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，并构成癌症相关死亡的重大风险，而大多数甲状腺癌是惰性的，可以通过手术切除治愈。这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> 95%，而分化差的癌症的生存率降至50%，未分化癌的生存率降至<10%。事实上，间变性甲状腺癌是最致命的人类癌症类型之一，诊断后患者的中位生存期为5个月。深入了解甲状腺癌去分化的分子机制，寻找新的治疗靶点，是降低甲状腺癌发病率和死亡率的关键。最近，我们在甲状腺癌（包括低分化癌和未分化癌）中发现了ALK融合。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，也是去分化和致死性甲状腺癌中最常见的ALK融合型。此外，在该提案的前一个周期中，我们建立了两种甲状腺特异性表达STRN-ALK的动物模型，并表明这些小鼠发生了重演人类肿瘤的去分化甲状腺癌。我们还生成的数据指出存在两种分化不良的甲状腺癌亚型，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，在其他癌症类型中发生的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仍不清楚。在目前的提案中，我们将利用丰富的初步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，检查STRN-ALK阳性肿瘤对ALK抑制剂的反应，并确定是否可以利用ALK抑制来恢复碘摄取并增加甲状腺癌去分化不同阶段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ALK抑制剂，并有望首次验证一种有效治疗甲状腺癌的毁灭性和经常致命的形式。

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.