Notch-1 and IGF-1 crosstalk: new therapeutic strategies for NSCLC

Notch-1 和 IGF-1 串扰:NSCLC 的新治疗策略

基本信息

  • 批准号:
    8456065
  • 负责人:
  • 金额:
    $ 28.29万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-06-11 至 2015-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer related deaths in the USA. The most frequent form of lung cancer is non small cell lung cancer (NSCLC). Among the three major histological types of NSCLC, adenocarcinoma of the lung (ACL) is the most prevalent, and its incidence is steadily raising. ACL is relatively common (from 15 to 20% of cases) in people who have never smoked, therefore ACL will remain a major health problem even after cigarette smoking eradication. ACL is normally diagnosed at advanced stages because early detection methods remain problematic. Median survival after advanced ACL diagnosis is only 5 months, and chemotherapy only slightly improves it. It is therefore imperative to find novel therapeutic strategies to treat this deadly disease. Our preliminary data indicate that the evolutionarily conserved Notch-1 receptor provides critical survival signals to ACL cells in hypoxia, a condition that best recapitulates ACL microenvironment. Hypoxic conditions are those that interfere with standard chemotherapy and favor the preservation of niches for cancer stem cells. Therefore, targeting a signaling pathway that favor survival of cancer cells in hypoxia represents a particularly promising therapeutic strategy for the treatment of ACL. To be activated, Notch-1 requires a number of proteolitic cleavages, including the participation of a ?-secretase. Since this protein also participates in the accumulation of ¿-amyloid in Alzheimer's Disease, a great effort has been spent to synthesize specific small molecules that inhibit ?-secretase (?-secretase inhibitors or GSI). Therefore, GSI are indirect inhibitors of Notch signaling because, in the absence of the activating proteolitic cleavage catalyzed by ?-secretase, Notch-1 (as well as other Notch receptors) cannot translocate in the nucleus and affect transcription. We used as GSI a compound developed by Merck (MRK-003). This compound proved very efficient in killing ACL cells specifically under hypoxia. Our hypothesis is that Notch-1 provides survival signals to ACL cells mediating an intricate network of signaling pathways that includes PTEN, STAT, IGF-1, IGF-1R, Akt and its downstream targets. We also hypothesize that targeting Notch signaling in vivo is a valid therapeutic strategy for the treatment of ACL. We want to verify our hypotheses according to the following Specific Aims: (1) Verify whether there is interplay and a positive feedback loop between Notch-1 and the IGF-1 signaling pathway and what are the biological consequences of such interaction in hypoxia. (2) Study the molecular mechanisms through which hypoxia strengthen Notch-1 signaling and how Notch-1 protects ACL cells from apoptosis specifically under hypoxia. We will focus on Notch-1 regulation of PTEN and the PI3 kinase/PDK-1/Akt/mTOR axis. (3) Verify the therapeutic efficacy of MRK-003, alone or in combination with cisplatin, or with an inhibitory antibody for the IGF-1R (MK-0646), or with an Akt specific inhibitor (MK-2206) in a mouse preclinical model of advanced ACL. We will use cisplatin in combination with MRK-003 to simultaneously target non-hypoxic and hypoxic tumor areas. MK-0646 and MK-2206 will be also used in separate experiments because these compounds may have synergistic effects with MRK-003 because of our preliminary results sustaining Aims 1 and 2. We will dissect the contribution of Notch inhibition mechanistically using ACL cell lines in which we can artificially downregulate Notch-1. The results obtained in Aim 1 and 2 will be verified in vivo in the mouse model and in human clinical samples. The outcome of the research proposed here will provide a better understanding of the molecular processes that contribute to the maintenance of the malignant phenotype in ACL. Furthermore, the study will test the clinical usefulness of targeting Notch signaling to treat NSCLC using GSI. Finally, these experiments will elucidate the role of Notch-1 in lung tumorigenicity in vitro and in vivo.
描述(由申请人提供): 肺癌是美国癌症相关死亡的主要原因,最常见的肺癌类型是非小细胞肺癌 (NSCLC),其中非小细胞肺癌是腺癌。肺癌 (ACL) 是最常见的,并且其发病率在从未吸烟的人群中相对常见(占病例的 15% 至 20%),因此 ACL 仍将是一个主要的健康问题。即使在根除吸烟后,ACL 通常也会在晚期被诊断出来,因为晚期 ACL 诊断后的中位生存期仍然只有 5 个月,因此必须找到新的治疗策略来治疗这种情况。我们的初步数据表明,进化上保守的 Notch-1 受体在缺氧条件下向 ACL 细胞提供关键的生存信号,这是最能概括 ACL 微环境的条件。缺氧条件会干扰标准化疗并有利于保存。因此,针对有利于癌细胞在缺氧条件下存活的信号通路代表了治疗 ACL 的一种特别有前景的治疗策略,Notch-1 需要许多蛋白水解酶的参与才能被激活。因为该蛋白质也参与 ¿ 的积累。阿尔茨海默病中的β-淀粉样蛋白,已经花费了很大的努力来合成抑制β-分泌酶的特定小分子(β-分泌酶抑制剂或GSI),因此,GSI是Notch信号传导的间接抑制剂,因为在缺乏激活的蛋白水解酶的情况下。在β-分泌酶的催化下,Notch-1(以及其他Notch受体)不能在细胞核中易位并影响转录。我们使用默克公司开发的一种化合物作为GSI。 (MRK-003)。事实证明,这种化合物在缺氧条件下能够非常有效地杀死 ACL 细胞。我们的假设是,Notch-1 向 ACL 细胞提供存活信号,介导包括 PTEN、STAT、IGF-1、IGF 在内的复杂信号通路网络。 -1R、Akt 及其下游靶标。我们还认为体内靶向 Notch 信号是治疗 ACL 的有效治疗策略,我们希望根据以下具体目标验证我们的假设:(1)验证是否存在。 Notch-1 和 IGF-1 信号通路之间的相互作用和正反馈循环以及缺氧时这种相互作用的生物学后果是什么 (2) 研究缺氧增强 Notch-1 信号传导的分子机制以及 Notch-1 如何发挥作用。特别是在缺氧下保护ACL细胞免于凋亡。我们将重点关注Notch-1对PTEN和PI3激酶/PDK-1/Akt/mTOR轴的调节(3)验证其治疗效果。我们将在小鼠晚期 ACL 的临床前模型中单独使用 MRK-003,或与顺铂、IGF-1R 抑制性抗体 (MK-0646) 或 Akt 特异性抑制剂 (MK-2206) 联合使用。顺铂与 MRK-003 联合使用,同时靶向非缺氧和缺氧肿瘤区域。也将用于单独的实验中,因为我们的初步结果维持了目标 1 和 2,这些化合物可能与 MRK-003 具有协同作用。我们将使用 ACL 细胞系从机制上剖析 Notch 抑制的贡献,在该细胞系中我们可以人为下调 Notch- 1. 目标 1 和 2 中获得的结果将在小鼠模型和人类临床样本中进行体内验证。此处提出的研究结果将提供对分子过程的更好理解。此外,该研究将测试使用 GSI 靶向 Notch 信号传导治疗 NSCLC 的临床有效性,最后,这些实验将阐明 Notch-1 在体外和体内肺部致瘤性中的作用。 。

