Novel effectors of ERK signaling and their potential roles in the treatment of en

ERK 信号传导的新型效应物及其在治疗 en 中的潜在作用

基本信息

批准号：
7727351
负责人：
Liang Ma
金额：
$ 9.34万
依托单位：
WASHINGTON UNIVERSITY
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：
2009-09-18 至 2012-08-12
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7727351
关键词：
Accounting Antibodies Apoptosis Biological Models Biological Response Modifier Therapy Caenorhabditis elegans Cancer Biology Cancer Cell Growth Cancer Model Cancer cell line Cell Cycle Regulation Cell Line Cell Proliferation Cell Survival Cells Clinical Detection Diagnostic Disease Endometrial Endometrial Carcinoma Endometrium Event FGFR2 gene Hemorrhage Human Instruction KRAS2 gene Lead Malignant Female Reproductive System Neoplasm Malignant Neoplasms Maps Methods Mitogen-Activated Protein Kinases Mitogens Modeling Molecular Abnormality Morbidity - disease rate Mutation Neoplasm Metastasis Operative Surgical Procedures Orthologous Gene Pathway interactions Patients Pharmacotherapy Phosphorylation Phosphorylation Site Phosphotransferases Play Population Postmenopause Prevention Proteins Recurrent Malignant Neoplasm Reproduction spores Reverse Transcriptase Polymerase Chain Reaction Role Signal Pathway Signal Transduction Signal Transduction Pathway Small Interfering RNA Staging Systemic disease Therapeutic Therapeutic Intervention Tissue Microarray Tissues Tumor Suppressor Genes Uterine Cancer Western Blotting Work angiogenesis carcinogenesis cell growth cell motility chemotherapy clinically relevant cohort effective therapy extracellular functional genomics glycogen synthase kinase 3 beta improved mortality multimodality neoplastic novel novel strategies novel therapeutic intervention small hairpin RNA treatment strategy tumorigenesis

项目摘要

Endometrial carinoma is the most common cancer of the female reproductive tract. Most endometrial cancers are found at an early stage and present with postmenopausal bleeding. These patients are initially treated with comprehensive surgical staging. This treatment is often diagnostic ofthe extent of disease and therapeutic. However, a key clinical problem in the management of patients with uterine cancers is how to best fre¿t~ab\r¿rhced'stagieclisease ahdlhe aggressive pathoTogic histotypes that account for signficant mortality. Patients with high stage or recurrent cancers have systemic disease requiring novel therapeutic interventions. Effective therapies are largely lacking. A better understanding ofthe cancer biology, such as signal transduction pathways, will lead to new treatment strategies that will improve the survival of these patients. Activation of the Mitogen Activating Pathway Kinase signaling pathway contributes substantially to endometrial tumorigenesis. Our group has identified thirty novel ERK substrates through a three-part functional genomic approach in the C. elegans model. The human orthologs of these proteins expressed in endometrial cancer cell lines are candidate ERK substrates. Thus far, of the candidates studied, we showed that GSK3n is important to cell growth in multiple endometrial cancer cell lines and has potential for therapeutic interventions.. In this proposal, we will continue to characterize novel ERK candidate substrates in endometrial cancer. In Aim 1, we will assess expression of candidate ERK1/2 substrates in the normal endometrium, primary endometrial cancers and endometrial cancer cell lines and determine if substrate phosphorylation is ERK-dependent. Then in aim 2, we will determine the relationship between ERK substrate phosphorylation status and upstream ERK signaling pathway activation in primary endometrial cancers and clinicopathologic significance of ERK substrate expression. Finally in aim 3, we will explore GSKSD inhibition as potential therapy for endometrial cancer and assess the role of inhibiting other ERK substrates plays in endometrial cancer cell lines. Together these studies should provide a better understanding of the role the ERK pathway plays in endometrial carcinogenesis and may lead to improved clinical biological therapies. RELEVANCE (See instructions): The work proposed will lead to both an improved understanding of endometrial cancer biology and new approaches to the detection, prevention and treatment of uterine cancers which will result in reduced cancer morbidity and mortality.

子宫内膜癌是女性生殖道最常见的癌症。癌症在早期被发现并出现绝经后出血。通过全面的手术分期，这种治疗通常可以诊断所治疗疾病的程度和程度。然而，子宫癌患者治疗中的一个关键临床问题是如何治疗。最好的频率t~ab\r¿ rhced'stagieclisease ahdlhe 侵袭性病理组织型，占重要地位死亡。晚期或复发性癌症患者患有全身性疾病，需要新的治疗方法很大程度上缺乏对癌症生物学的更好理解，例如。信号转导途径，将导致新的治疗策略，从而提高这些患者的生存率丝裂原激活途径激酶信号通路的激活对患者的预后有很大贡献。我们的小组通过三部分鉴定了三十种新型 ERK 底物。线虫模型中的功能基因组方法表达了这些蛋白质的人类直系同源物。子宫内膜癌细胞系是候选 ERK 底物到目前为止，我们在研究的候选细胞系中展示了这一点。 GSK3n 对多种子宫内膜癌细胞系的细胞生长很重要，并且有潜力治疗干预......在本提案中，我们将继续表征新型 ERK 候选底物在目标 1 中，我们将评估正常细胞中候选 ERK1/2 底物的表达。子宫内膜、原发性子宫内膜癌和子宫内膜癌细胞系并确定底物磷酸化是 ERK 依赖性的。然后在目标 2 中，我们将确定 ERK 底物之间的关系。原发性子宫内膜癌的磷酸化状态和上游 ERK 信号通路激活 ERK 底物表达的临床病理意义最后，在目标 3 中，我们将探讨 GSKSD。抑制作为子宫内膜癌的潜在疗法并评估抑制其他 ERK 底物的作用这些研究一起应该可以更好地理解子宫内膜癌细胞系中的作用。 ERK 通路在子宫内膜癌发生中的作用并可能改善临床生物学疗法。相关性（参见说明）：拟议的工作将提高对子宫内膜癌生物学的理解和新的子宫癌的检测、预防和治疗方法，从而减少癌症的发生发病率和死亡率。