June 21, 2007 With nearly $1 million in government funding, University of Rochester scientists are testing a new innovation in biotherapy by altering a common childhood respiratory virus, the adenovirus, to destroy cancer cells.
Exploring the potential of biotherapy through oncolytic adenoviruses is a hot area in cancer research. The approach is analogous to the police employing a snitch to reach the bad guys: For years scientists have been engineering relatively benign viruses to selectively infiltrate and deliver genetic materials into more dangerous cells.
However, the current generation of mutant viruses under study has limitations. So far, they are proving to be effective only in tumor cells that express certain proteins. The Rochester group designed an entirely new version of the adenovirus that might have broader, more powerful potential. The first experiments will be on pancreatic cancer, one of the deadliest malignancies.
"Our concept is very promising and we hope it will open the door to safer and more effective treatments," said Baek Kim, Ph.D., associate professor of Microbiology and Immunology at the University of Rochester Medical Center and study co-investigator. "If this works, the most exciting part is that patients would be able to generate their own internal weapons to kill the malignant cells without having to endure a toxic element such as chemotherapy."
Kim and co-investigator Stephen Dewhurst, Ph.D., senior associate dean for basic research at the University of Rochester, began looking at a novel approach to cancer treatment after investigating HIV/AIDS. Even though HIV and cancer are unrelated illnesses, they discovered a common link in the deadly efficiency of HIV cells and cancer cells.
Cancer cells are known to have a high concentration of dNTP, a building block of DNA. In fact, cancer cells require high dNTP concentrations in order to replicate their chromosomes fast enough to continually divide and invade the body. Two years ago, Dewhurst and Kim discovered that a driving force behind HIV's efficiency was also its unique ability to use dNTP to make DNA. Indeed, the DNA polymerase (an enzyme) of HIV allows the virus to infect cells within the immune system that lack dNTP.
They wondered if they could make a mutant form of HIV that could go head-to-head against cancer, binding to the dNTP and replicating only in malignant cells.
"This theory was a terrific but it had one big problem: you cannot test it in people because you cannot give people HIV," explained Kim. "So we had to find another route. That's when we came up with the idea of modifying the adenovirus with dNTP."
Thus, the Rochester team set out to construct a new weapon. Their adenovirus vector contains mutant DNA polymerase (dNTP) that should activate only in cells with a high concentration of dNTP, such as cancer cells. Once the virus enters the cancer cell, it should also create new "soldiers" to destroy neighboring cancer cells while leaving normal cells alone, Kim said.
When the job is done, the adenovirus should die out. Side effects should be minimal. Since the adenovirus does not contain toxic elements, the worst-case scenario would be that it would cause an infection in the body's healthy cells, producing flu-like symptoms that are treatable, Kim said.
Investigators are testing the concept in mice and in the laboratory with human pancreatic cancer cells. Pancreatic cancer was selected because of its poor prognosis and current lack of effective therapies. Although it accounts for only about two percent of new cancer cases diagnosed annually in the United States, it accounts for six percent of cancer deaths.
The National Cancer Institute and the U.S. Department of Defense is funding the research.
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