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SLFN5: A Novel Therapeutic Target for Glioblastoma

SLFN5：胶质母细胞瘤的新治疗靶点

基本信息

批准号：
10468276
负责人：
Charles David James
金额：
$ 34.56万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468276
关键词：
Accounting Address Animals Antitumor Response Biological Biology Brain Cell physiology Cells Complex Data Development Elements Engraftment Family Family member Feedback Gene Expression Gene Family Gene Proteins Genes Genetic Transcription Glioblastoma Goals Growth Human Immune response Immune system Interferon Activation Interferon Suppression Interferon Type I Interferons Investigation Lead Malignant Neoplasms Mediating Modeling Morbidity - disease rate Mus Nature Nude Mice Pathway interactions Patients Performance at work Property Protein Family Proteins Research Research Support Response Elements Role STAT1 gene Sampling Signal Transduction Transcription Coactivator Tumor Biology Work Xenograft Model brain tissue cancer stem cell cellular targeting checkpoint therapy effective therapy gene repression in vivo in vivo Model knock-down member mortality mouse model new therapeutic target novel novel strategies novel therapeutic intervention overexpression patient derived xenograft model protein expression protein function public database response stem cells tumor tumor immunology

项目摘要

PROJECT SUMMARY/ABSTRACT Glioblastoma (GBM) is a highly aggressive malignancy with very high morbidity and mortality, due to lack of effective therapies. The overall goal of this proposal is to identify novel cellular targets in GBM cells that could lead to new therapeutic approaches. We have found that a member of the Schlafen (SLFN) gene family, SLFN5, is significantly overexpressed in GBM as compared to normal brain, and that high levels of SLFN5 expression correlate with poor survival among GBM patients. Our data indicates that SLFN5 promotes GBM growth by repressing IFN signaling and IFN stimulated gene (ISG) expression via an interaction with the transcriptional activator STAT1. This highly novel finding forms the basis of the current proposal. Aim 1 will identify elements of SLFN5-STAT1 complexes, define upstream regulatory signals required for the formation of such complexes, and determine relationships between elements of these complexes and SLFN5-associated transcriptional repression. The functions of different SLFN5 structural motifs and their importance to the suppression of IFN-responses will be examined. Studies using primary samples from GBM patients will be also employed for such studies. Aim 2 will define the effects of SLFN5 expression in vivo using three distinct orthotopic engraftment models and GBM cell pairs with and without SLFN5 expression: i) conventional xenograft models using athymic mice for examining the effects of SLFN5 on tumor establishment and growth; ii) humanized orthotopic PDX models to examine SLFN5 effects for human-on-human immune response against tumor, as well as to examine tumor response to immune checkpoint therapy; and iii) same a ii but using mouse GBM syngeneic models in which the host animals have a fully functional immune system. Altogether, the results of this work will provide important information on the mechanisms by which SLFN5 expression suppresses IFN-responses and promotes GBM growth. The successful performance of this work should facilitate development of highly novel approaches for the treatment of GBM using SLFN5 as a target.

项目总结/文摘