Project 3: Notch signaling in oHSV therapy for GBM

项目 3：oHSV 治疗 GBM 中的 Notch 信号传导

• 批准号: 10019365
• 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
• 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/10019365
• 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; 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; outcome forecast; preclinical study; response; systemic toxicity; traditional therapy; tumor; tumor microenvironment

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 Our preliminary unpublished results have uncovered that treatment with gamma secretase inhibitor (GSI) that inhibits the NOTCH intracellular domain (NICD) release and hence NOTCH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.

项目概要-项目3 NOTCH信号在GBM中被异常激活，并且对于维持GBM起始细胞也很重要。 as angiogenesis血管生成.因此，可以调节NOTCH信号传导的治疗策略是特别感兴趣的 对于GBM。我们未发表的初步结果表明，用γ分泌酶抑制剂治疗 (GSI)抑制NOTCH胞内结构域（NICD）释放，因此NOTCH活化改善 在携带颅内GBM的小鼠中体内GBM的病毒治疗。我们进一步发现oHSV（和 由oHSV编码的miRH 16）诱导感染的GBM上五种NOTCH配体之一的Jagged-1（Jag 1）增加 并且还增加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，NOTCH活化在巨噬细胞活性和巨噬细胞增殖中起重要作用。 极化此外，我们的数据还表明，阻断致癌NOTCH信号传导可改善抗肿瘤作用。 oHSV在体内的功效。因此，我们假设：（a）在oHSV 1感染的小鼠中Notch配体表达增加， 肿瘤细胞中的NOTCH活性将导致未感染的肿瘤细胞中NOTCH活性的增加（目的1），（B） 巨噬细胞增加肿瘤炎症（目的2），和（c）抑制NOTCH活性与oHSV 1 治疗将提高疗效（目标3）。因此，用oHSV治疗阻断NOTCH信号传导应该具有 重要的临床和翻译意义。