Targeted molecular therapies in thyroid carcinoma

Abstract

Thyroid cancer incidence has significantly increased in the last three decades and many patients seek medical attention for its treatment every year. Among follicular cell-derived tumors, the majority are differentiated thyroid carcinomas (DTC), whose prognosis is very good with only 15% of the cases presenting disease persistence or recurrence after initial treatment. Medullary thyroid carcinoma has a worse prognosis, especially in patients with diffused cancers at the time of initial surgery. Traditional treatment options for persistent or recurrent disease include additional surgery, radioiodine treatment and TSH-suppression in DTC patients; external beam radiotherapy, and cytotoxic chemotherapy, often have low efficacy and many patients with advanced disease ultimately die. In the last two decades many of the molecular events involved in cancer formation have been uncovered. This knowledge has prompted the development of novel therapeutic strategies mainly based on the inhibition of key molecular mediators of the tumorigenic process. In particular the class of small-molecule tyrosine kinase inhibitors was enriched by many compounds that have reached clinical trials and in some cases have had approval for clinical use in specific cancers. Many of these compounds entered clinical trials also for locally advanced or metastatic thyroid carcinomas showing very promising results. Arq Bras Endocrinol Metab. 2009;53(9):1061-73 Keywords Thyroid carcinoma; radioiodine therapy; external beam radiation therapy; cytotoxic chemotherapy; targeted therapies; tyrosine kinase inhibitors ReSumo O câncer de tireoide tem aumentado significativamente nas últimas três décadas e muitos pacientes têm buscado cuidados médicos para o tratamento a cada ano. Entre os tumores derivados de células foliculares, a maioria é carcinoma diferenciado de tireoide (CDT), cujo prognóstico é muito bom, em que somente em 15% dos casos a doença é persistente ou recorrente após o tratamento inicial. O carcinoma medular de tireoide tem um prognóstico pior, especialmente em pacientes com câncer difuso no momento da cirurgia inicial. As opções no tratamento tradicional para a doença persistente ou recorrente incluem cirurgia adicional, radioiodoterapia e supressão de TSH em pacientes CDT; a radioterapia externa e a quimioterapia citotóxica apresentam com frequência uma baixa eficácia e muitos pacientes com doença avançada não sobrevivem. Nas últimas duas décadas, muitos dos eventos envolvidos na formação do câncer tornaram-se conhecidos. Esse conhecimento possibilitou o desenvolvimento de novas estratégias terapêuticas, baseadas principalmente na inibição de mediador molecularchave no processo tumorigênico. Em particular, a classe das pequenas moléculas inibidoras de tirosina-quinase foi enriquecida por muitos compostos investigados em estudos clínicos e alguns casos foram aprovados para uso clínico em tipos específicos de câncer. Muitos desses compostos foram aplicados em estudos clínicos de câncer de tireoide com extensa invasão local ou metást...

Platelet‐derived growth factor receptor‐α promotes lymphatic metastases in papillary thyroid cancer

“…Although comprising a relatively small proportion of thyroid cancer patients, these individuals suffer disproportionately and radioactive iodine resistance in thyroid cancer has prompted trials using tyrosine kinase inhibitors to address these difficult cases, as reviewed by Gild et al 29. The rationale for selecting TKIs in treating thyroid cancer, including axitinib, motesanib, sorafenib, and sunitinib, has essentially been empirical, relying on observations in other tumours such as breast and colon cancer 29–32. Most of these drugs are multi‐kinase inhibitors that target the different PDGF and VEGF receptors, and in most cases, it is not clear which receptor subgroup is most effectively targeted 29, 30.…”

“…The rationale for selecting TKIs in treating thyroid cancer, including axitinib, motesanib, sorafenib, and sunitinib, has essentially been empirical, relying on observations in other tumours such as breast and colon cancer 29–32. Most of these drugs are multi‐kinase inhibitors that target the different PDGF and VEGF receptors, and in most cases, it is not clear which receptor subgroup is most effectively targeted 29, 30. Differences in PDGFR or VEGFR targeting by TKIs may account for the varied responses (0–55%) to TKI therapy in thyroid cancer.…”

“…Tyrosine kinase inhibitors (TKIs) targeting different VEGF and PDGF receptors have been used to slow disease progression in metastatic PTC 28, 29. Clinical development of multi‐kinase TKIs proceeds quickly and at least five different drugs have been tested in phase I and II clinical trials for metastatic or progressive PTC 29–34. The results of these trials are mixed but sunitinib is now used selectively by our centre and others worldwide to treat progressive, metastatic PTC 28, 29.…”

Sunitinib inhibits papillary thyroid carcinoma with RET/PTC rearrangement but not BRAF mutation

“…3 Ten-year survival rate drops to 25% when distant metastasis is detected. 4 Furthermore, long-term overall survival drops to below 10% when the tumor becomes resistant to RAI. 5 Few therapeutic options exist for persistent/recurrent differentiated thyroid carcinomas (DTC).…”

Therapeutic effects of adenovirus‑mediated CD and NIS expression combined with Na131I/5‑FC on human thyroid cancer

“…Thyroid cancer is also the seventh most common type of cancer in Canadians, and there were ~5,650 cases of thyroid cancer diagnosed in 2012 (1,2). Concurrently, equal trends in the increase in incidence rate have been identified all over the world (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). The age-standardized incidence rate of thyroid cancer has increased from 1.1/100,000 to 6.1/100,000 for males, and from 3.3/100,000 to 22.2/100,000 for females, from 1970 to 1972 in the USA (1,15).…”