Oncolytic Virotherapy of Meningeal Cancer

脑膜癌的溶瘤病毒疗法

• 批准号: 8088048
• 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/8088048
• 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; Health; 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Medulloblastoma is the most common CNS tumor in pediatric patients and advanced disease with meningeal dissemination does not respond to available treatment. We have unraveled molecular mechanisms controlling protein synthesis in these tumors that render them susceptible to the prototype oncolytic poliovirus, PVS-RIPO. This project will prepare PVS-RIPO for clinical trials in patients with metastatic medulloblastoma and possibly other cancers commonly associated with leptomeningeal metastasis.

描述（由申请方提供）：恶性转化与控制细胞生长和增殖的异常活跃的信号转导途径密切相关。致癌信号是多效性的，在任何可能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都集中在蛋白质合成的两个关键调节因子上。真核生物起始因子（eIF）4 E和4G分别通过与真核生物mRNA的通用5'帽结构结合并组装前起始复合物来吸引核糖体亚基。Akt和Ras信号传导对翻译因子的影响是已知的，但它们对癌症中蛋白质合成调节的影响尚不清楚。我们发现致癌信号通过调节eIF 4 E活性来控制原型溶瘤脊髓灰质炎病毒PVS-RIPO的抗癌活性。我们观察到，髓母细胞瘤（最常见的小儿CNS恶性肿瘤）中的特定信号环境使得病毒翻译猖獗，导致对PVS-RIPO感染的惊人反应。这项工作测试了我们的假设，即癌症中的蛋白质合成控制是由改变eIF 4 E功能，支持在病毒基因组和PVS-RIPO溶瘤的替代翻译起始。我们的研究准备了一个新的溶瘤药物的临床试验，对鞘内恶性肿瘤。该项目的具体目标是：1）揭示控制eIF 4 E功能的机制和帽非依赖性翻译起始的效率。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帽依赖与非依赖翻译的平衡。2)髓母细胞瘤患者翻译起始因子网络的研究。我们将研究髓母细胞瘤的分子组成，重点是PVS-RIPO溶瘤的蛋白质合成机制和决定因素。3)在体外和大鼠鞘内髓母细胞瘤模型中研究PVS-RIPO及其与PI 3激酶抑制剂的协同作用。我们将在临床前动物研究中研究PVS-RIPO，包括Akt-mTOR信号传导的协同抑制剂。溶瘤重组PVS-RIPO目前正在进行IND指导的剂量范围确定和毒理学研究。在与FDA进行的IND前全面讨论和随后的经验研究中，解决了重大安全性问题。本项目旨在使PVS-RIPO适用于eIF 4 E功能异常（一种与恶性肿瘤广泛相关的分子标志物）患者的鞘内给药。我们的项目将建立必要的基础，开始与FDA的讨论，并提交一份研究性新药申请，用于治疗髓母细胞瘤伴脑膜播散的临床试验。公共卫生相关性：髓母细胞瘤是儿科患者中最常见的CNS肿瘤，并且具有脑膜扩散的晚期疾病对可用的治疗没有反应。我们已经解开了控制这些肿瘤中蛋白质合成的分子机制，使它们对原型溶瘤脊髓灰质炎病毒PVS-RIPO易感。该项目将准备PVS-RIPO用于转移性髓母细胞瘤和其他可能与软脑膜转移相关的癌症患者的临床试验。