Oncolytic Virotherapy of Meningeal Cancer

脑膜癌的溶瘤病毒疗法

基本信息

批准号：
8476784
负责人：
Matthias Gromeier
金额：
$ 29.52万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8476784
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

项目摘要

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.

恶性转化与控制细胞的异常活跃的信号转导途径密切相关生长和增殖。致癌信号是多效性的，可以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条主要信号传导途径 Akt 和 Ras 都集中在两个信号通路上：蛋白质合成的关键调节因子。真核起始因子 (eIF) 4E 和 4G 吸引核糖体亚基通过与真核 mRNA 的通用 5' 帽结构结合并组装预起始复合物，分别。 Akt 和 Ras 信号传导对翻译因子的影响是已知的，但它们对翻译因子的影响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 活性发挥抗癌活性。我们观察到髓母细胞瘤是最常见的儿童中枢神经系统恶性肿瘤，其特殊的信号传导环境使病毒翻译猖獗，从而对 PVS-RIPO 感染产生惊人的反应。这项工作检验了我们的假设，即癌症中的蛋白质合成控制受到 eIF4E 功能改变的影响，支持病毒基因组的替代翻译起始和 PVS-RIPO 溶瘤作用。我们的研究准备了用于针对鞘内恶性肿瘤的临床试验的新型溶瘤剂。该项目的具体目标是：1）揭示控制 eIF4E 功能的机制以及不依赖于帽的翻译起始的效率。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以及依赖于帽与不依赖于帽的翻译的平衡。 2）研究翻译髓母细胞瘤患者的起始因子网络。我们将研究髓母细胞瘤的分子组成重点关注 PVS-RIPO 溶瘤的蛋白质合成机制和决定因素。 3) 研究PVS-RIPO 及其在体外和大鼠鞘内髓母细胞瘤模型中与 PI3 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指导的剂量范围寻找和毒理学研究。在与 FDA 进行彻底的 IND 前讨论以及随后的实证调查，发现了重大的安全问题已解决。该项目旨在使PVS-RIPO适用于患者鞘内给药 eIF4E 功能异常，这是一种与恶性肿瘤广泛相关的分子标记。我们的项目将为开始与 FDA 讨论并提交研究性新药奠定必要的基础申请针对髓母细胞瘤脑膜播散的临床试验。