Project 3: Notch signaling in oHSV therapy for GBM

项目摘要 – 项目 3 NOTCH 信号在 GBM 中异常激活，对于 GBM 起始细胞的维持也很重要 作为血管生成。因此，能够调节 NOTCH 信号传导的治疗策略特别令人感兴趣 对于GBM。我们初步未发表的结果表明，用 γ 分泌酶抑制剂治疗 (GSI) 抑制 NOTCH 胞内结构域 (NICD) 释放，从而改善 NOTCH 激活 对患有颅内 GBM 的小鼠进行体内 GBM 病毒治疗。我们进一步发现 oHSV（和 由 oHSV 编码的 miRH16）诱导感染 GBM 上五个 NOTCH 配体之一的 Jagged-1 (Jag1) 增加 并且还增加未感染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 激活在巨噬细胞活性和 极化。此外，我们的数据还表明，阻断致癌的 NOTCH 信号传导可提高抗肿瘤效果 oHSV 在体内的功效。因此，我们假设：(a) oHSV1 感染的 Notch 配体表达增加 肿瘤细胞将导致未感染肿瘤细胞中的 NOTCH 活性增加（目标 1），(b) 巨噬细胞增加肿瘤炎症（目标 2），并且 (c) 与 oHSV1 一起抑制 NOTCH 活性 治疗将提高疗效（目标 3）。因此，用 oHSV 疗法阻断 NOTCH 信号传导应该具有 显着的临床和转化意义。

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 Our preliminary unpublished results have uncovered that treatment with gamma secretase inhibitor (GSI) that inhibits the NOTCH intracellular domain (NICD) release and hence NOTCH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