Project 3: Notch signaling in oHSV therapy for GBM
Project 3: Notch signaling in oHSV therapy for GBM
批准号:
10491211
负责人:
Balveen Kaur
金额:
$31.42万
依托单位国家:
美国
项目类别:
财政年份:
2013
资助国家:
美国
项目状态:
已结题
起止时间:
2013-02-07 至 2023-08-31
关键词:
Biological Response Modifier TherapyBiometryCell physiologyCellsClinicalClinical TrialsDataFDA approvedGenerationsGlioblastomaGoalsHerpesvirus 1InfectionInflammationLigandsMaintenanceMalignant - descriptorMalignant GliomaMediatingMetastatic MelanomaMicrogliaModalityModelingMusNatural Killer CellsNotch Signaling PathwayOncogenicOncolytic virusesPatientsPeptidesPlayResearchResistanceRoleSafetySerum MarkersServicesSignal TransductionStromal CellsTIMP3 geneTherapeuticVertebral columnViral PhysiologyVirotherapyVirusWorkangiogenesiscancer typegamma secretaseimprovedimproved outcomein vivoinflammatory markerinhibitorinhibitor therapyinterestjagged1 proteinmacrophagemelanomaneoplastic cellnext generationnotch proteinnoveloncolytic herpes simplex virusoncolytic virotherapypatient prognosispreclinical studyresponsesystemic toxicitytraditional therapytumortumor microenvironment
中文摘要
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。
英文摘要
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 Our preliminary unpublished results have uncovered that treatment with gamma secretase inhibitor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.
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海外基金