SLFN5: A Novel Therapeutic Target for Glioblastoma

项目概要/摘要 胶质母细胞瘤（GBM）是一种高度侵袭性的恶性肿瘤，由于缺乏免疫抑制剂， 有效的治疗。该提案的总体目标是在GBM细胞中鉴定新的细胞靶点， 导致新的治疗方法。我们已经发现Schlafen（SLFN）基因家族的一个成员， 与正常脑相比，SLFN 5在GBM中显著过表达，并且高水平的SLFN 5 在GBM患者中，表达与较差的存活率相关。我们的数据表明SLFN 5促进GBM 通过抑制IFN信号传导和IFN刺激的基因（ISG）的表达，通过与 转录激活因子STAT 1。这一非常新颖的发现构成了当前提案的基础。目标1将 确定SLFN 5-STAT 1复合物的元件，确定形成SLFN 5-STAT 1复合物所需的上游调控信号， 这种复合物，并确定这些复合物的元素和SLFN 5相关的 转录抑制不同SLFN 5结构基序的功能及其对细胞凋亡的重要性 将检查IFN应答的抑制。将使用GBM患者的原始样本进行研究， 也被用于此类研究。目的2将使用三种不同的方法来确定SLFN 5表达在体内的作用。 原位移植模型和具有和不具有SLFN 5表达的GBM细胞对： 使用无胸腺小鼠的异种移植模型，用于检查SLFN 5对肿瘤建立和生长的影响; ii）人源化原位PDX模型，以检查SLFN 5对人对人免疫应答的作用 抗肿瘤，以及检查肿瘤对免疫检查点疗法的应答;和iii）相同的a ii，但 使用小鼠GBM同系模型，其中宿主动物具有全功能免疫系统。 总之，这项工作的结果将提供有关SLFN 5的机制的重要信息。 表达抑制IFN-应答并促进GBM生长。这项工作的成功执行 应该有助于开发使用SLFN 5作为靶点治疗GBM的高度新颖的方法。

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.