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：
10640864
负责人：
YURI E NIKIFOROV
金额：
$ 35.06万
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/10640864
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 Phosphotransferases Radioactive Iodine SLC5A5 gene Signal Transduction Testing Therapeutic Thyroglobulin Thyroid Gland Time Transgenic Mice Undifferentiated Withdrawal anaplastic thyroid cancer cancer risk cancer subtypes cancer type effective therapy experimental study improved inducible gene expression inhibitor 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.

甲状腺癌是美国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略性行为，并构成了与癌症相关死亡的实质性风险，而大多数甲状腺癌则是懒惰的，并且通过手术恢复是懒惰的。对于分化良好的甲状腺乳头状和卵泡癌尤其如此，其5年生存率> 95％，而分化较差的癌症的存活率降至50％，而对变性癌的生存率降低到50％。实际上，塑性甲状腺癌是最致命的人类癌症类型之一，诊断后5个月患者的中位数生存期。需要更好地了解甲状腺癌的分子去分化并为这些肿瘤寻找新的治疗靶标，以降低甲状腺癌的发病率和死亡率。最近，我们确定了甲状腺癌中的ALK融合，包括分化较差的癌和肿瘤癌。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，并且在去分化和致命的甲状腺癌中也是最普遍的ALK融合型。此外，在提案的上一个周期中，我们建立了两个甲状腺特异性表达的动物模型，并表明这些小鼠会发展出脱离甲状腺癌，从而概括了人类肿瘤。我们还产生了指出的数据，指出存在两种亚型的甲状腺癌分化较差的亚型，甲状腺分化标志物的明显表达以及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重排是一个极好的治疗靶点，由FDA开发和批准了几种ALK抑制剂，用于治疗ALK阳性肺癌。但是，是否可以使用ALK抑制剂来治疗ALK阳性甲状腺的分化不足和播种癌，或改善用放射性碘治疗这些肿瘤的影响。 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去分化。这些实验还将提供一个机会，以测试不断增长的ALK抑制剂清单，并希望首次对甲状腺癌的毁灭性和致命形式进行有效治疗。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Can TP53-mutant follicular adenoma be a precursor of anaplastic thyroid carcinoma?

TP53突变型滤泡性腺瘤可能是甲状腺未分化癌的先兆吗？

DOI：
10.1530/erc-21-0095
发表时间：
2021
期刊：
Endocrine-related cancer
影响因子：
3.9
作者：
Nikitski,AlyaksandrV;Nikiforova,MarinaN;Yip,Linwah;Karslioglu-French,Esra;Carty,SallyE;Nikiforov,YuriE
通讯作者：
Nikiforov,YuriE

Inhibition of ALK-Signaling Overcomes STRN-ALK-Induced Downregulation of the Sodium Iodine Symporter and Restores Radioiodine Uptake in Thyroid Cells.

抑制 ALK 信号传导可克服 STRN-ALK 诱导的钠碘同向转运蛋白下调，并恢复甲状腺细胞对放射性碘的摄取。