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

• 批准号: 8232996
• 负责人: Joseph C Glorioso
• 金额: $ 27.35万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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/8232996
• 关键词: A/J Mouse; ADAMTS; 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 Culture Techniques; Cell Line; Cells; Cellular biology; Cephalic; Characteristics; Clinical Treatment; Clinical Trials; Collaborations; Collagen Type IV; Data; Deposition; Development; Diffusion; Dioxygenases; Disadvantaged; Dominant-Negative Mutation; Dorsal; Dose; Engineering; Environment; Epidermal Growth Factor Receptor; Firefly Luciferases; Fluorescent Dyes; G207; Gene Combinations; Genes; Genetic; Genotype; Glioblastoma; Glioma; Goals; Growth; HSV vector; Herpesvirus 1; Histopathology; Homologous Gene; Human; I-kappa B Proteins; IRF3 gene; Image; Imagery; Immediate-Early Genes; 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; 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; 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; Stem cells; T cell anergy; Tail; Testing; Therapeutic; Time; Toxic effect; Translating; Treatment Efficacy; Tryptophan; Tryptophan 2,3 Dioxygenase; Tumor Necrosis Factor-alpha; Tumor Stem Cells; Tumor Tissue; Tumor-Derived; Vaccinia virus; Veins; Viral Genes; Virion; Virus; Virus Replication; aggrecanase; aggressive therapy; arm; base; brain tissue; cell killing; charge coupled device camera; chemotherapy; cytokine; cytotoxicity; design; effective therapy; efficacy evaluation; gene therapy; glioma cell line; imaging modality; immunocytochemistry; improved; in vivo; in vivo Model; inhibitor/antagonist; insight; interest; killings; loss of function; meetings; methyl tryptophan; mutant; neoplastic cell; novel; novel strategies; oncolysis; oncolytic vector; particle; permissiveness; programs; promoter; receptor; receptor expression; research study; response; standard care; success; tumor; tumor growth; tumor specificity; tumorigenic; two-photon; vector; vector control

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.

胶质母细胞瘤（GBM）是原发性脑癌的最常见形式。尽管有进取心 包括手术，放疗和化学疗法在内的疗法几乎总是致命的。 溶瘤HSV载体（例如G207）在GBM的治疗中表现出了一些希望 很少有完整的回复，令人失望的结果很可能与矢量不足有关 感染和生长，特别是在从肿瘤质量迁移并入侵的肿瘤细胞中 正常的脑组织。因此，项目3的核心目标是改善溶瘤矢量交付，复制 并在保持安全性和肿瘤特异性的同时扩散。因为肿瘤微环境的变化 极大地影响病毒的生长，我们进一步提议将这些肿瘤向量武装 改善载体分布，克服局部抗病毒反应并增强易感性的基因 凋亡机制。具体而言，我们建议：（i）探索生长，传播和抗肿瘤 高度活性的HSV -1菌株KOS Oncolytic Vector（KOV）已删除了针对非必需品 立即提早（即）基因ICPO，ICP22和ICP47，（ii）使用重组KOV载体 表达具有强抗血管生成的分泌基质金属蛋白酶蛋白酶（ADAMTS-8） 活动以增加初始矢量分布并促进复制过程中的向量扩散， （iii）检查能够表达VH1，BINL和主要负面的重组KOV的使用 IKB（KBAM）作为干扰素伽马（IFNY）和吲哚胺2,3-二氧酶（IDO）抗病毒的抑制剂 和细胞因子诱导途径以及（IV）评估重组KOV表达能力的能力 （a）阻止其抗凋亡功能的新型显性负PKCE（DNP），（b）caspase 8a至 启动凋亡的级联反应和（c）一条优化的重组可溶性步道（ORSTRAIL）诱导 肿瘤细胞凋亡。最终，我们打算创建一个强大的溶瘤矢量来利用 这些结合的增长抗肿瘤功能将为这种形式设定新标准 神经瘤治疗。该新向量将与G207进行比较，以证明抗肿瘤的改善 回答。高度工程的向量还将提供更好地了解神经胶质瘤的机会 细胞生物学，大大改善了与项目1合作的抗癌药物的使用，并协助 与项目2合作诱导肿瘤特异性免疫力。 基因载体应该在开发有效的多模式疗法的发展中有用，这是一个重要的 我们计划项目赠款的总体目标。