Targeting the HGF/c-Met Pathway in Lung Cancer

靶向肺癌中的 HGF/c-Met 通路

基本信息

项目摘要

DESCRIPTION (provided by applicant): Hepatocyte growth factor (HGF) is an important paracrine mediator of growth, invasion, and angiogenesis in non-small cell lung cancer (NSCLC). We have previously shown that an elevated level of HGF in primary human lung tumor tissues is strongly associated with poor prognosis. HGF acts via its receptor c-Met, a tyrosine kinase receptor, to produce pro-tumorigenic responses. These functions of the HGF/c-Met pathway make it an excellent target for cancer therapeutics. We focused past research on functional actions of HGF/c-Met signaling. In the previous grant period, we demonstrated that the cyclooxygenase-2 (COX-2) pathway was activated in NSCLC cells by HGF. We further showed that HGF induced COX-2 protein via c- Met by activating MAPK and p38. Induction of COX-2 led to increased release of prostaglandin E2 (PGE2), a product of the COX-2 enzyme. We also demonstrated the ability of PGE2 to induce release of ligands for the epidermal growth factor receptor (EGFR) and to cause EGFR-dependent phosphorylation of c-Met, which was HGF-independent. PGE2 induced invasion in NSCLC, which was dependent upon an EGFR-c-Met cross- activation. Combined targeting of the HGF/c-Met and the COX-2 pathway led to maximum reduction in NSCLC invasion induced by HGF. Using a transgenic (TG) mouse that over-expresses human HGF in the airways, we further demonstrated in the last grant period that the increased susceptibility of this TG mouse strain to lung cancer induction by a tobacco carcinogen can be reversed by a neutralizing antibody (NA) to human HGF. Tumors resistant to the HGF NA exhibit a higher rate of K-ras mutation than observed in TG mice treated with an isotope-matched control antibody. This suggests ability to target the HGF/c-Met pathway therapeutically may be less effective in lung tumors with an activating K-ras mutation. In this renewal, we propose to examine the mechanism of signaling interaction between EGFR and c-Met that is initiated by PGE2 (Aim 1). We further propose to examine the extent to which biological effects of EGFR activation such as COX-2 activation, invasion, and wound healing are mediated by an EGFR-c-Met interaction, and whether c-Met and EGFR are co-expressed in human primary lung tumors (Aim 2). We will utilize the HGF TG mouse to determine if combined inhibition of HGF with inhibition of either COX-2 or EGFR results in increased anti-tumor effects, and if K-ras mutant tumors are resistant to these inhibitors (Aim 3). We will produce an immunocompromised mouse strain over-expressing human HGF in the lungs that will support orthotopic growth of human lung tumors. This model will allow pre-clinical study of HGF/c-Met inhibitors on growth of human lung tumors in the presence of elevated human HGF (Aim 4). Research in the pharmaceutical industry is ongoing to produce inhibitors of the HGF/c-Met pathway, which are either in pre-clinical or early Phase I clinical testing. Results from the new aims will provide a mechanistic rationale for the clinical use of inhibitors of the HGF/c-Met pathway alone or in combination with EGFR TKIs or COX-2 inhibitors in treatment of lung cancer. PUBLIC HEALTH RELEVANCE: Lung cancer kills more Americans every year than any other type of cancer. Lung cancer typically is diagnosed at a late stage and does not respond well to current treatments. This project will investigate a new pathway, the HGF/c-Met pathway that controls lung cancer growth. In this project we will test different mechanisms by which the HGF/c-Met pathway controls the activity of other growth-promoting proteins in lung cancer cells, in order to understand how to inhibit this pathway most effectively.
描述(由申请人提供):肝细胞生长因子(HGF)是非小细胞肺癌(NSCLC)生长,侵袭和血管生成的重要旁分泌介体。我们先前已经表明,原发性人肺肿瘤组织中HGF水平升高与预后不良密切相关。 HGF通过其受体C-MET(一种酪氨酸激酶受体)起作用,以产生促肿瘤反应。 HGF/C-MET途径的这些功能使其成为癌症治疗剂的绝佳目标。我们将过去的研究集中在HGF/C-MET信号传导的功能作用上。在上一个赠款期间,我们证明了HGF在NSCLC细胞中激活了环氧合酶-2(COX-2)途径。我们进一步表明,HGF通过激活MAPK和p38诱导了C-Met诱导COX-2蛋白。 COX-2的诱导导致前列腺素E2(PGE2)的释放增加,这是COX-2酶的产物。我们还证明了PGE2诱导表皮生长因子受体(EGFR)释放配体的能力,并引起C-MET的EGFR依赖性磷酸化的能力,C-MET是HGF独立的。 PGE2诱导NSCLC的侵袭,该侵袭取决于EGFR-C-MET跨激活。 HGF/C-MET和COX-2途径的联合靶向导致HGF诱导的NSCLC侵袭的最大降低。使用过表达气道中人类HGF的转基因(TG)小鼠,我们在最后一个批准期间进一步证明,这种TG小鼠菌株对烟草诱导的TG小鼠菌株的易感性增加,可以通过中和抗体(NA)对人HGF的中和抗体来逆转。在用同位素匹配的对照抗体处理的TG小鼠中,对HGF NA的肿瘤具有比观察到的K-RAS突变的速率更高。这表明在治疗上靶向HGF/C-MET途径的能力可能在激活K-RAS突变的肺肿瘤中效果较差。在此续约中,我们建议研究由PGE2启动的EGFR和C-MET之间信号相互作用的机制(AIM 1)。我们进一步提议研究EGFR激活(例如COX-2激活,侵袭和伤口愈合)的生物学作用的程度是由EGFR-C-C-MET相互作用介导的,以及C-MET和EGFR是否在人类原发性肺肿瘤中共表达(AIM 2)。我们将利用HGF TG小鼠来确定HGF是否合并抑制COX-2或EGFR会导致抗肿瘤作用增加,以及K-RAS突变肿瘤是否对这些抑制剂有抗性(AIM 3)。我们将在肺部产生过表达的人类HGF的免疫功能低下的小鼠菌株,以支持人类肺肿瘤的原位生长。该模型将允许在人类HGF升高的情况下对HGF/C-MET抑制剂对人肺肿瘤生长的临床研究(AIM 4)。制药行业的研究正在进行中,以产生HGF/C-MET途径的抑制剂,该途径在临床前或早期I期临床测试中。新目标的结果将提供一个机械原理,用于单独使用HGF/C-MET途径的抑制剂,或与EGFR TKIS或COX-2抑制剂结合使用肺癌治疗。公共卫生相关性:每年肺癌杀死的美国人比其他任何类型的癌症都多。肺癌通常在后期被诊断出,对当前治疗方法反应不佳。该项目将研究一种新的途径,即控制肺癌生长的HGF/C-MET途径。在该项目中,我们将测试HGF/C-MET途径控制肺癌细胞中其他促进生长蛋白的活性的不同机制,以了解如何最有效地抑制该途径。

