Researchers have found a way to activate Epstein-Barr viruses inside tumors to identify patients whose infection can be manipulated to destroy their tumors. They believe this strategy could offer a way of treating cancers associated with Epstein-Barr, including four types of lymphoma, nasopharyngeal, and gastric cancers.
Researchers have been working on ways to activate the reproductive, or lytic cycle, within the Epstein-Barr virus to make it replicate within the tumor cell. When enough viral particles are produced, the tumor will burst, releasing the virus, they explain. In animal experiments, this therapy, called lytic induction therapy, results in tumor death.
A team of scientists from Johns Hopkins Medical Institutions screened 2,700 agents and finally used two agents already on the market, one of which is the multiple myeloma drug Velcade, to light up tumor viruses on a gamma camera. The technique is the first to use in vivo molecular-genetic imaging without transfecting tumors with a reporter gene, according to the researchers.
“The beauty of this is that you don’t have to introduce any reporter genes into the tumor because they are already there,” says radiologist Martin G. Pomper, M.D., Ph.D. “This is the only example we know of where it is possible to image activated endogenous gene expression without having to transfect cells.”
One of the genes that is expressed on viral lytic induction is EBV’s thymidine kinase (EBV-TK), an enzyme that helps the virus begin to reproduce. Regarding the use of Velcade, Dr. Pomper explains that it “is a proteasome inhibitor, but it also induces the lytic cycle thereby activating the TK in the Epstein-Barr virus. Once the TK is activated, we can image the tumors.”
To test their findings, the researchers used mice carrying human Burkitt’s lymphoma, a cancer often associated with Epstein-Barr viral infection. Tumors glowed in mice given Velcade followed by an injection of a radiolabeled chemical FIAU but not in mice that weren’t given Velcade. Mice whose Burkitt’s lymphoma did not contain Epstein-Barr virus also did not respond to either Velcade or FIAU, according to researchers.
“Velcade woke up the virus in the tumors, which increased viral load by 12-fold, all the while cranking out TK,” Dr. Pomper notes. “An injection of FIAU made it easy to image the tumors with virus in them.”
The method is highly sensitive, he adds; as few as five percent of the cells within the tumor mass needed to be induced into the lytic cycle to be detected.
Not only can FIAU light up the tumors, it can also potentially kill them, Dr. Pomper comments. For imaging purposes, he explains, FIAU can carry a radionuclide that emits a low energy gamma photon but it can also be engineered to carry therapeutic radionuclides, which are lethal to cells in which TK is activated.
Results of this study, reported in the March 1 issue of Clinical Cancer Research, suggests that this strategy could be applied to other viruses associated with tumors, and that other drugs may potentially be used to activate these viruses, according to Dr. Pomper. “Velcade is only one of an array of new, as well as older agents, that can induce lytic infection, and a particular agent could be tailored for use in a specific patient through imaging.”