ALK Rearrangements in Aggressive Thyroid Cancer

侵袭性甲状腺癌中的 ALK 重排

基本信息

批准号：
10206038
负责人：
YURI E NIKIFOROV
金额：
$ 35.21万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10206038
关键词：
ALK gene Aggressive behavior Anaplastic Carcinomas Animal Model Animals Appearance Avidity Behavior Biological Cancer Histology Carcinoma Cells Cessation of life Clinical DNA copy number Data Diagnosis Differentiated Gene Differentiation Antigens Down-Regulation Doxycycline Endocrine Excision FDA approved Gene Fusion Genes Genetic Human Human Characteristics I131 isotope Indolent Iodine Knock-out Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of thyroid Modeling Molecular Molecular Profiling Morbidity - disease rate Morphology Mus Mutation Neoplasm Metastasis Neoplasms Oncogenes Papillary Pathway interactions Patients Phenotype Phosphotransferases Radioactive Iodine SLC5A5 gene Signal Transduction Testing Therapeutic Thyroglobulin Thyroid Gland Thyroid carcinoma Time Transgenic Mice Undifferentiated Withdrawal anaplastic thyroid cancer cancer risk cancer subtypes cancer type effective therapy experimental study improved inducible gene expression inhibitor/antagonist mortality mouse model new therapeutic target novel novel therapeutic intervention promoter radioiodine therapy response restoration therapeutic target treatment effect tumor tumor initiation tumor progression uptake virtual

项目摘要

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.

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，并构成与癌症相关的死亡的巨大风险，而大多数甲状腺癌是惰性且不活跃的。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状癌尤其如此，其 5 年生存率 >95%，而低分化癌的生存率降至 50%，未分化癌的生存率降至 <10%。事实上，甲状腺未分化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并寻找这些肿瘤的新治疗靶点。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。我们进一步表明，STRN-ALK 融合类型是甲状腺癌中最常见的 ALK 融合类型，也是去分化和致死性甲状腺癌中最常见的 ALK 融合类型。此外，在该提案的上一个周期中，我们建立了两种甲状腺特异性表达 STRN-ALK 的动物模型，并表明这些小鼠会发展为再现人类肿瘤的去分化甲状腺癌。我们还生成了数据，表明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记物表达和对放射性碘治疗的反应。重要的是，其他癌症类型中发生的 ALK 重排是一个极好的治疗靶点，FDA 开发并批准了多种 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未分化癌或改善放射性碘治疗这些肿瘤的效果仍不清楚。在当前的提案中，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来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ALK是否抑制作用可用于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可用 ALK 抑制剂，并有望首次验证对毁灭性且经常致命的甲状腺癌的有效治疗方法。