Characterizing Notch3 Signaling in Ovarian Cancer

描述(申请人提供)：这项研究的主要目的是阐明Notch3信号在卵巢癌发病机制中的作用，卵巢癌是女性最致命的肿瘤疾病之一。Notch信号通路在多种发育和生理过程中都是必需的，该信号通路的异常参与了肿瘤的发生发展。根据我们最近的发现，Notch3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)Notch3信号通路的激活启动肿瘤形成和/或推动肿瘤进展；ii)Notch3调节的基因Pbx1通过其与Hox蛋白的相互作用负责Notch3的促癌表型；iii)靶向Notch3信号通路在Notch3信号活跃的癌细胞中具有抗肿瘤的潜力。为了验证上述假设，我们提出了以下具体目标：目的1：分析Notch3通路激活在卵巢癌发生发展中的作用。目的：探讨Pbx1介导Notch3信号转导促肿瘤作用的机制。目的3：评价Notch3通路的药理靶向抗肿瘤作用。这项研究的结果将解决围绕Notch3在癌症生物学中的作用的几个关键问题，并应该对基于Notch3的靶向治疗的未来发展有所启示。

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.