Project 3: Notch signaling in oHSV therapy for GBM

项目摘要--项目3 Notch信号在基底膜中异常激活，对基底膜启动细胞的维持也很重要 作为血管生成。因此，能够调节缺口信号的治疗策略特别令人感兴趣。 对于GBM。我们未发表的初步结果发现，用伽马分泌酶抑制剂治疗 (GSI)抑制缺口细胞内域(NICD)的释放，从而改善缺口激活 GBM对颅内GBM小鼠的体内病毒治疗。我们进一步发现OHSV(和 OHSV编码的miRH16诱导感染的GBM上5个缺口配体之一的Jag1增加 并增加未感染的肿瘤细胞和肿瘤微环境中的Noch信号活性。 越来越多的证据表明，缺口激活在巨噬细胞活性和 极化。此外，我们的数据还表明，阻断致癌缺口信号可以提高抗肿瘤能力。 OHSV在体内的疗效。因此，我们假设：(A)OHSV1感染后Notch配体表达增加 肿瘤细胞将导致未感染的肿瘤细胞的缺口活性增加(目标1)，(B)缺口活性在 巨噬细胞增加肿瘤炎症(目标2)，和(C)抑制缺口活性与OHSV1共同作用 治疗将提高疗效(目标3)。因此，用OHSV疗法阻断Noch信号应该有 具有重要的临床和翻译意义。

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 Our preliminary unpublished results have uncovered that treatment with gamma secretase inhibitor (GSI) that inhibits the NOTCH intracellular domain (NICD) release and hence NOTCH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