ALK Rearrangements in Aggressive Thyroid Cancer

甲状腺癌是美国最常见的内分泌肿瘤类型，也是增长最快的癌症类型。重要的是，只有一小部分甲状腺癌有侵袭性行为，并构成与癌症相关的死亡的巨大风险，而大多数甲状腺癌是惰性的，可以通过手术切除治愈。尤其是分化良好的甲状腺乳头状癌和滤泡癌，其5年存活率为95%，而低分化癌的存活率降至50%，间变性癌的存活率降至10%。事实上，间变性甲状腺癌是人类癌症中最致命的类型之一，确诊后患者的中位生存期为5个月。为了减少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，寻找治疗这些肿瘤的新靶点。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。我们进一步表明，STRN-ALK融合型是甲状腺癌中最常见的ALK融合类型，也是在去分化和致死性甲状腺癌中发现的最常见的ALK融合类型。此外，在该提案的前一个周期中，我们建立了两个甲状腺特异表达STRN-ALK的动物模型，并表明这些小鼠患上了与人类肿瘤重现的去分化甲状腺癌。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，FDA开发并批准了几种ALK抑制剂用于ALK阳性肺癌的治疗。然而，ALK抑制剂是否可以用于治疗ALK阳性的甲状腺低分化和未分化癌，或者是否可以改善放射性碘对这些肿瘤的治疗效果，目前尚不清楚。在目前的方案中，我们将利用丰富的初步数据和现有的和新产生的小鼠模型来更好地了解甲状腺癌去分化的分子机制，检测STRN-ALK阳性肿瘤对ALK抑制剂的反应，并确定是否可以利用ALK抑制来恢复甲状腺癌去分化不同阶段的碘摄取和增加对放射性碘的敏感性。这些实验还将提供一个机会来测试越来越多的可用的ALK抑制剂，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方法。

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.