Characterizing Notch3 Signaling in Ovarian Cancer

卵巢癌中 Notch3 信号传导的特征

• 批准号: 8104583
• 负责人: Tian-Li Wang
• 金额: $ 34.03万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8104583
• 关键词: ABCB1 gene; Address; Animal Model; Binding; Biological Process; Cancer Biology; Cancer Patient; Cell Nucleus; Cell Proliferation; Cell Survival; Clinical; Collaborations; Complex; Development; Developmental Process; Disease; Etiology; Foundations; Future; Gene Amplification; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Human; Injection of therapeutic agent; Lead; Ligands; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Modeling; Molecular; Multi-Drug Resistance; Mus; Oncogenic; Outcome; Ovarian; Ovarian Carcinoma; Ovarian Serous Adenocarcinoma; Pathogenesis; Pathway interactions; Peptide Hydrolases; Phenotype; Physiological Processes; Polymers; Proteins; Proto-Oncogenes; RB1 gene; Reporting; Role; Signal Pathway; Signal Transduction; TP53 gene; Testing; Tissues; Transgenic Mice; Up-Regulation; Woman; base; cancer cell; cancer therapy; embryonic stem cell; inhibitor/antagonist; mouse model; neoplastic; neoplastic cell; notch protein; ovarian neoplasm; overexpression; receptor; secretase; small molecule; tumor; tumor progression; tumor xenograft; tumorigenesis

DESCRIPTION (provided by applicant): The main objective of this study is to elucidate the role of Notch3 signaling in the pathogenesis of ovarian cancer, one of the most lethal neoplastic diseases in women. It has been well-established that the Notch signaling is required during diverse developmental and physiological processes and aberration of the signaling pathway participates in cancer development. Based on our recent findings showing Notch3 gene amplification in ovarian cancers and its role in maintaining cell survival, we hypothesize that i) activation of Notch3 signaling pathway initiates tumor formation and/or propel tumor progression; ii) Pbx1, a Notch3-regulated gene, is responsible for the tumor-promoting phenotypes of Notch3 through its interaction with Hox proteins; iii) targeting the Notch3 signaling pathway has anti-tumor potential in cancer cells with active Notch signaling. To test the above hypotheses, we propose the following specific aims: Aim 1: Analyze the roles of Notch3 pathway activation in the development of ovarian carcinoma. Aim 2: Investigate the mechanism by which Pbx1 mediates tumor-promoting effects of Notch3 signaling. Aim 3: Assess anti- tumor potential of pharmacological targeting of the Notch3 pathway. The results from this study will address several critical questions centering the roles of Notch3 in cancer biology and should have implication for future development of Notch3-based target therapy. PUBLIC HEALTH RELEVANCE: The purpose of this study is to determine the molecular mechanism by which Notch3 pathway activation contributes to the development of ovarian cancer. Furthermore, we will delineate the role of a Notch3 target gene in modulating oncogenic phenotypes in ovarian cancer. We will test tumor suppressive effect using newly developed small molecules to block Notch3-Pbx1 pathway. The results from this study will further our understanding the molecular mechanisms in the tumorigenesis of ovarian cancer and will provide foundation for Notch3-based cancer therapy.

描述（由申请人提供）：本研究的主要目的是阐明Notch 3信号传导在卵巢癌发病机制中的作用，卵巢癌是女性中最致命的肿瘤性疾病之一。Notch信号通路在多种发育和生理过程中是必需的，并且信号通路的畸变参与癌症的发展。基于我们最近的研究结果显示Notch 3基因在卵巢癌中的扩增及其在维持细胞存活中的作用，我们假设i）Notch 3信号通路的激活启动肿瘤形成和/或推动肿瘤进展; ii）Pbx 1，一个Notch 3调节基因，通过其与Hox蛋白的相互作用负责Notch 3的肿瘤促进表型; iii）靶向Notch 3信号传导途径在具有活性Notch信号传导的癌细胞中具有抗肿瘤潜力。为了验证上述假设，我们提出了以下具体目标：目的1：分析Notch 3通路激活在卵巢癌发生发展中的作用。目的2：探讨Pbx 1介导Notch 3信号通路促肿瘤作用的机制。目的3：评估Notch 3通路的药理学靶向抗肿瘤潜力。这项研究的结果将解决Notch 3在癌症生物学中作用的几个关键问题，并对未来基于Notch 3的靶向治疗的发展具有意义。 公共卫生关系：本研究的目的是确定Notch 3通路激活有助于卵巢癌发展的分子机制。此外，我们将描述Notch 3靶基因在调节卵巢癌致癌表型中的作用。我们将测试使用新开发的小分子阻断Notch 3-Pbx 1通路的肿瘤抑制效果。本研究的结果将有助于我们进一步了解卵巢癌发生的分子机制，并为基于Notch 3的肿瘤治疗提供基础。