Oncolytic Virotherapy of Meningeal Cancer

恶性转化与异常活跃的信号转导通路密切相关， 生长和增殖。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都集中在两个 蛋白质合成的关键调节因子。真核生物起始因子（eIF）4 E和4G吸引核糖体亚基 通过与真核mRNA的通用5'帽结构结合并组装前起始复合物， 分别Akt和Ras信号传导对翻译因子的影响是已知的，但是它们对翻译因子的影响是不确定的。 癌症中的蛋白质合成调控尚不清楚。我们发现致癌信号控制着 原型溶瘤脊髓灰质炎病毒PVS-RIPO通过调节eIF 4 E活性的抗癌活性。我们观察到 髓母细胞瘤是最常见的小儿中枢神经系统恶性肿瘤， 使猖獗的病毒翻译，导致惊人的反应PVS-RIPO感染。 这项工作验证了我们的假设，即癌症中的蛋白质合成控制是由eIF 4 E功能改变引起的， 支持病毒基因组的替代翻译起始和PVS-RIPO溶瘤。我们的研究准备一个 用于鞘内恶性肿瘤临床试验的新型溶瘤剂。该项目的具体目标是：1） 揭示控制eIF 4 E功能和帽非依赖性翻译起始效率的机制。 我们将进行基本的分子分析来阐明致癌信号是如何控制溶瘤病毒的 复制和帽依赖与非依赖翻译的平衡。2)调查翻译 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 重点是PVS-RIPO溶瘤作用的蛋白质合成机制和决定因素。3)研究PVS-RIPO 以及其在体外和大鼠鞘内髓母细胞瘤模型中与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进行了全面的IND前讨论和随后的经验性研究， 处理。本项目旨在使PVS-RIPO适用于患者鞘内给药 eIF 4 E功能异常，这是一种与恶性肿瘤广泛相关的分子标志物。我们的项目将 建立必要的基础，开始与FDA讨论并提交研究性新药 申请针对髓母细胞瘤伴脑膜播散的临床试验。

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.