ALK Rearrangements in Aggressive Thyroid Cancer

甲状腺癌是最常见的内分泌肿瘤类型，也是美国增长最快的癌症类型。重要的是，只有一小部分甲状腺癌具有侵袭性行为，并造成癌症相关死亡的重大风险，而大多数甲状腺癌是惰性的，可通过手术切除治愈。对于分化良好的甲状腺乳头状癌和滤泡癌尤其如此，其5年生存率为95%左右，而低分化癌的5年生存率降至50%，间变性癌的5年生存率低于10%。事实上，间变性甲状腺癌是最致命的人类癌症之一，诊断后患者的中位生存期为5个月。为了降低甲状腺癌的发病率和死亡率，迫切需要更好地了解甲状腺癌去分化的分子机制，寻找新的治疗靶点。最近，我们在甲状腺癌中发现了ALK融合，包括低分化癌和间变性癌。我们进一步发现STRN-ALK融合型是甲状腺癌中最常见的ALK融合型，也是去分化和致死性甲状腺癌中最常见的ALK融合型。此外，在之前的提案周期中，我们建立了两个甲状腺特异性表达STRN-ALK的动物模型，并表明这些小鼠发生了再现人类肿瘤的去分化甲状腺癌。我们还生成了数据，指出存在两种低分化甲状腺癌亚型，它们具有不同的甲状腺分化标志物表达和对放射性碘治疗的反应。重要的是，发生在其他癌症类型中的ALK重排是一个很好的治疗靶点，有几种ALK抑制剂已被FDA开发并批准用于治疗ALK阳性肺癌。然而，ALK抑制剂是否可用于治疗ALK阳性甲状腺低分化癌和间变性癌，或改善放射性碘治疗这些肿瘤的效果尚不清楚。在目前的研究中，我们将利用丰富的前期数据以及现有和新生成的小鼠模型，更好地了解甲状腺癌去分化的分子机制，研究strn -ALK阳性肿瘤对ALK抑制剂的反应，并确定ALK抑制是否可以在甲状腺癌去分化的不同阶段恢复碘的吸收和增加对放射性碘的敏感性。这些实验也将为测试越来越多可用的ALK抑制剂提供机会，并有望首次验证对毁灭性和经常致命的甲状腺癌的有效治疗。

Thyroid cancer is the most common type of endocrine neoplasia and the fastest growing cancer type in the U.S.. Importantly, only small proportion of thyroid cancers have aggressive behavior and pose a substantial risk of cancer-related death, whereas the majority of them are indolent and cured by surgical removal. This is particularly true for well-differentiated thyroid papillary and follicular cancers, that have a 5-year survival of >95%, whereas the survival decreases to 50% for poorly differentiated cancer and to <10% for anaplastic cancer. In fact, anaplastic thyroid cancer is one of the most lethal types of human cancer with the median patient survival of 5 months after diagnosis. Better understanding of the molecular mechanisms of thyroid cancer dedifferentiation and finding novel therapeutic targets for these tumors is critically needed to decrease the morbidity and mortality from thyroid cancer. Recently, we identified ALK fusions in thyroid cancer, including poorly differentiated carcinomas and anaplastic carcinomas. We further showed that STRN-ALK fusion type is the most common ALK fusion found in thyroid cancer, and it is also most prevalent ALK fusion type found in dedifferentiated and lethal thyroid cancers. Moreover, during the previous cycle of the proposal, we established two animal models of thyroid-specific expression of STRN-ALK and showed that these mice develop dedifferentiated thyroid cancer that recapitulates human tumors. We also generated data pointing to the existence of two subtypes of poorly differentiated thyroid cancer with distinct expression of thyroid differentiation markers and response to radioiodine therapy. Importantly, ALK rearrangements that occur in other cancer types are an excellent therapeutic target, with several ALK inhibitors developed and approved by the FDA for treatment of ALK-positive lung cancer. However, whether ALK inhibitors can be used to treat ALK-positive thyroid poorly differentiated and anaplastic cancers or improve the effects of treatment of these tumors with radioactive iodine remain unknown. In the current proposal, we will take advantage of the abundant preliminary data and existing and newly generated mouse models to better understand the molecular mechanisms of thyroid cancer dedifferentiation, examine the response of STRN-ALK-positive tumors to ALK inhibitors, and determine if ALK inhibition can be exploited to restore iodine uptake and increase sensitivity to radioiodine at different stages of thyroid cancer dedifferentiation. These experiments will also provide an opportunity to test the growing list of available ALK inhibitors and hopefully validate for the first time an effective treatment for the devastating and frequently lethal forms of thyroid cancer.