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)：尽管神经鞘瘤通常是良性(非恶性)的，但它们可能会对患者造成毁灭性的后果。至于个别患者，往往没有有效的治疗方法。因此，神经鞘瘤治疗是一个尚未得到满足的主要临床需求。我们开发了一种新的治疗这些神经相关肿瘤的方法，包括在雪旺细胞特异性启动子(P0)下将携带促凋亡基因caspase-1(ICE)的腺相关病毒(AAV)载体注入肿瘤内；该载体被命名为AAV-P0-ICE。我们的临床前研究表明，AAV-P0-ICE载体具有显著的能力，可以在不损害神经的情况下延长肿瘤体积的缩小(提交的手稿)。我们的初步数据表明，AAV-PO-ICE不仅可以直接杀死表达caspase-1的肿瘤细胞(可能是通过诱导细胞凋亡)，还可以通过“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，这些机制涉及体液和细胞介导的途径。我们的首要目标是在我们分别在裸鼠和免疫活性小鼠体内建立的人和小鼠神经鞘瘤模型中研究AAV-P0-ICE介导的肿瘤破坏的生物学，并确定介导非媒介感染的肿瘤细胞被杀伤的分子和细胞途径，这与人和小鼠的凋亡死亡有关。 被感染的肿瘤细胞。简而言之，本研究的具体目的是：1)研究裸鼠人神经鞘瘤和免疫活性动物小鼠神经鞘瘤模型的肿瘤消退参数；2)研究caspase-1旁观者杀伤是否涉及未感染细胞的凋亡；3)分析宿主免疫机制是否参与AAV-P0-ICE启动的旁观者杀伤。体内肿瘤生长将分别通过生物发光成像和MRI对人类和小鼠神经鞘瘤模型进行监测；这两种技术都允许在给定动物中进行一段时间的连续评估。将使用各种生化和细胞生物学技术来确定表达caspase的肿瘤细胞是否产生能够转移到未感染的肿瘤细胞并导致其凋亡的因子--包括体液和微泡。组织学分析和各种基础免疫学分析将被用来研究注射AAV-P0-ICE后旁观者死亡的宿主机制。这一应用是新颖和创新的，因为它利用了我们所知的第一个在雪旺系细胞中限制性表达的病毒载体，从而可以在没有神经毒性的情况下靶向神经鞘瘤，并提出了对诱导旁观者肿瘤杀伤的途径-肿瘤和宿主特异性-的研究。对神经鞘瘤内注射AAV-P0-ICE诱导的广泛和特异的肿瘤杀伤机制的了解，可能会导致针对NF1、NF2和神经鞘瘤病以及各种其他肿瘤的新的治疗策略。 公共卫生相关性：神经鞘瘤是一种在神经上形成的肿瘤，会给患者带来巨大的痛苦；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，在这种方法中，一种病毒被用来将细胞死亡基因特异性地传递到肿瘤细胞。似乎这种病毒不仅杀死了它感染的肿瘤细胞，而且还杀死了未感染的肿瘤细胞；这项拨款的目标是了解这种病毒破坏神经鞘瘤细胞的机制。