Of the primary modalities used to treat cancer, few are selective and even less exhibit minimal toxicity. This underscores the need for new and effective therapeutic agents that meets both requirements. Oncolytic viruses appear to be such a treatment. The 55K-mutant adenovirus is in phase III clinical trials for use in cancer therapy. This lab has shown that the 55K-mutant virus selectively replicates in and kill S-phase infected cells. However, the basis for this selectivity is not known. Understanding the basis for the S-phase selectivity of the 55K-mutant virus may point to how the virus can be manipulated to be more effective at killing tumor cells.
The first aim of this project is to determine the mechanism in S-phase that leads to an increase in late viral gene translation of the 55K-mutant virus. Late viral messages with appropriate leader sequences will be made and the rate of protein production measured to test the hypothesis that the decrease in late viral gene translation of the 55K-mutant virus in G1 infected cells is due to a decrease in ribosomal shunting. Remarkably, deletion of the E4orf1 and E4orf2 genes from the 55K-mutant virus restores viral protein production to near wild-type virus levels and abrogates the G1-restriction. Using recombinant viruses, the second aim of this project will determine if the G1-restriction is due to the ability of E4orf1 or E4orf2 to attenuate late viral gene translation. This work tests the hypothesis that the S-phase selectivity of the 55K-mutant virus is due to an increase in translation of late viral messages which is restricted in G1 by E4orf1. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31CA110207-01
Application #
6829781
Study Section
Special Emphasis Panel (ZRG1-ONC-O (29))
Program Officer
Bini, Alessandra M
Project Start
2004-08-15
Project End
2007-08-14
Budget Start
2004-08-15
Budget End
2005-08-14
Support Year
1
Fiscal Year
2004
Total Cost
$40,307
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Biology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157