Vector delivery to modify the brain tumor and its microenvironment

载体递送以改变脑肿瘤及其微环境

基本信息

批准号：
7408986
负责人：
Joseph C Glorioso
金额：
$ 27.36万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-01 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7408986
关键词：
A/J Mouse Affect Angiogenic Factor Animal Experiments Animal Model Animals Antineoplastic Agents Antiviral Agents Antiviral Response Apoptosis Apoptotic Astrocytoma BALB/c Nude Mouse Basement membrane Behavior Biological Models Blood Vessels Brain Brain Neoplasms Caspase Catabolism Cell Line Cells Cellular biology Cephalic Characteristics Clinical Treatment Clinical Trials Collaborations Collagen Type IV Cultured Cells Data Deposition Depth Development Diffusion Dioxygenases Disadvantaged Dominant-Negative Mutation Dorsal Dose Endopeptidases Engineering Environment Epidermal Growth Factor Receptor Firefly Luciferases Fluorescent Dyes G207 Gelatinase B Gene Combinations Genes Genetic Genotype Glioblastoma Glioma Goals Growth HSV vector Herpesvirus 1 Histopathology Homologous Gene Human I-kappa B Proteins ICP47 IRF3 gene Image Imagery Immune Immune response Immunity Immunocompetent Immunohistochemistry In Vitro In complete remission Inbred BALB C Mice Individual Induction of Apoptosis Infection Infusion procedures Intention Interferon Type II Invaded Investigation Knockout Mice Kynurenine LY294002 Label Ligands Luciferases MMP9 gene Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Matrix Metalloproteinases Maximum Tolerated Dose Measurement Mediating Messenger RNA Metalloproteases Methods Microscopy Modeling Monitor Mouse Strains Mus Mutation Natural Immunity Nature Neoplasm Metastasis Neuroblastoma Non-Malignant Nude Mice Numbers Oncolytic Operative Surgical Procedures Outcome Pathway interactions Patients Pattern Peptide Hydrolases Performance Pharmaceutical Preparations Pharmacotherapy Phosphotransferases Predisposition Primary Neoplasm Principal Investigator Process Program Research Project Grants Progress Reports Property Proteins Proto-Oncogene Proteins c-akt Publications Radiation Radiation therapy Radiation-Sensitizing Agents Radiosurgery Recombinant Transgenes Recombinants Recurrence Recurrent disease Refractory Relative (related person)Reporting Research Role STAT1 gene Safety Signal Pathway Signal Transduction Simplexvirus Skin Specificity Standards of Weights and Measures Stem cells T-Lymphocyte Tail Testing Therapeutic Time Toxic effect Translating Treatment Efficacy Tryptophan Tryptophan 2,3 Dioxygenase Tumor Necrosis Factor-alpha Tumor Necrosis Factors Tumor Stem Cells Tumor Tissue Tumor-Derived Upper arm Vaccinia virus Veins Viral Genes Virion Virus Virus Replication aggrecanase anergy base brain tissue cancer cell cell killing charge coupled device camera chemotherapy cytokine cytotoxicity design efficacy evaluation gene therapy human TNF protein immunocytochemistry improved in vivo in vivo Model inhibitor/antagonist insight interest killings loss of function methyl tryptophan mutant neoplastic cell novel oncolysis oncolytic vector particle permissiveness programs promoter receptor receptor expression research study response success tumor tumor growth tumorigenic two-photon vector vector control

