Mechanisms of Caspase-1 Mediated Schwannoma Regression

Caspase-1 介导神经鞘瘤消退的机制

• 批准号: 8421092
• 负责人: GARY JAY BRENNER
• 金额: $ 36.41万
• 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: 2012-09-30 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8421092
• 关键词: Animals; Apoptosis; Apoptotic; Benign; Biochemical; Biological; Biological Assay; Biology; Bystander Effect; CASP1 gene; Caspase; Caspase-1; Cause of Death; Cell Death; Cell Lineage; Cells; Cessation of life; Clinical; Code; Culture Media; DNA; Data; Dependovirus; Development; Disease; Disease Management; Elements; Environment; Genes; Goals; Grant; Hereditary Disease; Human; Image; Immune; Immune response; Immunocompetent; Implant; In Vitro; Individual; Infection; Inflammatory; Injection of therapeutic agent; Investigation; Lead; Lesion; Location; Magnetic Resonance Imaging; Manuscripts; Mediating; Medical; Modeling; Molecular; Monitor; Mus; Myelin Sheath; Natural Killer Cells; Neoplasms; Nerve; Neurilemmoma; Neurofibromatoses; Neurofibromatosis 2; Neurons; Non-Malignant; Nude Mice; Pathway interactions; Patients; Peripheral Nerves; Peripheral Nervous System Neoplasms; Primary Neoplasm; Publishing; Research; Resistance to infection; Schwann Cells; Schwannomatosis; Stream; Techniques; Testing; Therapeutic; Therapeutic Effect; Time; Toxic effect; Treatment Efficacy; Tumor Volume; Tumor-Derived; Viral Vector; Virus; adaptive immunity; adeno-associated viral vector; cytokine; disability; gene therapy clinical trial; implantation; in vivo; innovation; killings; myelination; neoplastic cell; neurotoxicity; novel; novel therapeutic intervention; novel therapeutics; preclinical study; promoter; protein complex; response; sciatic nerve; treatment strategy; tumor; tumor growth; vector; vector control

DESCRIPTION (provided by applicant): While schwannoma tumors are typically benign (non-malignant) they can have devastating consequences for patients. As for an individual patient there is often no efficacious treatment. Thus, schwannoma therapy represents a major unmet clinical need. We have developed a new therapeutic approach to these nerve-associated tumors that involves intra-tumoral injection of an adeno-associated virus (AAV) vector carrying the pro-apoptotic gene caspase-1 (ICE) under a Schwann-cell specific promoter (P0); the vector is denoted AAV-P0-ICE. Our pre-clinical studies have shown a remarkable ability of the AAV-P0- ICE vector to produce a prolonged reduction in tumor volume with no nerve damage (manuscript submitted). Our preliminary data suggests that AAV-PO-ICE not only directly kills infected caspase-1-expressing tumor cells (presumably by inducing apoptosis), but also kills non-infected tumor cells through a "bystander" effect. It is hypothesize that this bystander killin is mediated by both tumor- and host-specific mechanisms that involve humoral- and cell-mediated pathways. The overriding goal is to investigate the biology of AAV-P0-ICE mediated tumor destruction in the human and mouse schwannoma models we have developed in nude and immunocompetent mice, respectively, and to identify the molecular and cellular pathways mediating the killing of non-vector-infected tumor cells that is associated with apoptotic death of infected tumor cells. In brief, the specific aims are to 1) investigate the parameters of tumor regression in two schwannoma models in mice - a human schwannoma in nude mice and a mouse schwannoma in immune competent animals, 2) investigate whether caspase-1 bystander killing involves apoptotic death of uninfected cells, and 3) analyze whether host immune mechanisms are involved in AAV-P0-ICE initiated bystander killing. In vivo tumor growth will be monitored via bioluminescent imaging and MRI for the human and mouse schwannoma models, respectively; both techniques allow serial assessment over time in a given animal. A variety of biochemical and cell biological techniques will be used to determine whether caspase expressing tumor cells produce factors - both humoral and microvesicle contained - that can be transferred to and cause apoptotic death of uninfected tumor cells. Histological analysis and a variety of fundamental immunological assays will be used to investigate host mechanisms of bystander killing after AAV-P0-ICE injection. This application is novel and innovative in that it utilizes the first viral vector we know of that is restrictively expressed in Schwann-lineage cells hence allowing targeting of schwannomas without neurotoxicity, and proposes investigation of the pathways - tumor and host specific - which underlie induction of bystander tumor killing. Mechanistic understanding of the extensive and specific tumor killing induced by AAV-P0-ICE injection into schwannomas has the potential lead to novel treatment strategies for NF1, NF2 and schwannomatosis, as well as, a variety of other neoplasms. PUBLIC HEALTH RELEVANCE: Schwannomas are tumors that form on nerves and cause significant suffering for patients; current treatment of this disease is very limited. Our research group has developed a new treatment for schwannoma in which a virus is used to deliver a cell-death gene specifically to the tumor cells. It appears that the virus kills not only the tumor cell that it infects, but also uninfected tumor cells; the goal of this grant is to understand the mechanisms through which this virus destroys schwannoma cells.

