权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanism of tumor promotion by the H3K9 histone demethylase KDM3A in Ewing Sarcoma.

尤文肉瘤中 H3K9 组蛋白去甲基化酶 KDM3A 促进肿瘤的机制。

基本信息

批准号：
9231397
负责人：
PAUL JEDLICKA
金额：
$ 35.57万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9231397
关键词：
Adverse effects Affect Animal Model Anoikis Biological Biological Assay Biology Bone Tissue Cell Line Cell Surface Proteins Cell Survival Cells Child Childhood Clinical Combination Drug Therapy Data Dependence Development Disease Disease Outcome Drops ETS1 gene Enzymes Epigenetic Process Ewings sarcoma Family Fusion Oncogene Proteins Genes Goals Growth Histones Impairment In Vitro Laboratories MCAM gene Malignant Bone Neoplasm Malignant Childhood Neoplasm Malignant Neoplasms Mediator of activation protein MicroRNAs Neoplasm Metastasis Oncogenic Oncoproteins Outcome Pathogenesis Pathway interactions Patients Pharmacology Phenotype Play Population Publications Recurrence Regulation Research Resistance Role Sampling Survival Rate Tail Testing Therapeutic Tumor Promotion Tumorigenicity Veins Work Xenograft Model Xenograft procedure cell growth cell motility chemotherapy cost demethylation efficacy testing histone demethylase improved in vivo inhibitor/antagonist insight knock-down migration novel novel therapeutics overexpression pre-clinical public health relevance small molecule inhibitor soft tissue targeted treatment therapeutic target transcription factor transcriptome tumor tumor growth tumorigenesis tumorigenic young adult

项目摘要

DESCRIPTION (provided by applicant): Ewing Sarcoma, a cancer of bone and soft tissue in children and young adults, is an aggressive malignancy with a poor long-term outcome. Even with optimal multi-agent chemotherapy, overall survival remains around 50%, drops to 25% for patients presenting with metastatic disease, and plummets to 10% for patients with recurrence. Thus, there is a tremendous need for better understanding of the biology of this disease, and the development of new therapies. The pathogenesis of Ewing Sarcoma is driven by EWS/Ets fusion oncoproteins. EWS/Ets oncoproteins, of which EWS/Fli1 is the most common, are aberrant transcription factors, which are necessary for Ewing Sarcoma oncogenesis. Although EWS/Ets fusion oncoproteins represent logical therapeutic targets in Ewing Sarcoma, such targeting has proven very difficult. Targeting of key downstream mediators of EWS/Ets oncogenic action is an important alternative strategy. We have identified an epigenetic regulator, the H3K9me1/2 histone demethylase KDM3A, which is overexpressed in Ewing Sarcoma downstream of EWS/Fli1, and promotes tumorigenesis and metastasis. Using transcriptome profiling and functional analysis, we have also identified candidate mediators of KDM3A action in Ewing Sarcoma. KDM3A is an enzyme belonging to the Jumonji-domain histone demethylase (JHDM) family, for which a small molecule inhibitor with in vivo efficacy has recently been developed, and shown by us to have activity against Ewing Sarcoma cells in vitro. Furthermore, our preliminary data identify at least one candidate mediator of KDM3A action with therapeutic targeting potential. The goal of this proposal is to gain better understanding of the precise roles and mechanism of action of KDM3A in Ewing Sarcoma, in order to determine the optimal strategies for inhibiting its pro-tumorigenic and pro-metastatic functions, and to test the efficacy of JHDM pharmacologic inhibition against these effects, as part of a long-term plan to develop new treatments for Ewing Sarcoma.