Oncolytic Virotherapy of Meningeal Cancer

脑膜癌的溶瘤病毒疗法

• 批准号: 8270555
• 负责人: Matthias Gromeier
• 金额: $ 31.4万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8270555
• 关键词: Address; Animals; Binding; Cell Adhesion Molecules; Cell Proliferation; Cell physiology; Cells; Central Nervous System Neoplasms; Childhood; Clinical; Clinical Trials; Complex; Correlative Study; Dose; Environment; Equilibrium; Eukaryotic Initiation Factor-4E; Evaluation; Event; Growth; Human poliovirus; In Vitro; Infection; Inositol; Internal Ribosome Entry Site; Investigation; Investigational New Drug Application; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of central nervous system; Malignant neoplasm of meninges; Mediating; Meningeal; Messenger RNA; Metastatic Neoplasm to the Leptomeninges; Modeling; Modification; Molecular; Neoplasms; Neuraxis; Nude Rats; Oncogenes; Oncogenic; Oncolytic; Oncolytic viruses; Patients; Peptide Initiation Factors; Phosphatidylinositide 3-Kinase Inhibitor; Phosphotransferases; Polioviruses; Property; Protein Biosynthesis; Rattus; Recombinants; Regulation; Research; Rest; Rodent; Safety; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Specificity; Structure; Testing; Tissues; Toxicology; Translation Initiation; Translations; Tropism; Viral; Viral Genome; Virus Replication; Work; advanced disease; base; cell growth; cell type; design; human FRAP1 protein; in vivo; inhibitor/antagonist; innovation; insight; medulloblastoma; medulloblastoma cell line; molecular marker; nonhuman primate; oncolysis; pre-clinical; prototype; response; small molecule; synergism; translation factor; tumor

Malignant transformation is intricately linked to abnormally active signal transduction pathways that control cell growth and proliferation. Oncogenic signaling is pleiotropic, modifying cell physiology at any conceivable level. Intriguingly, both major signaling pathways implicated in cancer growth control, Akt and Ras, converge on two key regulators of protein synthesis. The eukaryotic initiation factors (eIF) 4E and 4G attract ribosomal subunits via binding to the universal 5' cap structure of eukaryotic mRNAs and assembling the pre-initiation complex, respectively. The effects of Akt and Ras signaling on translation factors are known, but their consequences for protein synthesis regulation in cancer are not understood. We uncovered that oncogenic signaling controls anti-cancer activity of the prototype oncolytic poliovirus PVS-RIPO by modulating eIF4E activity. We observed that the particular signaling environment in medulloblastoma, the most common pediatric CNS malignancy, enables rampant viral translation resulting in astounding responses to PVS-RIPO infection. This work tests our hypothesis that protein synthesis control in cancer is unhinged by altered eIF4E function, supporting alternative translation initiation at viral genomes and PVS-RIPO oncolysis. Our studies prepare a new oncolytic agent for clinical trials against intrathecal malignancy. The Specific Aims of this project are: 1) Unravel the mechanisms controlling eIF4E function and the efficiency of cap-independent translation initiation. We will perform basic molecular analyses to elucidate how oncogenic signaling controls oncolytic virus replication and the balance of cap-dependent vs. -independent translation. 2) Investigate the translation initiation factor network in medulloblastoma patients. We will study the molecular make-up of medulloblastoma with a focus on the protein synthesis machinery and determinants of PVS-RIPO oncolysis. 3) Study PVS-RIPO and its synergism with PI3-kinase inhibitors in vitro and in a rat intrathecal medulloblastoma model. We will investigate PVS-RIPO in pre-clinical animal studies including synergistic inhibitors of Akt-mTOR signaling. The oncolytic recombinant PVS-RIPO currently is in IND-directed dose range finding and toxicology studies. In thorough pre-IND discussions with FDA and ensuing empirical investigations, significant safety concerns were addressed. This project is designed to make PVS-RIPO applicable for intrathecal administration in patients with abnormal eIF4E function, a molecular marker broadly associated with malignancy. Our project will establish the necessary groundwork to start discussion with FDA and submit an investigational new drug application for clinical trials against medulloblastoma with meningeal dissemination.

恶性转化错综复杂地与控制细胞的异常活跃的信号转导通路有关 生长和扩散。致癌信号是多效性的，在任何可以想象的水平上改变细胞生理学。 有趣的是，与癌症生长控制有关的两个主要信号通路Akt和RAS汇聚在两个 蛋白质合成的关键调节因子。真核细胞起始因子4E和4G吸引核糖体亚基 通过与真核mRNAs的通用5‘帽结构结合并组装预起始复合体， 分别进行了分析。Akt和RAS信号对翻译因子的影响是已知的，但它们对 癌症中的蛋白质合成调节尚不清楚。我们发现致癌信号控制 原型溶瘤脊髓灰质炎病毒PVS-RIPO通过调节eIF4E活性的抗癌活性。我们观察到 髓母细胞瘤是儿童最常见的中枢神经系统恶性肿瘤，其特殊的信号环境， 启用猖獗的病毒翻译，导致对PVS-Ripo感染的惊人反应。 这项工作验证了我们的假设，即癌症中蛋白质合成的控制是由于eIF4E功能的改变而错乱的， 支持病毒基因组的选择性翻译启动和PVS-RIPO溶瘤。我们的研究准备了一个 用于治疗鞘内恶性肿瘤临床试验的新型溶瘤剂。本项目的具体目标是：1) 揭示控制eIF4E功能和大小写无关翻译启动效率的机制。 我们将进行基本的分子分析，以阐明致癌信号如何控制溶瘤病毒 复制和大小写依赖翻译与独立翻译之间的平衡。2)调查翻译 髓母细胞瘤患者的启动因子网络。我们将研究髓母细胞瘤的分子组成。 重点介绍PVS-RIPO溶瘤的蛋白质合成机制和决定因素。3)研究PVS-RIPO 以及它在体外和在大鼠髓母细胞瘤模型中与PI3-激酶抑制剂的协同作用。我们会 在临床前动物实验中研究PVS-Ripo，包括Akt-mTOR信号的协同抑制剂。 溶瘤的重组PVS-RIPO目前正在IND指导的剂量范围内发现和毒理学研究。在……里面 IND前与FDA的彻底讨论和随后的经验调查，重大的安全问题是 地址。该项目旨在使PVS-RIPO适用于患者的鞘内给药 EIF4E功能异常，是一种与恶性肿瘤广泛相关的分子标记。我们的项目将 建立必要的基础工作以开始与FDA的讨论并提交研究新药 申请治疗髓母细胞瘤脑膜播散的临床试验。