项目成果

期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Notch signaling in lung cancer.
Depletion of Amyloid Precursor Protein (APP) causes G0 arrest in non-small cell lung cancer (NSCLC) cells.
  • DOI:
    10.1002/jcp.24875
  • 发表时间:
    2015-06
  • 期刊:
  • 影响因子:
    5.6
  • 作者:
    Sobol, Anna;Galluzzo, Paola;Weber, Megan J.;Alani, Sara;Bocchetta, Maurizio
  • 通讯作者:
    Bocchetta, Maurizio
Amyloid precursor protein (APP) affects global protein synthesis in dividing human cells.
  • DOI:
    10.1002/jcp.24835
  • 发表时间:
    2015-05
  • 期刊:
  • 影响因子:
    5.6
  • 作者:
    Sobol, Anna;Galluzzo, Paola;Liang, Shuang;Rambo, Brittany;Skucha, Sylvia;Weber, Megan J.;Alani, Sara;Bocchetta, Maurizio
  • 通讯作者:
    Bocchetta, Maurizio
Deubiquitinase OTUD6B Isoforms Are Important Regulators of Growth and Proliferation.
  • DOI:
    10.1158/1541-7786.mcr-16-0281-t
  • 发表时间:
    2017-02
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Sobol A;Askonas C;Alani S;Weber MJ;Ananthanarayanan V;Osipo C;Bocchetta M
  • 通讯作者:
    Bocchetta M
Multimodality Approaches to Treat Hypoxic Non-Small Cell Lung Cancer (NSCLC) Microenvironment.
  • DOI:
    10.1177/1947601912457025
  • 发表时间:
    2012-02-01
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Liang, Shuang;Galluzzo, Paola;Bocchetta, Maurizio
  • 通讯作者:
    Bocchetta, Maurizio
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MAURIZIO BOCCHETTA其他文献

MAURIZIO BOCCHETTA的其他文献

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{{ truncateString('MAURIZIO BOCCHETTA', 18)}}的其他基金

Notch-1 and IGF-1 crosstalk: new therapeutic strategies for NSCLC
Notch-1 和 IGF-1 串扰:NSCLC 的新治疗策略
  • 批准号:
    7741951
  • 财政年份:
    2009
  • 资助金额:
    $ 28.29万
  • 项目类别:
Notch-1 and IGF-1 crosstalk: new therapeutic strategies for NSCLC
Notch-1 和 IGF-1 串扰:NSCLC 的新治疗策略
  • 批准号:
    8256620
  • 财政年份:
    2009
  • 资助金额:
    $ 28.29万
  • 项目类别:
Notch-1 and IGF-1 crosstalk: new therapeutic strategies for NSCLC
Notch-1 和 IGF-1 串扰:NSCLC 的新治疗策略
  • 批准号:
    8062295
  • 财政年份:
    2009
  • 资助金额:
    $ 28.29万
  • 项目类别:
Selection of chemical inhibitors of oncoproteins
癌蛋白化学抑制剂的选择
  • 批准号:
    6334014
  • 财政年份:
    2001
  • 资助金额:
    $ 28.29万
  • 项目类别:
Selection of chemical inhibitors of oncoproteins
癌蛋白化学抑制剂的选择
  • 批准号:
    6515050
  • 财政年份:
    2001
  • 资助金额:
    $ 28.29万
  • 项目类别:

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针对 T-ALL 的有氧糖酵解
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