项目摘要

Glioblastoma mutliforme (GBM) is the most common form of primary brain cancer. Despite aggressive therapies including surgery, radiotherapy, and chemotherapy, recurrent disease is nearly always fatal. Oncolytic HSV vectors (e.g. G207) have shown some promise in the treatment of GBM however there have been few complete responses, a disappointing outcome most likely related to inadequate vector infection and growth, particularly among tumor cells that migrate from the tumor mass and invade normal brain tissue. Thus a central goal of Project 3 is to improve oncolytic vector delivery, replication and spread while maintaining safety and tumor specificity. Because changes in the tumor microenvironment greatly influence virus growth, we propose further to arm these oncolytic vectors with genes that improve vector distribution, overcome local anti-viral responses and enhance susceptibility to apoptotic mechanisms. Specifically, we propose to: (i) to explore the growth, spread and anti-tumor potential of a highly active HSV -1 strain KOS Oncolytic Vector (KOV) deleted for the non-essential immediate early (I.E.) genes ICPO, ICP22 and ICP47, (ii) to employ a recombinant KOV vector expressing a secreted matrix metalloproteinase protease (ADAMTS-8) with strong anti-angiogenic activity in an effort to increase initial vector distribution and to facilitate vector spread during replication, (iii) examine the use of a recombinant KOV capable of expressing VH1, binl and a dominant negative IKB (kBaM) as inhibitors of the interferon gamma (IFNy) and indoleamine 2,3-dioxygenase (IDO) antiviral and cytokine induction pathways and (iv) to evaluate the ability of recombinant KOV expressing (a) a novel dominant negative PKCe (DNP) that blocks its anti-apoptotic function, (b) caspase 8a to launch the apoptotic cascade and (c) an optimized recombinant soluble TRAIL (orsTRAIL) to induce tumor cell apoptosis. Ultimately, it is our intention to create a powerful oncolytic vector that exploits these combined growth-facilitating, anti-tumor functions that will set a new standard for this form of glioma therapy. This new vector will be compared to G207 to demonstrate improved anti-tumor responses. The highly engineered vector will also provide opportunities to better understand glioma cell biology, greatly improve the use of anti-cancer drugs in collaboration with Project 1 and assist the induction of tumor-specific immunity in collaboration with Project 2. Together our replication competent gene vectors should be useful in the development of an effective multi-modal therapy, an important overall goal of our program project grant.

多形性胶质母细胞瘤 (GBM) 是最常见的原发性脑癌。尽管咄咄逼人治疗包括手术、放疗和化疗，复发性疾病几乎总是致命的。溶瘤 HSV 载体（例如 G207）在治疗 GBM 方面已显示出一些前景，但仍有一些问题很少有完整的反应，令人失望的结果很可能与载体不足有关感染和生长，特别是从肿瘤块迁移并侵入的肿瘤细胞之间正常脑组织。因此，项目 3 的中心目标是改善溶瘤载体的递送、复制并在保持安全性和肿瘤特异性的同时进行扩散。因为肿瘤微环境的变化极大地影响病毒生长，我们建议进一步为这些溶瘤载体配备改善载体分布、克服局部抗病毒反应并增强易感性的基因至凋亡机制。具体来说，我们建议：（i）探索生长、扩散和抗肿瘤高活性 HSV -1 株 KOS 溶瘤载体 (KOV) 的潜力，删除了非必需的即刻早期 (I.E) 基因 ICPO、ICP22 和 ICP47，(ii) 采用重组 KOV 载体表达具有强抗血管生成作用的分泌型基质金属蛋白酶 (ADAMTS-8) 努力增加初始载体分布并促进复制过程中载体传播的活动， (iii)检查能够表达VH1、binl和显性失活的重组KOV的使用 IKB (kBaM) 作为干扰素 γ (IFNy) 和吲哚胺 2,3-双加氧酶 (IDO) 抗病毒药物的抑制剂和细胞因子诱导途径以及（iv）评估重组KOV表达的能力 (a) 一种新型显性失活 PKCe (DNP)，可阻断其抗凋亡功能，(b) caspase 8a 可阻断其抗凋亡功能启动细胞凋亡级联和 (c) 优化的重组可溶性 TRAIL (orsTRAIL) 来诱导肿瘤细胞凋亡。最终，我们的目的是创建一个强大的溶瘤载体，利用这些促进生长和抗肿瘤功能的结合将为这种形式的神经胶质瘤治疗。该新载体将与 G207 进行比较，以证明其抗肿瘤效果有所改善回应。高度工程化的载体还将提供更好地了解神经胶质瘤的机会细胞生物学，与项目1合作，大大提高抗癌药物的使用，协助与项目 2 合作诱导肿瘤特异性免疫。我们一起复制能力基因载体应该有助于开发有效的多模式治疗，这是一个重要的我们计划项目拨款的总体目标。