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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。大多数子宫内膜