Virus attack on cancer: heat makes neglected technology work better.

Pitting one bad actor against another, scientists are enlisting a virus to take on cancer. Tests in animals and some limited trials in patients have suggested that the technology could be effective. But before the trials progressed to their final phases, drug companies cooled to the idea and set the approach aside.

Some scientists couldn't let go, however. They continued experimenting with viral drugs, which had worked impressively in some patients and poorly in others. One team now reports that adding a little heat to cancer cells in a lab dish enables a virus-based drug to kill cancer cells that at body temperature were unaffected by the drug.

The drug, called ONYX-015, is a common cold virus that's been genetically modified, says study coauthor Frank McCormick, a molecular biologist at the University of California, San Francisco. The genetic engineering removed a gene that encodes the protein E1B-55K, which is instrumental in the growth and survival of a host cell.

When viruses invade a cell, they use it as a factory to make viral proteins and hence virus particles. ONYX-015 fails to consistently infect and kill healthy cells, says Fadlo R. Khuri, an oncologist at Emory University School of Medicine in Atlanta, who didn't participate in this study.

Cancer cells respond to ONYX-015 differently than healthy cells do. The researchers find that colon cancer cells, for example, produce proteins that ultimately permit the virus to make copies of itself. In contrast, bone cancer cells enlist a different set of proteins to replace missing E1B-55K, which makes the cells resistant to ONYX-015 replication, the researchers report in the July Cancer Cell. As a result, the genetically engineered virus replicates in colon cancer cells roughly 100 times as well as it does in bone cancer cells.

In a ploy to make the bone cancer cells more susceptible to the modified virus, researchers warmed them to fever temperatures. Heat throws cells into an emergency mode in which normal protein synthesis stops and only certain proteins are made, McCormick says. His team also applied a drug that elicits the same so-called heat-shock proteins as fever does. Under either condition, the virus revved up manufacture of its proteins.

"That allows the virus to kill the cell," McCormick says. "It blows it up," a cataclysmic event that releases virus particles. Meanwhile, he says, the virus also subverts the infected cell's attempts to commit suicide before manufacturing more virus.

"It's an elegant study" says Khuri, who led the first ONYX-015 trial in people 5 years ago. He notes that once ONYX-015 is injected into a tumor, it spreads on its own from cell to cell.

Sunway Biotech of Shanghai, China, recently ran a clinical test on a genetically engineered virus called H101, which is similar to ONYX-015. The Sunway drug plus chemotherapy was roughly twice as effective as chemotherapy alone in stopping head-and-neck cancers, Sunway scientists reported last year at a medical meeting.