Grant: Operating Grant

During the process of transformation, a cancer cell acquires many different mutations. However, these mutations can sometimes create an "Achilles heel" in that they often render cancer cells sensitive to virus infection. Oncolytic virus therapies try to exploit these deficiencies by using viruses as tools for killing cancer cells. This project examines whether the poxvirus once used as a smallpox vaccine, vaccinia virus, can be used to safely and selectively kill cancer cells. We have been studying a virus-encoded protein called ribonucleotide reductase (RR). RRs play a key role in making the deoxyribonucleotides (dNTPs) that are used as building blocks for DNA synthesis. We have discovered that if one mutates the virus RR gene, the virus becomes dependent upon the host cell to provide the dNTPs that are needed for virus replication. This is important, because the levels of dNTPs fluctuate with the growth of the cell and are elevated in rapidly dividing cancer cells. Because these mutant viruses grow poorly in non-dividing cells, but grow well in tumor cells, we hypothesize that they would be safer and more selective oncolytic agents. Because cancer cells require dNTPs for growth, the biochemical pathways that produce dNTPs are important targets for chemotherapeutic drugs. Cellular RR is one of the most important of these drug targets, and many cancers are treated with RR inhibitors. Unfortunately, these treatments can select for drug resistant cells due to increased RR activity. Since these drugs may be the last line of therapy for some patients, the consequences are often fatal. We also hypothesize that RR-deficient poxviruses might offer special advantages for treating such drug-resistant cancers. This project will test whether RR-defective vaccinia viruses are safe and effective oncolytic agents in preclinical models for breast cancer and bladder cancer, and whether these viruses would offer an effective treatment for drug-resistant cancers.