Kinase Target of Diverse Cell Surface Receptors in Cancer Invasion and Metastasis

癌症侵袭和转移中多种细胞表面受体的激酶靶点

基本信息

  • 批准号:
    8458615
  • 负责人:
  • 金额:
    $ 30.22万
  • 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:
    2011-07-21 至 2016-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Activation of an invasive program is a critical event in the multi-step process of tumor metastasis driven by the activation of tyrosine kinases and ligand-stimulated chemokine receptors. We now show that the Abl family of nonreceptor tyrosine kinases, Abl (Abl1) and Arg (Abl2), which are activated downstream of multiple receptor tyrosine kinases (RTKs), are also activated by chemokine receptors and play a critical role in the regulation of cancer cell invasion. We show that Abl kinases are required for epithelial cancer cell invasion and matrix degradation and identify a novel signaling pathway that links the Abl kinases to the regulation of the matrix metalloproteinase MT1-MMP in breast cancer cells. Moreover, we found that endogenous Abl kinases are hyperactivated in a subset of breast cancer cell lines that are negative for Her2 and hormone receptors. Further, expression of activated Abl kinases elicits a striking disruption of epithelial cell polarity which is associated with cancer progression. Based on these findings, we hypothesize that Abl kinases are required for metastasis of a subset of epithelial tumors through regulation of invasive programs and thus combination therapies that target inhibition of Abl kinases might be exploited for the treatment of a subset of invasive breast tumors. To this end we propose the following aims: 1) Identify the phosphoproteomic signature for activated Abl kinases in human breast cancer cells. Knowledge of the molecular signature induced by activated Abl kinases in breast tumors will allow for identification of patients that might benefit from targeted therapy with approved and novel Abl kinase inhibitors; 2) Elucidate the mechanisms employed by Abl kinases to regulate breast cancer cell invasion; and 3) Define the role of Abl kinases in mammary tumor progression and metastasis using mouse models. Together these aims will uncover Abl-dependent signaling networks that regulate invasive programs that drive cancer tumor progression and metastasis. The long-term goal of these studies is to develop novel therapeutic approaches with greater specificity and reduced toxicity than those provided by current therapies for the treatment of specific tumor subtypes. Inhibition of the Abl kinases is expected to simultaneously block multiple signaling pathways required for tumor invasion that converge on the activation of these unique kinases.
描述(由申请人提供):侵入性程序的激活是由酪氨酸激酶和配体刺激的趋化因子受体激活驱动的肿瘤转移多步骤过程中的关键事件。我们现在表明,Abl家族的非受体酪氨酸激酶,Abl(RK 1)和Arg(RK 2),这是激活下游的多个受体酪氨酸激酶(RTK),也被激活的趋化因子受体,并在调节癌细胞的侵袭发挥了关键作用。我们发现,Abl激酶是上皮癌细胞的侵袭和基质降解所必需的,并确定了一种新的信号通路,将Abl激酶与乳腺癌细胞中基质金属蛋白酶MT 1-MMP的调节联系起来。此外,我们发现内源性Abl激酶在Her 2和激素受体阴性的乳腺癌细胞系亚群中被过度激活。此外,活化的Abl激酶的表达引起与癌症进展相关的上皮细胞极性的显著破坏。基于这些发现,我们假设Abl激酶是通过调节侵袭性程序转移上皮肿瘤亚组所必需的,因此靶向抑制Abl激酶的联合疗法可能用于治疗侵袭性乳腺肿瘤亚组。为此,我们提出了以下目标:1)鉴定人乳腺癌细胞中激活的Abl激酶的磷酸化蛋白质组学特征。乳腺肿瘤中激活的Abl激酶诱导的分子特征的知识将允许鉴定可能受益于使用批准的和新型Abl激酶抑制剂的靶向治疗的患者; 2)阐明Abl激酶用于调节乳腺癌细胞侵袭的机制;和3)使用小鼠模型定义Abl激酶在乳腺肿瘤进展和转移中的作用。这些目标将共同揭示调节驱动癌症肿瘤进展和转移的侵入性程序的依赖于信号传导网络。这些研究的长期目标是开发新的治疗方法,与目前治疗特定肿瘤亚型的方法相比,具有更高的特异性和更低的毒性。预期Abl激酶的抑制同时阻断肿瘤侵袭所需的多个信号传导途径,所述信号传导途径集中于这些独特激酶的活化。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)

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Ann Marie Pendergast其他文献

Ann Marie Pendergast的其他文献

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{{ truncateString('Ann Marie Pendergast', 18)}}的其他基金

Targeting tumor-neural cell interactions to inhibit lung cancer brain metastasis
靶向肿瘤-神经细胞相互作用抑制肺癌脑转移
  • 批准号:
    10164550
  • 财政年份:
    2021
  • 资助金额:
    $ 30.22万
  • 项目类别:
Targeting tumor-neural cell interactions to inhibit lung cancer brain metastasis
靶向肿瘤-神经细胞相互作用抑制肺癌脑转移
  • 批准号:
    10581652
  • 财政年份:
    2021
  • 资助金额:
    $ 30.22万
  • 项目类别:
Targeting tumor-neural cell interactions to inhibit lung cancer brain metastasis
靶向肿瘤-神经细胞相互作用抑制肺癌脑转移
  • 批准号:
    10366021
  • 财政年份:
    2021
  • 资助金额:
    $ 30.22万
  • 项目类别:
Targeting ABL kinases to regulate epithelial cell plasticity and regeneration following injury
靶向 ABL 激酶调节损伤后上皮细胞可塑性和再生
  • 批准号:
    10666351
  • 财政年份:
    2020
  • 资助金额:
    $ 30.22万
  • 项目类别:
Targeting ABL kinases to regulate epithelial cell plasticity and regeneration following injury
靶向 ABL 激酶调节损伤后上皮细胞可塑性和再生
  • 批准号:
    10396637
  • 财政年份:
    2020
  • 资助金额:
    $ 30.22万
  • 项目类别:
Novel target for therapy refractory lung tumors
治疗难治性肺部肿瘤的新靶点
  • 批准号:
    9269186
  • 财政年份:
    2015
  • 资助金额:
    $ 30.22万
  • 项目类别:
Novel target for therapy refractory lung tumors
治疗难治性肺部肿瘤的新靶点
  • 批准号:
    9065535
  • 财政年份:
    2015
  • 资助金额:
    $ 30.22万
  • 项目类别:
Novel target for therapy refractory lung tumors
治疗难治性肺部肿瘤的新靶点
  • 批准号:
    8882940
  • 财政年份:
    2015
  • 资助金额:
    $ 30.22万
  • 项目类别:
Kinase Target of Diverse Cell Surface Receptors in Cancer Invasion and Metastasis
癌症侵袭和转移中多种细胞表面受体的激酶靶点
  • 批准号:
    8657899
  • 财政年份:
    2011
  • 资助金额:
    $ 30.22万
  • 项目类别:
Kinase Target of Diverse Cell Surface Receptors in Cancer Invasion and Metastasis
癌症侵袭和转移中多种细胞表面受体的激酶靶点
  • 批准号:
    8199099
  • 财政年份:
    2011
  • 资助金额:
    $ 30.22万
  • 项目类别:

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由两类细菌肌动蛋白 MreB 驱动的新型运动系统
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