Oncolytic Virotherapy of Meningeal Cancer

描述（由申请人提供）：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有着复杂的联系。致癌信号是多效性的，在任何可能的水平上改变细胞生理。有趣的是，涉及癌症生长控制的两种主要信号通路Akt和Ras都集中在蛋白质合成的两个关键调节因子上。真核起始因子（eIF） 4E和4G分别通过结合真核mrna的通用5'帽结构和组装起始前复合物来吸引核糖体亚基。Akt和Ras信号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eIF4E活性来控制原型溶瘤性脊髓灰质炎病毒PVS-RIPO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，其特殊的信号环境使病毒转译猖獗，导致对PVS-RIPO感染的惊人反应。这项工作验证了我们的假设，即癌症中的蛋白质合成控制被改变的eIF4E功能扰乱，支持病毒基因组和PVS-RIPO肿瘤分解的替代翻译起始。本研究为临床治疗鞘内恶性肿瘤准备了一种新的溶瘤剂。本项目的具体目标是：1)揭示控制eIF4E功能和帽独立翻译起始效率的机制。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的复制以及帽依赖性和非依赖性翻译的平衡。2)研究成神经管细胞瘤患者的翻译起始因子网络。我们将研究成神经管细胞瘤的分子组成，重点是蛋白质合成机制和PVS-RIPO肿瘤溶解的决定因素。3)在体外和鞘内成神经管细胞瘤模型中研究PVS-RIPO及其与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信号的协同抑制剂。溶瘤重组PVS-RIPO目前正处于ind导向剂量范围和毒理学研究中。在与FDA进行彻底的ind前讨论和随后的实证调查中，解决了重大的安全问题。本项目旨在使PVS-RIPO适用于eIF4E功能异常患者的鞘内给药，eIF4E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，并提交一份用于脑膜播散性成神经管细胞瘤临床试验的研究性新药申请。公共卫生相关性：髓母细胞瘤是儿科患者中最常见的中枢神经系统肿瘤，伴有脑膜播散的晚期疾病对现有治疗无效。我们已经揭示了这些肿瘤中控制蛋白质合成的分子机制，使它们对原型溶瘤性脊髓灰质炎病毒PVS-RIPO敏感。该项目将准备PVS-RIPO用于转移性髓母细胞瘤患者的临床试验，以及可能与轻脑膜转移相关的其他癌症。

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.