项目成果

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Jill M Siegfried其他文献

Jill M Siegfried的其他文献

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{{ truncateString('Jill M Siegfried', 18)}}的其他基金

Role of hormone pathways in chemoprevention for high risk smokers
激素途径在高危吸烟者化学预防中的作用
  • 批准号:
    9117501
  • 财政年份:
    2015
  • 资助金额:
    $ 29.06万
  • 项目类别:
P1 - Intersection of Estrogen Receptor Signaling and EGF Receptor
P1 - 雌激素受体信号传导与 EGF 受体的交叉点
  • 批准号:
    8092830
  • 财政年份:
    2010
  • 资助金额:
    $ 29.06万
  • 项目类别:
P1 - Intersection of Estrogen Receptor Signaling & EGF Receptor
P1 - 雌激素受体信号传导的交叉点
  • 批准号:
    7843710
  • 财政年份:
    2009
  • 资助金额:
    $ 29.06万
  • 项目类别:
SPORE in Lung Cancer
肺癌中的孢子
  • 批准号:
    7914675
  • 财政年份:
    2009
  • 资助金额:
    $ 29.06万
  • 项目类别:
ADMINISTRATIVE CORE
行政核心
  • 批准号:
    7088500
  • 财政年份:
    2006
  • 资助金额:
    $ 29.06万
  • 项目类别:
INTERSECTION OF ESTROGEN RECEPTOR SIGNALING AND EPIDERMAL GROWTH FACTOR RECEPTOR
雌激素受体信号传导与表皮生长因子受体的交叉点
  • 批准号:
    7088489
  • 财政年份:
    2006
  • 资助金额:
    $ 29.06万
  • 项目类别:
Therapeutic Mechanisms of Co-Targeting of EGFR and Src Family Kinases
EGFR 和 Src 家族激酶联合靶向的治疗机制
  • 批准号:
    7893352
  • 财政年份:
    2004
  • 资助金额:
    $ 29.06万
  • 项目类别:
Therapeutic Mechanisms of Co-Targeting of EGFR and Src Family Kinases
EGFR 和 Src 家族激酶联合靶向的治疗机制
  • 批准号:
    8541589
  • 财政年份:
    2004
  • 资助金额:
    $ 29.06万
  • 项目类别:
TARGETING EGFR AND GPCR SIGNALING IN SCCHN
SCCHN 中靶向 EGFR 和 GPCR 信号传导
  • 批准号:
    6990399
  • 财政年份:
    2004
  • 资助金额:
    $ 29.06万
  • 项目类别:
Therapeutic Mechanisms of Co-Targeting of EGFR and Src Family Kinases
EGFR 和 Src 家族激酶联合靶向的治疗机制
  • 批准号:
    8380699
  • 财政年份:
    2004
  • 资助金额:
    $ 29.06万
  • 项目类别:

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