Project 3: Notch signaling in oHSV therapy for GBM

项目 3：oHSV 治疗 GBM 中的 Notch 信号传导

基本信息

批准号：
10251084
负责人：
Balveen Kaur
金额：
$ 32.06万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-07 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10251084
关键词：
Antiviral Agents Biological Response Modifier Therapy Biometry Cell physiology Cells Clinical Clinical Trials Data FDA approved Generations Glioblastoma Goals Herpesvirus 1 Infection Inflammation Ligands Maintenance Malignant - descriptor Malignant Glioma Mediating Metastatic Melanoma Microglia Modality Modeling Mus Natural Killer Cells Notch Signaling Pathway Oncogenic Oncolytic viruses Patients Peptides Play Prognosis Research Resistance Role Safety Serum Markers Services Signal Transduction Stromal Cells TIMP3 gene Therapeutic Vertebral column Viral Physiology Virotherapy Virus Work angiogenesis cancer type gamma secretase improved improved outcome in vivo inflammatory marker inhibitor/antagonist interest jagged1 protein macrophage melanoma neoplastic cell next generation notch protein novel oncolytic herpes simplex virus oncolytic virotherapy preclinical study response systemic toxicity traditional therapy tumor tumor microenvironment

项目摘要

PROJECT SUMMARY – PROJECT 3 NOTCH signaling is aberrantly activated in GBM and is important for maintenance of GBM initiating cells, as well as angiogenesis. Therefore, therapeutic strategies that can modulate NOTCH signaling are of particular interest for GBM. Our preliminary unpublished results have uncovered that treatment with gamma secretase inhibitor (GSI) that inhibits the NOTCH intracellular domain (NICD) release and hence NOTCH activation improves virotherapy of GBM in vivo in mice bearing intracranial GBM. We have further discovered that oHSV (and miRH16 encoded by oHSV) induce increased Jagged-1 (Jag1) one of the five NOTCH ligands on infected GBM and also increases NOTCH signaling activity in uninfected tumor cells and the tumor microenvironment. Increasing evidence suggests that NOTCH activation plays a significant role in macrophage activity and polarization. Further, our data also show that blockade of oncogenic NOTCH signaling improves anti-tumor efficacy of oHSV in vivo. Thus, we hypothesize that: (a) increased Notch ligand expression in oHSV1-infected tumor cells will result in increased NOTCH activity in uninfected tumor cells (Aim 1), (b) NOTCH activity in macrophages increases tumor inflammation (Aim 2), and (c) inhibiting NOTCH activity in conjunction with oHSV1 therapy will increase efficacy (Aim 3). Thus blocking NOTCH signaling with oHSV therapy should have significant clinical and translational implications.

项目摘要 - 项目3 Notch信号在GBM中异常激活，对于维持GBM启动细胞也很重要作为血管生成。因此，可以调节Notch信号传导的理论策略特别感兴趣对于GBM。我们的初步未发表的结果发现了使用伽马泌尿酶抑制剂治疗（GSI）抑制缺口细胞内结构域（NICD）释放，因此Notch激活有所改善携带颅内GBM的小鼠中GBM体内GBM的病毒疗法。我们进一步发现OHSV（和由OHSV编码的miRH16）诱导的锯齿状-1（JAG1）增加了感染GBM上的五个缺口配体之一还增加了未感染的肿瘤细胞和肿瘤微环境中的Notch信号传导活性。越来越多的证据表明，缺口激活在巨噬细胞活性中起着重要作用极化。此外，我们的数据还表明，对致癌缺口信号的封锁可改善抗肿瘤 OHSV在体内的效率。这是我们假设的：（a）在OHSV1感染中增加缺口配体表达肿瘤细胞将导致未感染的肿瘤细胞的凹口活性增加（AIM 1），（b）在巨噬细胞增加肿瘤注射（AIM 2），并且（c）与OHSV1结合抑制缺口活性治疗将提高效率（AIM 3）。通过OHSV疗法阻止Notch信号传导应具有显着的临床和翻译意义。