ALK Rearrangements in Aggressive Thyroid Cancer

描述(申请人提供)：甲状腺癌是美国最常见的内分泌肿瘤类型，也是生长最快的癌症类型。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，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，5年生存率为95%，而随着肿瘤去分化，生存率急剧下降，在低分化癌中接近50%，在间变性癌中接近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，更好地了解间变性甲状腺癌的遗传机制和确定治疗这些肿瘤的新靶点是至关重要的。最近，利用全转录组(RNA-Seq)分析以及FISH和RT-PCR分析，我们在甲状腺癌中发现了两种形式的ALK重排，包括低分化甲状腺癌和未分化甲状腺癌。此外，我们的初步数据表明，在甲状腺肿瘤中还存在其他类型的ALK融合，也表明STRN-ALK融合导致结构性ALK活性和促进甲状腺细胞的增殖。最重要的是，发生在其他癌症类型中的alk重排是一个很好的治疗靶点，已经开发了一些alk激酶抑制剂，并在临床前和临床研究中确定了其特征，其中一种是crizotinib，已被批准。 被FDA用于治疗EML4-ALK阳性肺癌。如果STRN-ALK重排也是致癌的，并且对Crizotinib或其他ALK抑制剂的抑制有反应，它可能首次为已经存在的治疗高度侵袭性和最致命类型的甲状腺癌的药物提供有效的治疗靶点。在目前的提案中，我们将通过检验以下假设来检验这种可能性：ALK重排代表了侵袭性类型甲状腺癌的一种新的遗传机制，并可作为甲状腺癌的药物靶点。具体地说，我们将确定STRN-ALK和其他类型的ALK重排在甲状腺癌中的患病率及其在间变性转化中的作用，确定ALK激活的机制，表征甲状腺细胞中ALK重排的转化和致瘤特性，并在临床前研究中检查STRN-ALK阳性的甲状腺细胞对ALK抑制剂的反应。体外研究和小鼠模型的结合应该会为我们提供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治疗方法。

DESCRIPTION (provided by applicant): Thyroid cancer is the most common type of endocrine neoplasia and the fastest growing cancer type in the U.S. Importantly, only a 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 dramatically with tumor dedifferentiation, approaching 50% in poorly differentiated cancer and <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 genetic mechanisms of anaplastic thyroid cancer and identification of novel therapeutic targets for these tumors is critical in order to decrease the morbidity and mortality from thyroid cancer. Recently, using the whole-transcriptome (RNA-Seq) analysis followed by additional FISH and RT-PCR analyses, we identified two forms of ALK rearrangements, STRN-ALK and EML4-ALK, in thyroid cancer, including poorly differentiated thyroid cancer and anaplastic thyroid cancer. Moreover, our preliminary data suggest that other types of ALK fusion exist in thyroid tumors and also show that STRN-ALK fusion results in constitutive ALK activity and increase proliferation of thyroid cells. Most importantly, ALK rearrangements that occur in other cancer types are an excellent therapeutic target, and a number of ALK kinase inhibitors have been developed and characterized in pre-clinical and clinical studies, and one of which, crizotinib, has been approved by the FDA for treatment of EML4-ALK-positive lung cancer. If STRN-ALK rearrangement is also tumorigenic and is responsive to inhibition by crizotinib or other ALK inhibitors, it may offe for the first time an effective therapeutic target for already existing drugs in the highly aggressve and most lethal types of thyroid cancer. In the current proposal, we will examine this possibility by testing the hypothesis that ALK rearrangements represent a novel genetic mechanism of aggressive types of thyroid cancer and can serve as a drug target for thyroid cancers. Specifically, we will establish the prevalence of STRN-ALK and other types of ALK rearrangements in thyroid cancer and their role in anaplastic transformation, determine the mechanisms of ALK activation, characterize transforming and tumorigenic properties of ALK rearrangements in thyroid cells, and examine in pre-clinical studies the response of STRN-ALK-positive thyroid cells to ALK inhibitors. The combination of in vitro studies and mouse models should provide us the opportunity to test the growing list of available ALK inhibitors, and hopefully validate for the first time a treatment for the devastating and frequently lethal forms o thyroid cancer.