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，由于缺乏治疗手段，其发病率和死亡率非常高。 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，这些靶标可以 导致新的治疗方法。我们发现 Schlafen (SLFN) 基因家族的一个成员， 与正常大脑相比，SLFN5 在 GBM 中显着过度表达，并且高水平的 SLFN5 表达与 GBM 患者的不良生存率相关。我们的数据表明 SLFN5 促进 GBM 通过与 IFN 相互作用来抑制 IFN 信号传导和 IFN 刺激基因 (ISG) 表达来抑制生长 转录激活因子 STAT1。这一非常新颖的发现构成了当前提案的基础。目标1将 识别 SLFN5-STAT1 复合物的元件，定义形成 SLFN5-STAT1 复合物所需的上游调控信号 此类复合物，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结构基序的功能及其对 将检查干扰素反应的抑制。使用 GBM 患者的原始样本进行的研究将 也受雇进行此类研究。目标 2 将使用三种不同的方法定义 SLFN5 体内表达的影响 原位移植模型和具有和不具有 SLFN5 表达的 GBM 细胞对：i) 常规 使用无胸腺小鼠的异种移植模型来检查 SLFN5 对肿瘤建立和生长的影响； ii) 人源化原位 PDX 模型，用于检查 SLFN5 对人间免疫反应的影响 对抗肿瘤，以及检查肿瘤对免疫检查点治疗的反应；和 iii) 相同 a ii 但 使用小鼠 GBM 同基因模型，其中宿主动物具有功能齐全的免疫系统。 总而言之，这项工作的结果将为 SLFN5 的机制提供重要信息。 表达抑制 IFN 反应并促进 GBM 生长。本次作品的成功演出 应促进以 SLFN5 作为靶点治疗 GBM 的高度新颖的方法的开发。

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.