In the Nov. 5, 2003, Proceedings of the National Academy of Sciences (PNAS) online, University of Wisconsin Medical School researchers report that Epstein-Barr virus (EBV) does, in fact, contribute directly to the survival of Burkitt's lymphoma tumors. By elucidating the exact mechanism involved in maintenance of the tumors, the researchers open the door to the development of effective, targeted therapies for all EBV-associated tumors.
Tumor viruses-such as human papilloma virus, hepatitis B virus and EBV--are responsible for 15 percent of all cancers in humans. The viruses combine with acquired genetic mutations to produce disease. While EBV lives unnoticed in as many as 95 percent of all humans, it also produces cancers that kill nearly 100,000 people around the world each year.
There are two ways to prevent tumor viruses from doing damage, according to Bill Sugden, PhD, professor of oncology at the McArdle Laboratory for Cancer Research. One is to develop a vaccine that triggers immune responses that neutralize the virus; the other is to cripple viral gene products that maintain cells as tumors.
"If you can find viral gene products that contribute not just to creating the tumor but also to maintaining it, you can conceivably destroy those gene products--and kill the tumor--without harming other tissues," says Sugden, the senior author on the PNAS paper who has worked on EBV for 30 years.
Sugden and lead author Greg Kennedy, MD, PhD, a surgery resident at UW Hospital and Clinics, and former post-doctoral fellow Jun Komano, PhD, examined the precise way in which EBV affects B cells that evolve to be tumors. Under normal conditions, B cells mount responses to invading organisms by making protective antibodies and then dying.
But with Burkitt's lymphoma, the system breaks down. "Burkitt's lymphoma is an aggressive B cell malignancy characterized by rapid cell proliferation that can be fatal within months if not treated immediately," says Sugden. The standard treatment is chemotherapy, which can destroy healthy as well as cancerous cells.
The Wisconsin researchers focused on one protein expressed by EBV and found in all EBV-related tumors-called Epstein-Barr nuclear antigen 1 (EBNA-1). "We and others had learned that not only is this protein required for the viral DNA to be replicated in cells, but it does so by binding to specific sites on the viral DNA," explains Sugden.
Almost 10 years ago, Sugden and his colleagues made a derivative of EBNA-1, which inhibits the real protein. When the derivative binds to its site on the EBV DNA, it prevents EBNA-1 from doing so, interrupting its functioning.
In the current experiments, begun five years ago, the scientists introduced the derivative into three kinds of B cells-EBV-infected Burkitt's lymphoma cells, normal EBV-infected cells and uninfected cells. They found that in all cells containing EBV, the derivative prevented the cells from proliferating--and unexpectedly induced them to die.
"In effect, EBNA-1 rescues B cells from their programmed death, and allows the cells to continue to proliferate," says Sugden. "In children destined to develop Burkitt's lymphoma, multiple events must occur in addition to infection with EBV. But the continued functioning of EBNA-1 is pivotal to the survival of these tumor cells."
An obvious approach to preventing the cell proliferation is inhibiting EBNA-1 from doing its job. "My hope is that scientists can now develop small molecules that carry out the same function as the EBNA-1 inhibitor we've made in the laboratory, but in a way that can be delivered readily to the tumor cells in patients," Sugden says. "Such therapy would induce programmed cell death in Burkitt's lymphoma."
It's reasonable to expect, he says, that a small molecule could be designed to attach to a specific location on EBNA-1 to keep it from functioning, without disturbing any other human proteins. "Finding such a therapy--one with no or minimal side effects--is our goal," says Sugden. "Tumor viruses that encode proteins not found in normal cells provide this unique possibility."
The UW cancer researcher will apply to the Grand Challenges in Global Health, which supports research addressing major health problems prevalent in Africa, for funding for more research.
"In addition to helping patients with Burkitt's lymphoma and Hodgkin's disease, treatment could help people with suppressed immune systems, who also are susceptible to B cell lymphomas," adds Sugden. The latter group includes bone marrow transplant, kidney transplant and AIDS patients.