Overcoming therapeutic resistance of gliomas

克服神经胶质瘤的治疗耐药性

• 批准号: 8385058
• 负责人: Khalid A Shah
• 金额: $ 21.8万
• 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/8385058
• 关键词: Affect; Apoptosis; Apoptotic; Beds; Bioluminescence; 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; 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; Screening procedure; 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; 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; 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. PUBLIC HEALTH RELEVANCE: In this proposal, we will evaluate the effect of novel oncolytic virus, oHSV-TRAIL in oHSV and TRAIL resistant established and primary glioma cells in culture and in vivo in mouse models of glioma. The developed agents and strategies will be designed to be clinically translatable and should have a major impact in understanding current therapies targeting resistant brain tumors and also developing future therapies for brain tumors.

描述（由申请人提供）：溶瘤疱疹病毒（OHSV）-1的特定病毒基因的突变已证明可以赋予癌细胞的选择性，这使得癌细胞赋予了人类的翻译研究。但是，只有接种OHSV-1的一部分癌症患者在第1阶段和第2阶段试验中显示出客观反应。我们最近确定了对OHSV介导的肿瘤分解具有抗性的GBM线。根据我们的发现，我们创建了重组OHSV-TRAIL，这是一种具有可分泌的促凋亡肿瘤坏死因子因子相关的凋亡诱导配体（TRAIL）（TRAIL）的OHSV，并假设OHSV-Trail可以用作一种癌症，以靶向一种癌症，以靶向具有基于机械的基于机械的抗抗药性粉状的癌症。在此提案中，我们将筛选一个从患者衍生的初级GBM线中分离出的神经胶质瘤干细胞（GSC），以使其对OHSV的敏感性并进行跟踪，并识别对OHSV或OHSV或OHSV和TRAIL都具有抗性的线。 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. OHSV-S-TRAIL的功效将在体外和小鼠模型中进行评估，并最终以筛查一组新鲜切除的患者肿瘤鉴定的耐药线。将基因设计的荧光（GFP和MCHERRY）以及生物发光（Firefly Luciferase; Fluc和Renilla荧光素酶； RLUC）成像标记物掺入到OHSV和GliomaMoma细胞中，并使我们能够跟随OHSV在Vivo中的传递和传播；神经胶质瘤体积和入侵的变化；以及体内生物发光成像（BLI）和浸润显微镜（IVM）的OHSV-Trail的功效。我们预计我们的发现将对：1）阐明OHSV介导的肿瘤分解和TRAIL的分子机制可以协同起作用，以靶向抗抗病病毒术和/或细胞毒素疗法的异质性神经胶质瘤细胞； 2）最终为脑肿瘤患者开发基于OHSV的新型疗法。 公共卫生相关性：在此提案中，我们将评估新型的溶瘤病毒，OHSV-Trail在OHSV中的作用以及在培养物和体内抗胶质瘤模型中在培养物和体内耐药性和原代神经胶质瘤细胞的影响。发达的药物和策略将被设计为可以在临床上翻译，并且应该对了解靶向抗性脑肿瘤的当前疗法产生重大影响，并为脑肿瘤开发未来的疗法。