium/iodide symporter expression, radioiodine uptake and gene expression profiles in a human anaplastic thyroid carcinoma cell line. Nucl Med Biol. 2006; 33(7):875–82.

15. Hoffmann S, Rockenstein A, Ramaswamy A, Celik I, Wunderlich A, Lingelbach S. et al. Retinoic acid inhibits angiogenesis and tumor growth of thyroid cancer cells. Mol Cell Endocrinol. 2007; 264(1-2):74–81.

16. Simon D, Kohrle J, Schmutzler C, Mainz K, Reiners C, Roher HD. Redifferentiation therapy of differentiated thyroid carcinoma with retinoic acid: basics and first clinical results. Exp Clin Endocrinol Diabetes. 1996; 104(Suppl 4):13–5.

17. Simon D, Koehrle J, Reiners C, Boerner AR, Schmutzler C, Mainz K. et al. Redifferentiation therapy with retinoids: therapeutic option for advanced follicular and papillary thyroid carcinoma. World J Surg. 1998; 22(6):569–74.

18. Grunwald F, Menzel C, Bender H, Palmedo H, Otte R, Fimmers R. et al. Redifferentiation therapy-induced radioiodine uptake in thyroid cancer. J Nucl Med. 1998; 39(11):1903–6.

19. Simon D, Korber C, Krausch M, Segering J, Groth P, Gorges R. et al. Clinical impact of retinoids in redifferentiation therapy of advanced thyroid cancer: final results of a pilot study. Eur J Nucl Med Mol Imaging. 2002; 29(6):775–82.

20. Chung JK, Lee YJ, Jeong JM, Lee DS, Lee MC, Cho BY. et al. Clinical significance of hepatic visualization on iodine-131 whole-body scan in patients with thyroid carcinoma. J Nucl Med. 1997; 38(8):1191–5.

21. Short SC, Suovuori A, Cook G, Vivian G, Harmer C. A phase II study using retinoids as redifferentiation agents to increase iodine uptake in metastatic thyroid cancer. Clin Oncol (R Coll Radiol). 2004; 16(8):569–74.

22. Courbon F, Zerdoud S, Bastie D, Archambaud F, Hoff M, Eche N. et al. Defective efficacy of retinoic acid treatment in patients with metastatic thyroid carcinoma. Thyroid. 2006; 16(10):1025–31.

23. Handkiewicz-Junak D, Roskosz J, Hasse-Lazar K, Szpak-Ulczok S, Puch Z, Kukulska A. et al. 13-cis-retinoic acid re-differentiation therapy and recombinant human thyrotropinaided radioiodine treatment of non-Functional metastatic thyroid cancer: a single-center, 53-patient phase 2 study. Thyroid Res. 2009; 2(1):8.

24. Gruning T, Tiepolt C, Zophel K, Bredow J, Kropp J, Franke WG. Retinoic acid for redifferentiation of thyroid cancer–does it hold its promise? Eur J Endocrinol. 2003; 148(4):395–402.

25. Kim WG, Kim EY, Kim TY, Ryu JS, Hong SJ, Kim WB. et al. Redifferentiation therapy with 13-cis retinoic acids in radioiodine-resistant thyroid cancer. Endocr J. 2009; 56(1):105–12.

26. Fernandez CA, Puig-Domingo M, Lomena F, Estorch M, Camacho Marti V, Bittini AL. et al. Effectiveness of retinoic acid treatment for redifferentiation of thyroid cancer in relation to recovery of radioiodine uptake. J Endocrinol Invest. 2009; 32(3):228–33.

27. Oh SW, Moon SH, Park do J, Cho BY, Jung KC, Lee DS. et al. Combined therapy with 131I and retinoic acid in Korean patients with radioiodine-refractory papillary thyroid cancer. Eur J Nucl Med Mol Imaging. 2011; 38(10):1798–805.

28. Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer. 2013; 13(3):184–99.

29. Kitazono M, Robey R, Zhan Z, Sarlis NJ, Skarulis MC, Aikou T. et al. Low concentrations of the histone deacetylase inhibitor, depsipeptide (FR901228), increase expression of the Na(+)/I(-) symporter and iodine accumulation in poorly differentiated thyroid carcinoma cells. J Clin Endocrinol Metab. 2001; 86(7):3430–5.

30. Furuya F, Shimura H, Suzuki H, Taki K, Ohta K, Haraguchi K. et al. Histone deacetylase inhibitors restore radioiodide uptake and retention in poorly differentiated and anaplastic thyroid cancer cells by expression of the sodium/iodide symporter thyroperoxidase and thyroglobulin. Endocrinology. 2004; 145(6):2865–75.

31. Zarnegar R, Brunaud L, Kanauchi H, Wong M, Fung M, Ginzinger D. et al. Increasing the effectiveness of radioactive iodine therapy in the treatment of thyroid cancer using Trichostatin A, a histone deacetylase inhibitor. Surgery. 2002; 132(6):984–90. discussion 990.

32. Fortunati N, Catalano MG, Arena K, Brignardello E, Piovesan A, Boccuzzi G. Valproic acid induces the expression of the Na+/I- symporter and iodine uptake in poorly differentiated thyroid cancer cells. J Clin Endocrinol Metab. 2004; 89(2):1006–9.

