权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The Role of BRAF Mutation in Thyroid Cancer Invasion

BRAF突变在甲状腺癌侵袭中的作用

基本信息

批准号：
8804921
负责人：
Sareh Parangi
金额：
$ 31.98万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-14 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8804921
关键词：
Avidity BRAF gene Biological Markers Cancer Patient Cancer cell line Cell Adhesion Molecules Cell Line Cells Clinical Detection Diagnosis Diagnostic Disease Disease Progression Distant Distant Metastasis Endocrine Extracellular Matrix Figs - dietary Gelatinase A Gelatinase B Genes Genomics Goals Health Human Immigration In Vitro Incidence Induced Mutation Integrins Lymph Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of thyroid Matrix Metalloproteinases Metalloproteases Modeling Morbidity - disease rate Mus Mutate Mutation Neoplasm Metastasis Nodal Outcome Papillary thyroid carcinoma Pathology Pathway interactions Patients Peptide Hydrolases Play Radioactive Iodine Recurrent disease Role Safety Staging Testing Therapeutic Thrombospondin 1 Thyroid carcinoma Time Urine Validation Woman cancer diagnosis cancer recurrence chorioallantoic membrane efficacy testing in vivo inhibitor/antagonist membrane model mouse model novel pre-clinical response thyroid neoplasm tumor growth urinary

项目摘要

DESCRIPTION (provided by applicant): Role of BRAF mutation in thyroid cancer invasion: Thyroid cancer is a common malignancy associated with substantial morbidity. Well-differentiated thyroid cancer is the most common endocrine malignancy and ranks as the seventh most common cancer diagnosed in women. Increasing incidence of thyroid cancer over the past few decades is reflected by the projected 37,000 new cases in 2009. While the majority of patients with well-differentiated thyroid cancer presents with limited disease and become disease-free after initial treatment, 20% of patients with thyroid cancer have local or regional recurrent disease, and 5% develop distant metastases. Prior studies have identified the BRAF gene as the most commonly mutated in papillary thyroid cancer, activation of this pathway leads to ERK translocation and downstream transcriptional dysregulation. This mutation is implicated in the initiation and progression of aggressive subtypes such as tall cell, and in those with extra-thyroidal extension, lymph nodal and distant metastases. Moreover, it is associated with both loss of radioiodine avidity and cancer recurrence. The mechanisms by which this mutation induces invasion and distant spread are not fully understood. We have recently carried out a detailed Gene Set Enrichment Analysis to analyze the genomic signature of papillary thyroid cancer patients with or without this BRAF mutation. We have found that BRAFV600E mutation results in the alteration of several cell adhesion molecules including Thrombospondin-1, integrins and other stromally active proteases, such as matrix metalloproteases. Here we posit that BRAF mutation and changes in these adhesion molecules plays a crucial role in the invasion and metastasis of the most aggressive and non-curable forms of papillary thyroid cancer. In addition, we postulate that selective BRAF inhibitors that are currently being validated in several forms of cancer could be utilized in the treatment of the thyroid cancers harbouring BRAF mutation. Our goal is to characterize the role of BRAF V600E mutation, as well as BRAF induced expression of TSP-1, matrix metalloproteases and other ECM molecules in thyroid cancer cell lines, as well as a novel preclinical mouse model of thyroid cancer. We also plan to test the efficacy of BRAFV600E specific inhibitors and to determine whether TSP-1, and MMPs could be utilized as a diagnostic biomarker for detection of the aggressive forms of thyroid cancer as well as therapeutic biomarkers to evaluate the response to BRAF inhibitors.

描述（由申请人提供）：BRAF突变在甲状腺癌侵袭中的作用：甲状腺癌是一种常见的恶性肿瘤，发病率很高。高分化甲状腺癌是最常见的内分泌恶性肿瘤，在女性最常见的癌症中排名第七。在过去的几十年里，甲状腺癌的发病率不断上升，2009年预计有37,000个新病例。虽然大多数分化良好的甲状腺癌患者在初始治疗后病情有限，无病，但20%的甲状腺癌患者出现局部或区域复发，5%的甲状腺癌患者发生远处转移。先前的研究已经确定BRAF基因是甲状腺乳头状癌中最常见的突变，该途径的激活导致ERK易位和下游转录失调。这种突变与侵袭性亚型（如高细胞）的发生和发展有关，也与甲状腺外扩散、淋巴结和远处转移有关。此外，它还与放射性碘的缺乏和癌症复发有关。这种突变诱导入侵和远距离传播的机制尚不完全清楚。我们最近进行了一项详细的基因集富集分析，以分析具有或不具有这种BRAF突变的甲状腺乳头状癌患者的基因组特征。我们发现BRAFV600E突变导致多种细胞粘附分子的改变，包括血小板反应蛋白-1、整合素和其他基质活性蛋白酶，如基质金属蛋白酶。在这里，我们假设BRAF突变和这些粘附分子的变化在最具侵袭性和不可治愈的甲状腺乳头状癌的侵袭和转移中起着至关重要的作用。此外，我们假设目前在几种癌症中得到验证的选择性BRAF抑制剂可用于治疗携带BRAF突变的甲状腺癌。我们的目标是表征BRAF V600E突变的作用，以及BRAF诱导TSP-1、基质金属蛋白酶和其他ECM分子在甲状腺癌细胞系中的表达，以及一种新的甲状腺癌临床前小鼠模型。我们还计划测试BRAFV600E特异性抑制剂的疗效，并确定TSP-1和MMPs是否可以用作检测侵袭性甲状腺癌的诊断性生物标志物，以及评估对BRAF抑制剂的反应的治疗性生物标志物。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Blocks to thyroid cancer cell apoptosis can be overcome by inhibition of the MAPK and PI3K/AKT pathways.

DOI：
10.1038/cddis.2014.78
发表时间：
2014-03-06
期刊：
Cell death & disease
影响因子：
9
作者：
通讯作者：

PD-L1 and IDO1 Are Expressed in Poorly Differentiated Thyroid Carcinoma.

PD-L1和IDO1在分化较差的甲状腺癌中表达。

DOI：
10.1007/s12022-018-9514-y
发表时间：
2018-03
期刊：
Endocrine pathology
影响因子：
4.4
作者：
Rosenbaum MW;Gigliotti BJ;Pai SI;Parangi S;Wachtel H;Mino-Kenudson M;Gunda V;Faquin WC
通讯作者：
Faquin WC

Potential role of 5-aza-2'-deoxycytidine induced MAGE-A4 expression in immunotherapy for anaplastic thyroid cancer.

DOI：
10.1016/j.surg.2013.07.009
发表时间：
2013-12
期刊：
SURGERY
影响因子：
3.8
作者：
Gunda, Viswanath;Cogdill, Alexandria P.;Bernasconi, Maria J.;Wargo, Jennifer A.;Parangi, Sareh
通讯作者：
Parangi, Sareh

Summary statement: utility of molecular marker testing in thyroid cancer.

摘要：分子标记物检测在甲状腺癌中的实用性。

DOI：
10.1016/j.surg.2010.09.023
发表时间：
2010
期刊：
Surgery
影响因子：
3.8
作者：
Yip,Linwah;Kebebew,Electron;Milas,Mira;Carty,SallyE;Fahey3rd,ThomasJ;Parangi,Sareh;Zeiger,MarthaA;Nikiforov,YuriE
通讯作者：
Nikiforov,YuriE

Combined BRAF(V600E)- and SRC-inhibition induces apoptosis, evokes an immune response and reduces tumor growth in an immunocompetent orthotopic mouse model of anaplastic thyroid cancer.