Overcoming therapeutic resistance of gliomas

克服神经胶质瘤的治疗耐药性

• 批准号: 8466388
• 负责人: Khalid A Shah
• 金额: $ 25.19万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8466388
• 关键词: Affect; Apoptosis; Apoptotic; Beds; Blood - brain barrier anatomy; Boston; Brain Neoplasms; Cancer Patient; Caspase; Cell Cycle; Cell Proliferation; Cell Survival; Cells; Characteristics; Clinical; Clinical Trials; Collaborations; Correlative Study; Cytotoxic Chemotherapy; Development; Diagnostic; Down-Regulation; Drug Kinetics; Engineering; Excision; Firefly Luciferases; Future; Genetic; Genetic Engineering; Glioma; Herpesvirus 1; Human; Image; In Vitro; Infection; Injection of therapeutic agent; Invaded; Laboratories; Ligands; MAPK14 gene; MAPK8 gene; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Modality; Modeling; Molecular; Mutation; Normal Cell; Oncolytic; Oncolytic viruses; Operative Surgical Procedures; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Pre-Clinical Model; Protein Family; Recombinants; Recurrence; Renilla Luciferases; Research Personnel; Resected; Resistance; Risk; Signal Transduction; Simplexvirus; Stem cells; Testing; Therapeutic; Therapeutic Effect; Time; Treatment Efficacy; Tumor Necrosis Factor-alpha; Tumor Volume; Up-Regulation; Viral; Viral Genes; Virus; antitumor agent; base; bioluminescence imaging; cancer cell; caspase-3; caspase-8; cell killing; cohort; death receptor-4; design; disorder control; efficacy testing; human TNFRSF10A protein; in vitro testing; in vivo; inhibitor/antagonist; intravital microscopy; killings; mouse model; neoplastic cell; neuropathology; neurosurgery; novel; oncolysis; response; screening; translational study; tumor

DESCRIPTION (provided by applicant): Mutations of specific viral genes of oncolytic herpes simplex virus (oHSV)-1 have been shown to confer selectivity to cancer cells, which has enabled translational studies in humans. However, only a subset of cancer patients inoculated with oHSV-1 have shown objective response in phase 1 and 2 clinical trials. We have recently identified GBM lines that are resistant to oHSV mediated oncolysis. Based on our findings, we have created recombinant oHSV-TRAIL, an oHSV bearing a secretable pro-apoptotic tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and hypothesize that oHSV-TRAIL could be used as a cancer therapeutic to target a broad spectrum of resistant tumors in a mechanism based manner. In this proposal, we will screen a panel of glioma stem cells (GSC) isolated from patient derived primary GBM lines, for their sensitivity to oHSV and TRAIL and identify lines that are resistant to oHSV or both oHSV and TRAIL. Based on our preliminary studies on the downregulation of ERK, activation of JNK and p38 and subsequent up- regulation of caspases in oHSV and TRAIL resistant glioma cells treated with oHSV-TRAIL, we hypothesize that oHSV will target cell proliferation pathway and prime oHSV and/or TRAIL resistant established glioma cells and primary GSCs to TRAIL mediated apoptosis. The efficacy of oHSV-S-TRAIL will be evaluated in vitro and in mouse models created from identified lines and ultimately in resistant lines identified from screening a panel of freshly resected patient tumors. The incorporation of genetically engineered fluorescent (GFP and mCherry) and bioluminescent (firefly luciferase; Fluc and Renilla luciferase;Rluc) imaging markers into oHSV and glioma cells will allow us to follow delivery and spread of oHSV in vivo; changes in glioma volumes and invasion; and the efficacy of oHSV-TRAIL by in vivo bioluminescence imaging (BLI) and intravital microscopy (IVM). We anticipate that our findings will have a major contribution towards: 1) elucidating molecular mechanisms of how oHSV mediated oncolysis and TRAIL can function in concert to target heterogeneous glioma cells which are resistant to viral oncolysis and/or cytotoxic therapies; and 2) ultimately developing novel oHSV based therapies for patients with brain tumors.

描述（由申请人提供）：溶瘤单纯疱疹病毒（oHSV）-1的特定病毒基因的突变已被证明赋予对癌细胞的选择性，这使得能够在人类中进行转化研究。然而，只有一小部分接种 oHSV-1 的癌症患者在 1 期和 2 期临床试验中显示出客观反应。我们最近发现了对 oHSV 介导的溶瘤作用具有抵抗力的 GBM 系。根据我们的研究结果，我们创建了重组 oHSV-TRAIL，这是一种带有可分泌的促凋亡肿瘤坏死因子相关凋亡诱导配体 (TRAIL) 的 oHSV，并假设 oHSV-TRAIL 可用作癌症治疗剂，以靶向以基于机制的方式治疗广谱耐药肿瘤。在本提案中，我们将筛选从患者来源的原代 GBM 系中分离出的一组神经胶质瘤干细胞 (GSC)，了解它们对 oHSV 和 TRAIL 的敏感性，并鉴定对 oHSV 或对 oHSV 和 TRAIL 均具有抗性的细胞系。基于我们对 oHSV-TRAIL 处理的 oHSV 和 TRAIL 耐药神经胶质瘤细胞中 ERK 下调、JNK 和 p38 激活以及随后 caspase 上调的初步研究，我们假设 oHSV 将靶向细胞增殖途径并启动 oHSV 和/或 TRAIL 抗性已建立的神经胶质瘤细胞和原代 GSC 对 TRAIL 介导的细胞凋亡。 oHSV-S-TRAIL 的功效将在体外和由已鉴定品系创建的小鼠模型中进行评估，并最终在通过筛选一组新切除的患者肿瘤而鉴定出的耐药品系中进行评估。将基因工程荧光（GFP 和 mCherry）和生物发光（萤火虫荧光素酶；Fluc 和海肾荧光素酶；Rluc）成像标记物纳入 oHSV 和神经胶质瘤细胞中，将使我们能够跟踪 oHSV 在体内的传递和传播；神经胶质瘤体积和侵袭的变化；以及通过体内生物发光成像 (BLI) 和活体显微镜 (IVM) 观察 oHSV-TRAIL 的功效。我们预计我们的研究结果将对以下方面做出重大贡献：1）阐明oHSV介导的溶瘤作用和TRAIL如何协同作用以靶向对病毒溶瘤和/或细胞毒性疗法具有抗性的异质神经胶质瘤细胞的分子机制； 2) 最终为脑肿瘤患者开发基于 oHSV 的新型疗法。