ALK Rearrangements in Aggressive Thyroid Cancer

描述（由申请人提供）：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，而其中大多数是惰性的，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> 95%，而随着肿瘤去分化，生存率急剧下降，低分化癌接近50%，间变性癌<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。更好地了解甲状腺未分化癌的遗传机制并确定这些肿瘤的新治疗靶点对于降低甲状腺癌的发病率和死亡率至关重要。最近，使用全转录组（RNA-Seq）分析，然后进行额外的FISH和RT-PCR分析，我们在甲状腺癌（包括低分化甲状腺癌和间变性甲状腺癌）中鉴定了两种形式的ALK重排，STRN-ALK和EML 4-ALK。此外，我们的初步数据表明，甲状腺肿瘤中存在其他类型的ALK融合，并且还表明STRN-ALK融合导致组成性ALK活性并增加甲状腺细胞的增殖。最重要的是，在其他癌症类型中发生的ALK重排是一个极好的治疗靶点，已经开发了许多ALK激酶抑制剂，并在临床前和临床研究中进行了表征，其中一种，克唑替尼，已被批准 用于治疗EML 4-ALK阳性肺癌。如果STRN-ALK重排也是致瘤性的，并且对克唑替尼或其他ALK抑制剂的抑制有反应，则它可能首次为高度侵袭性和最致命类型的甲状腺癌中的现有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ALK重排代表侵袭性类型甲状腺癌的新遗传机制并可作为甲状腺癌的药物靶点的假设来检查这种可能性。具体而言，我们将确定甲状腺癌中STRN-ALK和其他类型ALK重排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为我们提供机会来测试越来越多的可用ALK抑制剂，并有望首次验证对破坏性和经常致命形式的甲状腺癌的治疗。

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.