Triggering Viruses inside Tumors to Image then Kill Cancers

Researchers have found a way to activate Epstein-Barr viruses (EBVs) inside tumors as a way to identify patients whose infection can then be modified to destroy their tumors. They reported that this strategy could provide an innovative way of treating many cancers associated with Epstein-Barr, including at least four different types of lymphoma and nasopharyngeal and gastric cancers.

In the March 1, 2007, issue of the journal Clinical Cancer Research, a group of radiologists and oncologists from Johns Hopkins University Medical Institutions (Baltimore, MD, USA) described how they utilized 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 in the new field of in vivo molecular-genetic imaging that does not require transfecting tumors with a "reporter” gene, according to the scientists.

"The beauty of this is that you don't have to introduce any reporter genes into the tumor because they are already there,” remarked 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.”

A host of blood and solid tumors are more likely to occur in individuals who have been infected with the EBV, but not everyone with these cancers has such infections. For those who do, researchers, such as Hopkins oncologist and co-author Richard F. Ambinder, M.D., Ph.D., have been working on methods to activate the reproductive, or "lytic” cycle, within the virus to make it replicate within the tumor cell. When enough viral particles are generated, the tumor will burst, releasing the virus. In animal studies this experimental therapy, called lytic induction therapy, results in tumor death.

As the first phase in this study, researchers screened a wide variety of drugs to see if any of them could reactivate the virus. They were fortunate in that one of the genes that is expressed upon viral lytic induction is EBV's thymidine kinase (EBV-TK), an enzyme that helps the virus begin to reproduce. This kinase is of significance because researchers know its "sister” kinase, the one produced by the herpes simplex virus, can be imaged by an injected radiolabeled chemical fialuridine (FIAU), which can then be imaged using a gamma camera.

"To perform molecular-genetic imaging, we have always had to infect cells with active herpes simplex virus so that they can replicate, express TK, and only then could we use the FIAU tracer to make the cells light up,” Dr. Pomper stated. "So we were hoping to find a way to turn latent Epstein-Barr virus on in these cancers, and use the thymidine kinase it then produces to enable us to see the virus-associated tumors with radiolabeled FIAU.”

The researchers screened 2,700 agents until they found Velcade (bortezomib), a targeted chemotherapy drug already approved for use in multiple myeloma. Velcade was developed by Millennium (Cambridge, MA, USA).

"We were both surprised and lucky,” Dr. Pomper says. "Velcade 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 evaluate their findings, the researchers used mice carrying human Burkitt's lymphoma, a cancer frequently associated with Epstein-Barr viral infection. Tumors glowed in mice given Velcade followed by an injection of FIAU, but not in mice that were not given Velcade. Mice whose Burkitt's lymphoma did not contain Epstein-Barr virus also did not respond to either Velcade or FIAU, according to the researchers. "Velcade woke up the virus in the tumors, which increased viral load by 12-fold, all the while cranking out TK,” Pomper stated. "An injection of FIAU made it easy to image the tumors with virus in them.”

The method is highly sensitive, according to Dr. Pomper, as few as 5% 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, according to Dr. Pomper. For imaging purposes, FIAU can carry a radionuclide that emits a low energy gamma photon, but it can also be engineered to carry therapeutic radionuclides, which are deadly to cells in which TK is activated.

The findings of this study suggest 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.”


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