Feb. 5, 2005 ROCHESTER, Minn. -- An international team of Mayo Clinic-led researchers is first to devise a system that consistently converts the measles virus into a therapeutic killer that hunts down and destroys cancer cells -- and cancer cells only. Their research findings appear as an advanced electronic article of Nature Biotechnology.
The researchers harnessed the viral trait for attacking and commandeering cells, and then redirected the virus to attack diseased, rather than healthy cells. The work was done on laboratory animals implanted with two kinds of human cancer cells -- ovarian cancer and lymphoma -- and is probably still years away from use as a human therapy. But the concept has at last been proved in mice with human cancer tumors -- and that's an essential step toward using this approach to expand and improve human treatments for a variety of cancers.
The "Obedient Virus"
"When I saw the data, I was completely stunned. It's the sort of thing that, having worked on targeting viruses for about 15 years, I just couldn't believe that we'd finally got what we'd been hunting all that time," says Stephen Russell, M.D., Ph.D., lead researcher and director of Mayo Clinic's Molecular Medicine Program.
"It's very clean, very clear targeting. Our results show that we've efficiently ablated (destroyed) the ability of the measles virus to interact with its two natural receptors. And they also show that we can take our pick as to what new receptor we target and send the virus after it."
How They Did It
Using bioengineering techniques, the team reprogrammed the measles virus to seek a cancer cell to bind to instead of its natural binding partner. Then they invented a "molecular tag" that they attached to structures on the outside of the cancer-seeking measles virus. This tag is the key innovation of their work and central to the success of the team's investigation. It enables researchers to grow retargeted measles virus on special "universal substrate cells" -- while at the same time conserving the viral component for targeting and destroying tumors. Mass production of a retargeted virus was not possible before this specific innovation of the molecular tag -- and research in this area was at an impasse. Not any more.
"The virus goes where it's meant to go, and it destroys the tumors in a targeted way," says Dr. Russell.
Natural viruses are cellular parasites. To reproduce more viruses, they need to bind to a partner on their target cell, fuse membranes to enter the target cell and then take over the cellular machinery. When they succeed in doing this, an infection occurs. Viruses are so good at taking over cells that researchers have long dreamed of exploiting the specific attraction viruses have to certain cells and using it as a homing device to seek and enter cancer cells.
The measles virus became the focus of this vision several years ago when the surprising finding was made that the measles strain used internationally for vaccinations has natural anticancer activity.
"But we had a concern that the measles virus may be a little too promiscuous in its ability to infect both cancer cells and non-cancer cells, so we wanted to develop a method whereby we could retarget the virus to infect cancer cells only," says Dr. Russell. "And we succeeded."
Collaboration and Support
In addition to Dr. Russell, the Mayo Clinic research team includes Takafumi Nakamura, Ph.D.; Kah-Whye Peng, Ph.D.; Mary Harvey, Suzanne Greiner and Charles James. From the University of Ottawa, Ian A.J. Lorimer, Ph.D, contributed his expertise. The work was funded by The Mayo Clinic Foundation, the Harold W. Siebens Foundation, and the National Cancer Institute.
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