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：
MAURIZIO BOCCHETTA
金额：
$ 28.29万
依托单位：
LOYOLA UNIVERSITY CHICAGO
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

来源：
https://reporter.nih.gov/project-details/8456065
关键词：
1-Phosphatidylinositol 3-Kinase Acute T Cell Leukemia Affect Alzheimer&apos s Disease Amyloid Antibodies Antineoplastic Agents Apoptosis Area Biological Biological Preservation Breast Cancer Cell Cancer Biology Cancer Etiology Cell Death Cell Line Cell Nucleus Cells Cessation of life Chemicals Cisplatin Clinic Clinical Clinical Trials Data Development Diagnosis Disease Doctor of Philosophy Early Diagnosis Family Feedback Genetic Transcription Health Human Hypoxia In Vitro Incidence Insulin-Like Growth Factor I Life Life Expectancy Link Lung Lung Adenocarcinoma Maintenance Malignant Neoplasms Malignant neoplasm of cervix uteri Malignant neoplasm of lung Mediating Methods Molecular Mus Non-Small-Cell Lung Carcinoma Outcomes Research PTEN gene Pathway interactions Patients Pharmaceutical Preparations Phosphoric Monoester Hydrolases Positive Reinforcements Pre-Clinical Model Process Proteins Refractory Regulation Repression Role Sampling Second Messenger Systems Signal Pathway Signal Transduction Smoke Specific qualifier value Staging Stem cells Testing Therapeutic Treatment Efficacy Tumorigenicity cancer cell cancer stem cell chemotherapy cigarette smoking genetic manipulation human FRAP1 protein improved in vivo inhibitor/antagonist killings malignant phenotype mouse model notch protein novel therapeutics presenilin receptor research study screening second messenger secretase small molecule stem therapeutic target treatment strategy tumor tumor microenvironment

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（由适用提供）：肺癌是美国与癌症有关的主要原因。肺癌最常见的形式是非小细胞肺癌（NSCLC）。在NSCLC的三种主要组织学类型中，肺腺癌（ACL）最为普遍，其发病率正在悄然增加。在从未抽烟的人中，ACL相对普遍（从15％到20％），因此，即使在吸烟放疗后，ACL仍将仍然是一个主要的健康问题。通常在高级阶段诊断ACL，因为早期检测方法仍然有问题。晚期ACL诊断后的中位生存期仅为5个月，化学疗法仅略有改善。因此，必须找到治疗这种致命疾病的新型治疗策略。我们的初步数据表明，进化上构成Notch-1受体为缺氧的ACL细胞提供了关键的生存信号，这种情况最能概括ACL微环境。低氧条件是干扰标准化疗并有利于保护癌症干细胞的壁ni的条件。因此，靶向有利于癌细胞在缺氧中存活的信号通路代表了一种特别有前途的ACL治疗策略。为了被激活，Notch-1需要许多蛋白质裂解，包括参与？ - 分泌酶。由于该蛋白还参与了阿尔茨海默氏病中–淀粉样蛋白的积累，因此花了巨大的努力来综合抑制？ - 分泌酶（ - 分泌酶抑制剂或GSI）的特定小分子。因此，GSI是Notch信号传导的间接抑制剂，因为在没有？ - 分泌酶催化的激活蛋白裂解的情况下，Notch-1（以及其他Notch受体）无法在细胞核中转移并影响转录。我们用作默克（MRK-003）开发的GSI A化合物。该化合物证明在特异性下在缺氧下杀死ACL细胞非常有效。我们的假设是，Notch-1为介导包括PTEN，STAT，IGF-1，IGF-1R，IGF-1R，AKT及其下游靶标的复杂信号通路网络的ACL细胞提供了生存信号。我们还假设在体内靶向Notch信号传导是ACL治疗的有效疗法策略。我们希望根据以下特定目的验证我们的假设：（1）验证Notch-1和IGF-1信号通路之间是否存在相互作用和正反馈回路，以及这种相互作用在低氧中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如何保护ACL细胞在缺氧下特别保护凋亡。我们将专注于PTEN和PI3激酶/PDK-1/AKT/MTOR轴的Notch-1调节。（3）单独或与顺铂或与IGF-1R的抑制抗体（MK-0646）或AKT特异性抑制剂（MK-2206）中的抑制性抗体（MK-2206）中验证MRK-003的治疗效率。我们将与MRK-003结合使用顺铂，以同时靶向非催眠和低氧肿瘤区域。 MK-0646和MK-2206也将用于单独的实验中，因为这些化合物可能与MRK-003具有协同作用，因为我们的初步结果可持续目标1和2。我们将使用ACL细胞系进行Notch抑制作用的贡献，在此中，我们可以人为地下调NotCh-1。在AIM 1和2中获得的结果将在小鼠模型和人类临床样本中在体内进行验证。这里提出的研究结果将更好地理解有助于维持ACL中恶性表型的分子过程。此外，该研究将测试靶向Notch信号传导以使用GSI处理NSCLC的临床实用性。最后，这些实验将阐明Notch-1在体外和体内肺肿瘤性中的作用。

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.

DOI：
10.1586/era.10.158
发表时间：
2011-04
期刊：
Expert review of anticancer therapy
影响因子：
3.3
作者：
Galluzzo P;Bocchetta M
通讯作者：
Bocchetta M

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：
JOURNAL OF CELLULAR PHYSIOLOGY
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：
JOURNAL OF CELLULAR PHYSIOLOGY
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.