Markers of sensivity to the EGFR inhibitor erlotinib in breast cancer

乳腺癌中 EGFR 抑制剂厄洛替尼敏感的标志物

基本信息

  • 批准号:
    7252750
  • 负责人:
  • 金额:
    $ 29.26万
  • 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:
    2007-07-05 至 2012-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The epidermal growth factor receptor (EGFR) signaling pathway is a central regulator of cell growth and proliferation and modulates critical cell cycle regulatory molecules. This pathway has emerged as a promising target for cancer therapy. EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib (Tarceva) and gefitinib (Iressa), are approved for cancer treatment but have induced a clinical response in only a subgroup of patients. Therefore, EGFR-TKI's molecular mechanism of action needs to be better understood. My long-term goal is to elucidate the molecular mechanism of action of EGFR-TKI so that novel therapeutic approaches or diagnostic tools that are clinically relevant can be developed. I have recently shown that in vitro erlotinib sensitivity is partially dependent on the activity of cyclin-dependent kinase 2 (Cdk2), which is the most downstream kinase of the EGFR pathway that regulates the transition from the G1 phase to the S phase. The objective of this application is to determine which downstream molecules of the EGFR and non-EGFR signaling pathway predict the response to EGFR-TKIs. The central hypothesis of this proposal is that the effect of Cdk2 activity on EGFR-TKI-mediated cytotoxicity is regulated by downstream molecules of the cell signaling pathway, specifically ERK, p27, and PEA15. This hypothesis is based on the following observations. First, erlotinib inhibits the tyrosine kinase of EGFR in both erlotinib-sensitive and erlotinib-resistant breast cancer cells; however, erlotinib inhibits Cdk2 activity only in sensitive cells. These findings indicate that there is an abnormality in the EGFR signaling pathway in erlotinib-resistant cells. Second, phosphorylated ERK is downregulated and p27 is upregulated in erlotinib-sensitive cells, and the phosphorylation status of p27 affects its nuclear-cytoplasmic localization and expression level. Third, PEA15 sequesters ERK into the cytoplasm from the nucleus and reduces cell proliferation. I have designed three independent but interrelated specific aims to provide a comprehensive assessment of the downstream EGFR and non-EGFR signaling pathway in breast cancer cells treated with EGFR-TKI. Specific Aim 1. Establish how erlotinib regulates p27 to suppress Cdk2 activity in vitro. Specific Aim 2. Establish how PEA15 modulates erlotinib sensitivity in vitro and in vivo. Specific Aim 3. Establish in vivo biomarkers that predict erlotinib sensitivity. Relevance: This study will provide significant insight into the role of downstream molecules affected by EGFR-TKI. Our findings will improve the outcome of cancer patients by increasing EGFR-TKI efficacy and facilitating the selection of patients who may benefit from EGFR-TKI therapy.
描述(由申请人提供):表皮生长因子受体(EGFR)信号通路是细胞生长和增殖的中心调节因子,并调节关键的细胞周期调节分子。该途径已成为癌症治疗的一个有前途的靶点。EGFR酪氨酸激酶抑制剂(TKI),如厄洛替尼(Tarceva)和吉非替尼(Iressa),被批准用于癌症治疗,但仅在一个亚组的患者中诱导临床反应。因此,需要更好地了解EGFR-TKI的分子作用机制。我的长期目标是阐明EGFR-TKI作用的分子机制,以便开发临床相关的新治疗方法或诊断工具。我最近发现,体外厄洛替尼敏感性部分依赖于细胞周期蛋白依赖性激酶2(Cdk 2)的活性,Cdk 2是EGFR途径的最下游激酶,调节从G1期到S期的转变。本申请的目的是确定EGFR和非EGFR信号通路的哪些下游分子预测对EGFR-TKI的应答。该提议的中心假设是Cdk 2活性对EGFR-TKI介导的细胞毒性的影响受细胞信号传导途径的下游分子,特别是ERK、p27和PEA 15的调节。这一假设基于以下观察。首先,厄洛替尼在厄洛替尼敏感和厄洛替尼耐药乳腺癌细胞中抑制EGFR的酪氨酸激酶;然而,厄洛替尼仅在敏感细胞中抑制Cdk 2活性。这些发现表明,在厄洛替尼耐药细胞中EGFR信号通路存在异常。其次,在厄洛替尼敏感细胞中,磷酸化ERK下调,p27上调,p27的磷酸化状态影响其核质定位和表达水平。第三,PEA 15将ERK从细胞核隔离到细胞质中并减少细胞增殖。我设计了三个独立但相互关联的具体目标,以全面评估EGFR-TKI治疗的乳腺癌细胞中下游EGFR和非EGFR信号通路。具体目标1。确定厄洛替尼如何在体外调节p27以抑制Cdk 2活性。具体目标2。确定PEA 15如何在体外和体内调节厄洛替尼敏感性。具体目标3。建立预测厄洛替尼敏感性的体内生物标志物。相关性:本研究将为EGFR-TKI影响的下游分子的作用提供重要见解。我们的研究结果将通过增加EGFR-TKI疗效和促进选择可能受益于EGFR-TKI治疗的患者来改善癌症患者的结局。

