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:
    8041692
  • 负责人:
  • 金额:
    $ 32.1万
  • 依托单位:
  • 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 2015-12-31
  • 项目状态:
    已结题

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. PUBLIC HEALTH RELEVANCE: Role of BRAF mutation in thyroid cancer invasion Analyzing how BRAFV600E mutation alters critical molecules involved in thyroid tumor cell migration and leads to invasion and metastasis in the most aggressive and non-curable forms of papillary thyroid cancer.
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,发病率较高。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。2009年预计新增37 000例病例,反映出过去几十年甲状腺癌发病率不断上升。虽然大多数分化良好的甲状腺癌患者表现为有限的疾病,并在初始治疗后变得无病,但20%的甲状腺癌患者有局部或区域复发性疾病,5%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)的发生和进展以及甲状腺外延伸、淋巴结转移和远处转移有关。此外,它与放射性碘亲和力的丧失和癌症复发有关。这种突变诱导入侵和远距离传播的机制尚未完全了解。我们最近进行了一项详细的基因集富集分析,以分析有或没有这种BRAF突变的乳头状甲状腺癌患者的基因组特征。我们已经发现BRAFV 600 E突变导致几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。在此,我们证实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 V600 E突变的作用,以及BRAF诱导的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,以及甲状腺癌的新型临床前小鼠模型。我们还计划测试BRAFV 600 E特异性抑制剂的功效,并确定TSP-1和MMP是否可用作检测甲状腺癌侵袭性形式的诊断生物标志物以及评估对BRAF抑制剂的反应的治疗生物标志物。 公共卫生关系:BRAF突变在甲状腺癌侵袭中的作用分析BRAFV 600 E突变如何改变甲状腺肿瘤细胞迁移的关键分子,并导致最具侵袭性和不可治愈的甲状腺乳头状癌的侵袭和转移。

项目成果

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Sareh Parangi其他文献

Sareh Parangi的其他文献

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{{ truncateString('Sareh Parangi', 18)}}的其他基金

Adaptive immunotherapy of anaplastic thyroid cancer
甲状腺未分化癌的适应性免疫治疗
  • 批准号:
    9918263
  • 财政年份:
    2019
  • 资助金额:
    $ 32.1万
  • 项目类别:
The Role of BRAF Mutation in Thyroid Cancer Invasion
BRAF突变在甲状腺癌侵袭中的作用
  • 批准号:
    8804921
  • 财政年份:
    2011
  • 资助金额:
    $ 32.1万
  • 项目类别:
The Role of BRAF Mutation in Thyroid Cancer Invasion
BRAF突变在甲状腺癌侵袭中的作用
  • 批准号:
    8403763
  • 财政年份:
    2011
  • 资助金额:
    $ 32.1万
  • 项目类别:
The Role of BRAF Mutation in Thyroid Cancer Invasion
BRAF突变在甲状腺癌侵袭中的作用
  • 批准号:
    8596799
  • 财政年份:
    2011
  • 资助金额:
    $ 32.1万
  • 项目类别:
Antiangiogenic therapy of pancreatic cancer
胰腺癌的抗血管生成治疗
  • 批准号:
    6798657
  • 财政年份:
    2002
  • 资助金额:
    $ 32.1万
  • 项目类别:
Antiangiogenic therapy of pancreatic cancer
胰腺癌的抗血管生成治疗
  • 批准号:
    7115017
  • 财政年份:
    2002
  • 资助金额:
    $ 32.1万
  • 项目类别:
Antiangiogenic therapy of pancreatic cancer
胰腺癌的抗血管生成治疗
  • 批准号:
    6924633
  • 财政年份:
    2002
  • 资助金额:
    $ 32.1万
  • 项目类别:

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