Targeting melanoma with HIV?

Los Angeles - A modified form of the HIV virus has been shown to be effective in targeting melanoma in animal models, according to a study published in Nature Medicine in February.

Using genetic engineering, researchers here took the AIDS virus and modified it, removing 80 percent of its active components, and injected it into tumor cells in mice that had metastatic melanoma.

"What we were left with is a skeleton of the virus," according to Irvin Chen, M.D., director of the University of California at Los Angeles (UCLA) AIDS Institute. "It really is serving only as a carrier. We then gave the virus a new coat or envelope to allow it to enter the tumor cells and bind themselves to P-glycoproteins. Every virus has a unique coat. The coat of HIV, for example, binds to molecules on CD4."

Researchers attempted to use other coats, before the Sindbis virus, but they did not prove successful, Dr. Chen says.

Researchers also added luciferase, a protein that makes fireflies glow, to the virus to follow its journey. The modified HIV was injected into a mouse's tail, and a special optical camera was used to watch its movement.

"This is a proof-of-concept study," according to Dr. Chen, a professor of Medicine, Microbiology, Immunology and Molecular Genetics and a member of the Jonsson Comprehensive Cancer Center at the David Geffen School of Medicine at UCLA. "This shows that our approach can work. We can design the virus so that it binds to only those cells that we want it to bind to.

"We chose to target P-glycoproteins on the surface of metastatic melanoma cells because P-glycoproteins happen to be expressed in many types of tumor cells, and because it's an important molecule," Dr. Chen says. "It could have been anything else that was expressed on the cancer cell. In future applications, we will be using other molecules on the surface of the cancer cells, not just P-glycoproteins."

Future targets He gave the example of self-surface molecules on lymphocytes, CD20, or prostate-specific molecules on prostate cancer cells as future targets.

"It would really depend on what cancer we are focusing on," he says. "The broader implications are that it doesn't have to be cancer cells that we target. We could be targeting normal cells in the body, where you want to introduce gene products or drugs. It's very generally applicable."

The P-glycoproteins cause the tumor cells to be resistant to chemotherapy, so medications do not produce a response, and the tumors continue to grow, according to Dr. Chen.

The research team chose melanoma because it represents a challenge in treatment, particularly metastatic, and because in practical terms, there are good models for melanoma that can be exploited, using mice.

Next step: humans? The next step in the research would be to introduce into our stripped down HIV a genetically engineered therapeutic agent that would either kill the tumor cells, or enhance the immune response, or administer agents that would cut off the blood supply to tumor cells, Dr. Chen says. He estimates that it would be about four or five years before any phase 1 trials in humans would be conducted.

"We want to explore a number of approaches in animal models before we begin conducting trials in humans," he says. "Certainly, with genetic engineering, there are things that can happen that we can't anticipate. Trials in some gene therapy efforts, such as with the adenovirus, have been stopped because of that fact. Therefore, it's important to test safety first."