33. Puppin C, D'Aurizio F, D'Elia AV, Cesaratto L, Tell G, Russo D. et al. Effects of histone acetylation on sodium iodide symporter promoter and expression of thyroid-specific transcription factors. Endocrinology. 2005; 146(9):3967–74.

34. Kelly WK, O'Connor OA, Krug LM, Chiao JH, Heaney M, Curley T. et al. Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol. 2005; 23(17):3923–31.

35. Woyach JA, Kloos RT, Ringel MD, Arbogast D, Collamore M, Zwiebel JA. et al. Lack of therapeutic effect of the histone deacetylase inhibitor vorinostat in patients with metastatic radioiodine-refractory thyroid carcinoma. J Clin Endocrinol Metab. 2009; 94(1):164–70.

36. Hou P, Bojdani E, Xing M. Induction of thyroid gene expression and radioiodine uptake in thyroid cancer cells by targeting major signaling pathways. J Clin Endocrinol Metab. 2010; 95(2):820–8.

37. Kroll TG, Sarraf P, Pecciarini L, Chen CJ, Mueller E, Spiegelman BM. et al. PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected]. Science. 2000; 289(5483):1357–60.

38. Karger S, Berger K, Eszlinger M, Tannapfel A, Dralle H, Paschke R. et al. Evaluation of peroxisome proliferator-activated receptor-gamma expression in benign and malignant thyroid pathologies. Thyroid. 2005; 15(9):997–1003.

39. Park JW, Zarnegar R, Kanauchi H, Wong MG, Hyun WC, Ginzinger DG. et al. Troglitazone, the peroxisome proliferator-activated receptor-gamma agonist, induces antiproliferation and redifferentiation in human thyroid cancer cell lines. Thyroid. 2005; 15(3):222–31.

40. Philips JC, Petite C, Willi JP, Buchegger F, Meier CA. Effect of peroxisome proliferator-activated receptor gamma agonist, rosiglitazone, on dedifferentiated thyroid cancers. Nucl Med Commun. 2004; 25(12):1183–6.

41. Kebebew E, Peng M, Reiff E, Treseler P, Woeber KA, Clark OH. et al. A phase II trial of rosiglitazone in patients with thyroglobulin-positive and radioiodine-negative differentiated thyroid cancer. Surgery. 2006; 140(6):960–6. discussion 996-7.

42. Kebebew E, Lindsay S, Clark OH, Woeber KA, Hawkins R, Greenspan FS. Results of rosiglitazone therapy in patients with thyroglobulin-positive and radioiodine-negative advanced differentiated thyroid cancer. Thyroid. 2009; 19(9):953–6.

43. Tepmongkol S, Keelawat S, Honsawek S, Ruangvejvorachai P. Rosiglitazone effect on radioiodine uptake in thyroid carcinoma patients with high thyroglobulin but negative total body scan: a correlation with the expression of peroxisome proliferator-activated receptor-gamma. Thyroid. 2008; 18(7):697–704.

44. Liu Z, Hou P, Ji M, Guan H, Studeman K, Jensen K. et al. Highly prevalent genetic alterations in receptor tyrosine kinases and phosphatidylinositol 3-kinase/akt and mitogen-activated protein kinase pathways in anaplastic and follicular thyroid cancers. J Clin Endocrinol Metab. 2008; 93(8):3106–16.

45. Xing M, Westra WH, Tufano RP, Cohen Y, Rosenbaum E, Rhoden KJ. et al. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab. 2005; 90(12):6373–9.

46. Liu D, Hu S, Hou P, Jiang D, Condouris S, Xing M. Suppression of BRAF/MEK/MAP kinase pathway restores expression of iodide-metabolizing genes in thyroid cells expressing the V600E BRAF mutant. Clin Cancer Res. 2007; 13(4):1341–9.

47. Gupta-Abramson V, Troxel AB, Nellore A, Puttaswamy K, Redlinger M, Ransone K. et al. Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol. 2008; 26(29):4714–9.

48. Kloos RT, Ringel MD, Knopp MV, Hall NC, King M, Stevens R. et al. Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol. 2009; 27(10):1675–84.

49. Ahmed M, Barbachano Y, Riddell AM, Whittaker S, Newbold K, Harrington K. et al. An open labelled phase 2 study evaluating the safety and efficacy of sorafenib in metastatic advanced thyroid cancer [abstract]. Ann Oncol. 2008; 19(Suppl 8):218.

50. Hoftijzer H, Heemstra KA, Morreau H, Stokkel MP, Corssmit EP, Gelderblom 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):923–31.

51. Cohen EE, Rosen LS, Vokes EE, Kies MS, Forastiere AA, Worden FP. et al. Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study. J Clin Oncol. 2008; 26(29):4708–13.

52. Sherman SI, Wirth LJ, Droz JP, Hofmann M, Bastholt L, Martins RG. et al. Motesanib diphosphate in progressive differentiated thyroid cancer. N Engl J Med. 2008; 359(1):31–42.

53. Bible KC, Suman VJ, Molina JR, Smallridge RC, Maples WJ, Menefee ME. et al. Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study. Lancet Oncol. 2010; 11(10):962–72.