项目成果

期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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Naoto T Ueno其他文献

Navigating the androgen receptor landscape in triple-negative breast cancer
在三阴性乳腺癌中探索雄激素受体领域
  • DOI:
    10.1016/s1470-2045(25)00029-4
  • 发表时间:
    2025-03-01
  • 期刊:
  • 影响因子:
    35.900
  • 作者:
    Nithya Sridhar;Naoto T Ueno
  • 通讯作者:
    Naoto T Ueno
Clinical outcomes after 1 versus 2-3 lines of neoadjuvant therapy in stage III inflammatory breast cancer.
III 期炎性乳腺癌 1 线与 2-3 线新辅助治疗后的临床结果。
  • DOI:
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    3.8
  • 作者:
    F. Nakhlis;Samuel M. Niman;Naoto T Ueno;Elizabeth Troll;Sean J. Ryan;E. Yeh;Laura Warren;J. Bellon;Beth Harrison;T. Iwase;H. T. Carisa Le;S. Saleem;M. Teshome;Gary J. Whitman;Wendy A Woodward;Beth Overmoyer;S. Tolaney;M. Regan;F. Lynce;R. Layman
  • 通讯作者:
    R. Layman

Naoto T Ueno的其他文献

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{{ truncateString('Naoto T Ueno', 18)}}的其他基金

University of Hawaii Cancer Center CCSG
夏威夷大学癌症中心 CCSG
  • 批准号:
    10837568
  • 财政年份:
    2023
  • 资助金额:
    $ 29.26万
  • 项目类别:
Developing a novel combination immunotherapy for triple-negative breast cancer
开发针对三阴性乳腺癌的新型联合免疫疗法
  • 批准号:
    10734197
  • 财政年份:
    2023
  • 资助金额:
    $ 29.26万
  • 项目类别:
Development of a novel therapy targeting the tumor microenvironment in inflammatory breast cancer
开发针对炎性乳腺癌肿瘤微环境的新疗法
  • 批准号:
    10836263
  • 财政年份:
    2022
  • 资助金额:
    $ 29.26万
  • 项目类别:
Development of a novel therapy targeting the tumor microenvironment in inflammatory breast cancer
开发针对炎性乳腺癌肿瘤微环境的新疗法
  • 批准号:
    10390676
  • 财政年份:
    2022
  • 资助金额:
    $ 29.26万
  • 项目类别:
Development of PEA 15 as a Targeted Therapeutic Gene for Ovarian Cancer
开发 PEA 15 作为卵巢癌靶向治疗基因
  • 批准号:
    8146139
  • 财政年份:
    2007
  • 资助金额:
    $ 29.26万
  • 项目类别:
Markers of sensivity to the EGFR inhibitor erlotinib in breast cancer
乳腺癌中 EGFR 抑制剂厄洛替尼敏感的标志物
  • 批准号:
    8265321
  • 财政年份:
    2007
  • 资助金额:
    $ 29.26万
  • 项目类别:
Markers of sensivity to the EGFR inhibitor erlotinib in breast cancer
乳腺癌中 EGFR 抑制剂厄洛替尼敏感的标志物
  • 批准号:
    7630446
  • 财政年份:
    2007
  • 资助金额:
    $ 29.26万
  • 项目类别:
Development of PEA 15 as a Targeted Therapeutic Gene for Ovarian Cancer
开发 PEA 15 作为卵巢癌靶向治疗基因
  • 批准号:
    7500877
  • 财政年份:
    2007
  • 资助金额:
    $ 29.26万
  • 项目类别:
Markers of sensivity to the EGFR inhibitor erlotinib in breast cancer
乳腺癌中 EGFR 抑制剂厄洛替尼敏感的标志物
  • 批准号:
    7462422
  • 财政年份:
    2007
  • 资助金额:
    $ 29.26万
  • 项目类别:
Development of PEA 15 as a Targeted Therapeutic Gene for Ovarian Cancer
开发 PEA 15 作为卵巢癌靶向治疗基因
  • 批准号:
    7894611
  • 财政年份:
    2007
  • 资助金额:
    $ 29.26万
  • 项目类别:

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