Targeting Nucleotide Biosynthesis: A Strategy for Improving the Oncolytic Potential of DNA Viruses

Abstract

The rapid growth of tumors depends upon elevated levels of dNTPs, and while dNTP concentrations are tightly regulated in normal cells, this control is often lost in transformed cells. This feature of cancer cells has been used to advantage to develop oncolytic DNA viruses. DNA viruses employ many different mechanisms to increase dNTP levels in infected cells, because the low concentration of dNTPs found in non-cycling cells can inhibit virus replication. By disrupting the virus-encoded gene(s) that normally promote dNTP biosynthesis, one can assemble oncolytic versions of these agents that replicate selectively in cancer cells. This review covers the pathways involved in dNTP production, how they are dysregulated in cancer cells, and the various approaches that have been used to exploit this biology to improve the tumor specificity of oncolytic viruses. In particular, we compare and contrast the ways that the different types of oncolytic virus candidates can directly modulate these processes. We limit our review to the large DNA viruses that naturally encode homologs of the cellular enzymes that catalyze dNTP biogenesis. Lastly, we consider how this knowledge might guide future development of oncolytic viruses.

Keywords: adenovirus; cancer; herpes simplex virus-1; nucleotide metabolism; oncolytic virus; ribonucleotide reductase; thymidine kinase; vaccinia virus.

Figure 1

Key cellular nucleotide metabolism enzymes and their herpes simplex virus-1 (HSV-1) and vaccinia virus (VACV) homologs. Shown are the cellular enzymes that catalyze key steps in nucleotide metabolism. Green lettering indicates proteins that are expressed as both cytoplasmic and mitochondrial isoforms, while proteins found only in the cytoplasm are shown in light blue and those found only in the mitochondria are shown in purple. The figure also shows the viral genes encoding homologous proteins. HSV-1 genes are shown in dark blue, VACV in red and adenoviruse (Ad) in orange. Note that the figure over simplifies the biology because it is not possible to display all of the many different isoforms and enzymes, which sometimes also exhibit overlapping catalytic specificities.

Figure 2

Expression of deoxynucleotide biosynthesis genes is altered in a significant portion of cancer cells. A differential analysis of mRNA expression between cancer and normal tissue was performed for each gene using Oncomine Research Edition (Version 4.5) software. A change in mRNA expression greater than twofold, with a P-value <10⁻⁴, was considered significant. The percent of analyses where gene expression was significantly changed in cancer cells was then calculated and plotted. The fraction of samples where gene expression was among the top 1, 5 or 10% of genes whose expression was altered was also calculated. The total number of analyses surveyed in the data, are denoted in brackets beside each gene. Data were retrieved and analyzed on April 6, 2017. Two genes (Myc and VEGFA) whose expression is frequently altered in cancer cells are included for comparison.