Instituto do Câncer (ICESP) da Faculdade de Medicina da Universidade de São Paulo, Unidade de Suprarrenal e Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM-42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
Curr Opin Oncol. 2012 May;24(3):229-34. doi: 10.1097/CCO.0b013e328351c71a.
This review will focus on the recent advances in molecular pathogenesis and targeted therapies for medullary thyroid carcinoma (MTC). Unlike hereditary MTC in which rearranged during transfection (RET) mutations are the most important precipitating events, in sporadic MTC the genetic or molecular biomarkers are yet to be established.
Targeted molecular therapies that inhibit RET and other tyrosine kinase receptors involved in angiogenesis have shown great promise in the treatment of metastatic or locally advanced MTC and are under investigation. In addition, the recent findings of H-RAS mutations in 56% of RET-negative sporadic MTC and the activation of the mammalian target of rapamycin (mTOR) intracellular signaling pathway in hereditary MTC suggests that additional or alternative genetic events are important for MTC pathogenesis.
Recently, vandetanib (ZD6474), an inhibitor of vascular endothelial growth factor receptor (VEGFR) 2 and VEGFR 3, RET, and epidermal growth factor receptor (EGFR), was approved for the treatment of adults with symptomatic or progressive MTC. Significant advantages for vandetanib over placebo were seen in terms of response rate, disease control rate, and biochemical response in a phase III study. Furthermore, cabozantinib (XL184), an inhibitor of VEGFR 1 and VEGFR 2, hepatocyte growth factor receptor (MET), and RET, was associated with partial response and stable disease in 29 and 41%, respectively.
本篇综述聚焦于甲状腺髓样癌（MTC）分子发病机制和靶向治疗的最新进展。不同于遗传性 MTC，易位基因（RET）突变是最重要的诱发因素，散发性 MTC 的遗传或分子生物标志物尚未确定。
针对 RET 及其他参与血管生成的酪氨酸激酶受体的靶向分子治疗在转移性或局部晚期 MTC 的治疗中显示出巨大的应用前景，目前正在研究中。此外，最近在 56%的 RET 阴性散发性 MTC 中发现 H-RAS 突变，以及在遗传性 MTC 中激活哺乳动物雷帕霉素靶蛋白（mTOR）细胞内信号通路，提示在 MTC 的发病机制中可能存在其他或替代性遗传事件。
最近，血管内皮生长因子受体（VEGFR）2 和 VEGFR 3、RET 和表皮生长因子受体（EGFR）抑制剂凡德他尼（ZD6474）被批准用于治疗有症状或进行性 MTC 的成人患者。在一项 III 期研究中，与安慰剂相比，凡德他尼在缓解率、疾病控制率和生化缓解方面具有显著优势。此外，VEGFR 1 和 VEGFR 2、肝细胞生长因子受体（MET）和 RET 抑制剂卡博替尼（XL184）在 29%和 41%的患者中分别引起部分缓解和稳定疾病。
