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：
10240565
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/10240565
关键词：
Accounting Address Animals Antitumor Response Biological Biology Brain Cell physiology Cells Complex Data Databases 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 Structure 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 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.

项目摘要/摘要胶质母细胞瘤（GBM）是一种高度侵略性的恶性肿瘤，由于缺乏，发病率和死亡率很高有效的疗法。该提案的总体目标是确定GBM细胞中的新细胞靶标的导致新的治疗方法。我们发现Schlafen（SLFN）基因家族的成员，与正常脑相比表达与GBM患者的存活不良相关。我们的数据表明SLFN5促进GBM 通过抑制IFN信号传导和IFN刺激基因（ISG）表达的生长。转录激活器Stat1。这个高度新颖的发现构成了当前建议的基础。目标1意志确定SLFN5-Stat1复合物的元素，定义形成所需的上游调节信号这样的复合物，并确定这些复合物的元素与SLFN5相关的元素之间的关系转录抑制。不同SLFN5结构图案的功能及其对将检查对IFN响应的抑制。使用来自GBM患者的主要样本的研究将是也从事此类研究。 AIM 2将使用三个不同的不同有或没有SLFN5表达的原位植入模型和GBM细胞对：i）常规异种移植模型使用无胸腺小鼠检查SLFN5对肿瘤的建立和生长的影响； ii）人性化的原位PDX模型检查了人类免疫反应的SLFN5效应针对肿瘤，并检查肿瘤对免疫检查点疗法的反应； iii）同一ii，但使用小鼠GBM同步模型，其中宿主动物具有功能齐全的免疫系统。总之，这项工作的结果将提供有关SLFN5的机制的重要信息表达抑制IFN反应并促进GBM的生长。这项工作的成功表现应该促进使用SLFN5作为目标的高度新颖方法来治疗GBM。