Department of Radiation Oncology, Harvard Medical School, Massachusetts General Hospital, 55 Fruit St, Boston, MA, 02114, USA.
Alexandria Comprehensive Cancer center, Alexandria, Egypt.
Mol Cancer. 2018 Feb 19;17(1):51. doi: 10.1186/s12943-018-0786-0.
Thyroid cancer is a frequently encountered endocrine malignancy. Despite the favorable prognosis of this disease, 15-20% of differentiated thyroid cancer (DTC) cases and most anaplastic types, remain resistant to standard treatment options, including radioactive iodine (RAI). In addition, around 30% of medullary thyroid cancer (MTC) cases show resistance after surgery. The evolving understanding of disease-specific molecular therapeutic targets has led to the approval of two targeted therapies (Sorafenib and Lenvatinib) for RAI refractory DTC and another two drugs (Vandetanib and Cabozantinib) for MTC. These advanced therapies exert their effects by blocking the MAPK pathway, which has been widely correlated to different types of thyroid cancers. While these drugs remain reserved for thyroid cancer patients who failed all treatment options, their ability to improve patients' overall survival remain hindered by their low efficacy and other molecular factors. Among these factors is the tumor's ability to activate parallel proliferative signaling pathways other than the cascades blocked by these drugs, along with overexpression of some tyrosine kinase receptors (TKR). These facts urge the search for novel different treatment strategies for advanced thyroid cases beyond these drugs. Furthermore, the growing knowledge of the dynamic immune system interaction with tumor microenvironment has revolutionized the cancer immune therapy field. In this review, we aim to discuss the molecular escape mechanisms of thyroid tumors from these drugs. We also highlight novel therapeutic options targeting other pathways than MAPK, including PI3K pathway, ALK translocations and HER2/3 receptors and their clinical impact. We also aim to discuss the usage of targeted therapy in restoring thyroid tumor sensitivity to RAI, and finally turn to extensively discuss the role of immunotherapy as a potential alternative treatment option for advanced thyroid diseases.
甲状腺癌是一种常见的内分泌恶性肿瘤。尽管这种疾病的预后良好，但 15-20%的分化型甲状腺癌（DTC）病例和大多数间变性类型对标准治疗方案（包括放射性碘（RAI））仍然具有耐药性。此外，大约 30%的甲状腺髓样癌（MTC）病例在手术后也会出现耐药。对疾病特异性分子治疗靶点的不断认识，导致了两种靶向治疗药物（索拉非尼和仑伐替尼）被批准用于 RAI 难治性 DTC，另外两种药物（凡德他尼和卡博替尼）被批准用于 MTC。这些先进的治疗方法通过阻断 MAPK 通路发挥作用，该通路与不同类型的甲状腺癌广泛相关。虽然这些药物仍然保留给所有治疗方案都失败的甲状腺癌患者，但由于其疗效低和其他分子因素，它们改善患者总体生存的能力仍然受到限制。这些因素包括肿瘤激活除这些药物阻断的级联之外的平行增殖信号通路的能力，以及某些酪氨酸激酶受体（TKR）的过度表达。这些事实促使人们寻找除这些药物之外的新型治疗晚期甲状腺癌的策略。此外，对肿瘤微环境与动态免疫系统相互作用的认识不断深入，彻底改变了癌症免疫治疗领域。在这篇综述中，我们旨在讨论甲状腺肿瘤从这些药物中逃避的分子机制。我们还强调了靶向 MAPK 以外的其他通路的新型治疗选择，包括 PI3K 通路、ALK 易位和 HER2/3 受体及其临床影响。我们还旨在讨论靶向治疗在恢复甲状腺肿瘤对 RAI 的敏感性方面的作用，最后广泛讨论免疫治疗作为晚期甲状腺疾病的潜在替代治疗选择的作用。
