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.
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.
