Molecular signatures of HNSCC in response to targeted therapies

HNSCC 响应靶向治疗的分子特征

基本信息

  • 批准号:
    7618198
  • 负责人:
  • 金额:
    $ 37.95万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-07-20 至 2012-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Histopathologically similar neoplasms often represent diverse disease processes driven by distinct oncogenic events and pathways. Recognition of such differences in driving pathways between tumors is clearly the key to improving the success rate of therapies targeting these pathways. Epidermal growth factor receptor (EGFR) expression has prognostic significance in patients with head and neck squamous cell carcinoma (HNSCC) and antibodies targeting this receptor have been demonstrated in the clinic to be active in a subset of HNSCC patients. EGFR is overexpressed in over 95% of HNSCC and recently a truncation mutation, EGFR variant III (EGFRvlll), was found in 42% of HNSCC. EGFRvlll is always found with the wild-type receptor in co-expression, perhaps reflecting heterogeneity in individual cells or within clones of cells within a tumor. This heterogeneity may underlie clinically important mechanisms of resistance to targeted cancer treatment. Because EGFRvlll is constitutively activated independent of ligand-binding, it is postulated to be a mechanism of resistance to cetuximab, which inhibits EGFR activation by blocking ligand binding. Based on these data, we hypothesize that; 1) EGFRvlll is oncogenic and associated with cetuximab resistance in HNSCC, 2) the presence of an activated EGFR gene expression signature will allow us to select HNSCC patients with an increased likelihood of response to EGFR inhibitors. Our first Aim is to determine the activated EGFR signature in a genetically well defined model system of HaCaT cells overexpressing EGFR and to characterize the oncogenic properties of EGFRvlll in HaCaT cells. We will also examine gene expression differences regulated by ligand-dependent or ligand-independent activation of EGFR in this model system. The second Aim is to determine the activated EGFR signature in HNSCC cell lines to test and refine the signature as a biomarker of clinical response to EGFR inhibitors. We will also determine novel genes/pathways that are co-regulated with activation and inhibition of EGFR pathways to identify the off-target effect of cetuximab, mechanism of resistance and generate a rationale for combination therapy with current EGFR inhibitors. Our third aim is to determine presence of the activated EGFR signature generated from HaCaT cells and HNSCC cell lines and the EGFRvlll mutation as biomarkers of clinical response in HNSCC patients treated with cetuximab monotherapy. Ultimately, we expect that the findings from this study will be translated into improved patient selection and optimized treatment benefits from EGFR inhibitors in HNSCC patients.
描述(由申请方提供):组织学相似的肿瘤通常代表由不同致癌事件和途径驱动的不同疾病过程。认识到肿瘤之间驱动途径的这种差异显然是提高靶向这些途径的治疗成功率的关键。表皮生长因子受体(EGFR)表达在头颈部鳞状细胞癌(HNSCC)患者中具有预后意义,并且靶向该受体的抗体已在临床中被证明在HNSCC患者的亚组中具有活性。EGFR在超过95%的HNSCC中过表达,并且最近在42%的HNSCC中发现了截短突变EGFR变体III(EGFRvIII)。EGFRvIII总是与野生型受体共表达,这可能反映了单个细胞或肿瘤内细胞克隆内的异质性。这种异质性可能是临床上重要的靶向癌症治疗耐药机制的基础。因为EGFRvIII是不依赖于配体结合的组成型活化的,所以假定其是对西妥昔单抗的抗性机制,西妥昔单抗通过阻断配体结合来抑制EGFR活化。基于这些数据,我们假设:1)EGFRvIII是致癌的并且与HNSCC中的西妥昔单抗抗性相关,2)活化的EGFR基因表达特征的存在将允许我们选择对EGFR抑制剂具有增加的响应可能性的HNSCC患者。我们的第一个目的是确定在过表达EGFR的HaCaT细胞的遗传上明确定义的模型系统中活化的EGFR特征,并表征HaCaT细胞中EGFRvIII的致癌特性。我们还将研究在该模型系统中EGFR的配体依赖性或配体非依赖性激活调节的基因表达差异。第二个目的是确定HNSCC细胞系中活化的EGFR特征,以测试和改进作为EGFR抑制剂临床应答的生物标志物的特征。我们还将确定与EGFR通路的激活和抑制共调节的新基因/通路,以确定西妥昔单抗的脱靶效应、耐药机制,并为与当前EGFR抑制剂的联合治疗提供依据。我们的第三个目的是确定由HaCaT细胞和HNSCC细胞系产生的活化的EGFR标签和EGFRvIII突变的存在,作为用西妥昔单抗单一疗法治疗的HNSCC患者中临床应答的生物标志物。最终,我们预计这项研究的结果将转化为改善患者选择和优化EGFR抑制剂在HNSCC患者中的治疗获益。

项目成果

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CHRISTINE H CHUNG其他文献

CHRISTINE H CHUNG的其他文献

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{{ truncateString('CHRISTINE H CHUNG', 18)}}的其他基金

Decoding tobacco-related oral cancer ecosystem by integrative approach
通过综合方法解码烟草相关口腔癌生态系统
  • 批准号:
    10733337
  • 财政年份:
    2022
  • 资助金额:
    $ 37.95万
  • 项目类别:
Decoding tobacco-related oral cancer ecosystem by integrative approach
通过综合方法解码烟草相关口腔癌生态系统
  • 批准号:
    10677015
  • 财政年份:
    2022
  • 资助金额:
    $ 37.95万
  • 项目类别:
Decoding tobacco-related oral cancer ecosystem by integrative approach
通过综合方法解码烟草相关口腔癌生态系统
  • 批准号:
    10478213
  • 财政年份:
    2021
  • 资助金额:
    $ 37.95万
  • 项目类别:
Decoding tobacco-related oral cancer ecosystem by integrative approach
通过综合方法解码烟草相关口腔癌生态系统
  • 批准号:
    10367057
  • 财政年份:
    2021
  • 资助金额:
    $ 37.95万
  • 项目类别:
Smad4-independent TGF-b signaling in p16-negative HNSCC
p16 阴性 HNSCC 中不依赖 Smad4 的 TGF-b 信号传导
  • 批准号:
    8700647
  • 财政年份:
    2014
  • 资助金额:
    $ 37.95万
  • 项目类别:
Integrated Translational Genoproteomics Center at Washington University
华盛顿大学综合转化基因蛋白质组学中心
  • 批准号:
    8845178
  • 财政年份:
    2014
  • 资助金额:
    $ 37.95万
  • 项目类别:
Smad4-independent TGF-b signaling in p16-negative HNSCC
p16 阴性 HNSCC 中不依赖 Smad4 的 TGF-b 信号传导
  • 批准号:
    8889662
  • 财政年份:
    2014
  • 资助金额:
    $ 37.95万
  • 项目类别:
Integrated Translational Genoproteomics Center at Washington University
华盛顿大学综合转化基因蛋白质组学中心
  • 批准号:
    8605709
  • 财政年份:
    2014
  • 资助金额:
    $ 37.95万
  • 项目类别:
Integrated Translational Genoproteomics Center at Washington University
华盛顿大学综合转化基因蛋白质组学中心
  • 批准号:
    9036857
  • 财政年份:
    2014
  • 资助金额:
    $ 37.95万
  • 项目类别:
Molecular signatures of HNSCC in response to targeted therapies
HNSCC 响应靶向治疗的分子特征
  • 批准号:
    8204526
  • 财政年份:
    2007
  • 资助金额:
    $ 37.95万
  • 项目类别:

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