描述（由申请人提供）：虽然神经鞘瘤肿瘤通常是良性的（非恶性的），但它们可能对患者造成毁灭性的后果。至于个别病人，往往没有有效的治疗方法。因此，神经鞘瘤治疗是一个主要的未满足的临床需求。我们已经开发了一种新的治疗方法，这些神经相关的肿瘤，涉及肿瘤内注射腺相关病毒（AAV）载体携带促凋亡基因caspase-1（ICE）下的Schwann细胞特异性启动子（P0），该载体被称为AAV-P0-ICE。我们的临床前研究已经显示AAV-P0- ICE载体产生肿瘤体积的延长减小而没有神经损伤的显著能力（提交的手稿）。 我们的初步数据表明，AAV-PO-ICE不仅直接杀死感染的表达caspase-1的肿瘤细胞（可能是通过诱导凋亡），而且还通过“旁观者”效应杀死未感染的肿瘤细胞。据推测，这种旁观者杀伤是由肿瘤和宿主特异性机制介导的，涉及体液和细胞介导的途径。最重要的目标是研究我们分别在裸小鼠和免疫活性小鼠中开发的人和小鼠神经鞘瘤模型中AAV-P0-ICE介导的肿瘤破坏的生物学，并鉴定介导非载体感染的肿瘤细胞的杀伤的分子和细胞途径，所述非载体感染的肿瘤细胞与肿瘤细胞的凋亡性死亡相关。 感染的肿瘤细胞 简而言之，具体目的是1）研究小鼠中两种神经鞘瘤模型-裸鼠中的人神经鞘瘤和免疫活性动物中的小鼠神经鞘瘤中的肿瘤消退参数，2）研究半胱天冬酶-1旁观者杀伤是否涉及未感染细胞的凋亡性死亡，以及3）分析宿主免疫机制是否涉及AAV-PO-ICE引发的旁观者杀伤。将分别通过人类和小鼠神经鞘瘤模型的生物发光成像和MRI来监测体内肿瘤生长;这两种技术都允许在给定动物中随着时间的推移进行连续评估。将使用各种生物化学和细胞生物学技术来确定表达半胱天冬酶的肿瘤细胞是否产生可以转移到未感染的肿瘤细胞并引起未感染的肿瘤细胞凋亡的因子-体液和微泡。将使用组织学分析和各种基础免疫学测定来研究AAV-P0-ICE注射后旁观者杀伤的宿主机制。 该应用是新颖的和创新的，因为它利用了我们所知的第一种病毒载体，该病毒载体在许旺谱系细胞中限制性表达，因此允许靶向许旺细胞瘤而没有神经毒性，并提出了对途径的研究-肿瘤和宿主特异性-这是诱导旁观者肿瘤杀伤的基础。对AAV-P0-ICE注射到神经鞘瘤中诱导的广泛和特异性肿瘤杀伤的机制的理解有可能导致针对NF 1、NF 2和神经鞘瘤病以及各种其他肿瘤的新的治疗策略。 公共卫生关系：神经鞘瘤是在神经上形成的肿瘤，对患者造成重大痛苦;目前对这种疾病的治疗非常有限。我们的研究 该小组已经开发出一种治疗神经鞘瘤的新方法，其中使用病毒将细胞死亡基因特异性地传递到肿瘤细胞。看来病毒不仅杀死它感染的肿瘤细胞，而且还杀死未感染的肿瘤细胞;这项资助的目标是了解这种病毒破坏神经鞘瘤细胞的机制。