Now, Delta-24-RGD is expected to start the first phase of human testing in late summer 2004, with a two-staged clinical trial of 15 patients each. One stage will offer the treatment by injection to patients with recurrent gliomas who cannot be treated with surgery. Progress will be monitored with serial diagnostic scans. In the second stage, patients with a glioma will have the therapy, followed by surgery two weeks later. The excised tumor will be examined to see if it has been damaged.

This trial is just part of an ongoing larger "platform" of research that is continually refining Delta-24-RGD therapy, says Charles Conrad, M.D., an associate professor in the Department of Neuro-Oncology who works with Fueyo, Lang and others on the "Delta team."

They have already created a second and now a third generation of the therapy, each of which is proving more adept in infecting cancer cells and disarming them. One idea is to insert genes into the viral smart bomb that will switch on chemotherapy drugs. This way, a patient could receive an inert form of a chemotherapy drug that would be non-toxic to normal cells, but would be activated by the Delta virus when it spreads in cancer cells. "We would deliver the gene that activates the chemotherapy drug only to tumor cells," says Conrad.

The team, which includes other international and national investigators, also is exploring adapting Delta-24-RGD to other cancer types, such as colon cancer. Questions remain, however, as to whether the therapy will evoke a systemic immune response and just how the virus will be able to spread given physical barriers - such as bones or cavities - that are just a natural part of the body's interior. Many solid tumors also contain areas of dead tissue, which could stop the virus's ability to replicate. Finally, researchers are concerned about the issue that has dogged all adenovirus vectors - that, below the neck as it were, a patient could mount an immune response that would blunt the effectiveness of the therapeutic virus.

"We will have our proof of principle in treating gliomas," says Conrad. "If it is safe, and shows some benefit, we will want to try it in other cancers."Naked genesGene therapy's limitations may prove to be a boon to one area of cancer treatment. Knowing that, at least to date, the strategy works best when injected directly into tumors, M. D. Anderson researcher Gary Clayman is using "topical" gene therapy to treat patients at risk of developing oral cancer.

The first of a planned 44 patients has been enrolled in the phase I/II clinical trial, funded by Introgen, in which participants will gargle twice a day with a solution intended to replace the p53 gene that is likely missing from cells that are within several millimeters of the surface of their mouth and throat.

"This is more befitting of what this technology may be able to offer," says Clayman, M.D., a professor in the Department of Head and Neck Surgery. "The cells we need to treat are near the surface. We don't need to go deep. It's not a systemic disease."

There has been no way to prevent development of these head and neck cancers, and once they arise, they are diffuse and difficult to treat, says Clayman. But if a treatment can reach the thin layer of cells from which the cancer arises, it may be possible to reverse or even kill the cancer, he adds.

The trial, conducted only at M. D. Anderson, is the first to test a preventive cancer strategy using a novel gene therapy, says Clayman. He believes that while other forms of gene therapy have shown suggestions of clinical activity, "translation to clinical utility may not be there. We need to focus on the limited ways in which gene therapy may truly help patients."Gene therapy for metastasisOthers at M. D. Anderson heartily agree that most of the current gene therapy strategies do not effectively address the thorniest problem in cancer care - treating cancer that has spread - and that is why they are breaking new research ground.

One team has already harnessed the power of stem cells to act as seek-and-destroy missiles that can find cancer wherever it hides out - at least, so far, in animals.

This novel treatment, which was presented last year at a scientific meeting, takes advantage of the fact that tumors attract a certain kind of stem cell, mesenchymal progenitor cells (MSC), which acts as the body's natural tissue regenerators. These unspecialized cells migrate to an injury by responding to signals from the area, and there they develop the kind of connective tissue that is needed to repair the wound, and can become any kind of tissue required.

But they also respond to tumors - often described as "never healing wounds" - which "call" the stem cells to help build up normal tissue that is needed to support the cancer.

So a research team led by Michael Andreeff, M.D., Ph.D., professor in the Departments of Blood and Marrow Transplantation and Leukemia, is turning the tables on the cancer.

In experiments in mice, they have removed a small amount of MSC from bone marrow, expanded the quantity in the laboratory, and genetically altered the stem cells to carry a therapeutic gene. When given back to the mice through an intravenous injection, the millions of engineered stem cells home in on cancer cells that are signaling them, engraft and activate their genetic payload, which then disables the cancer.

So far, the therapy has been successfully tested in mice that have a variety of human solid cancers, such as ovarian, brain, breast and melanoma, and even blood-based leukemia.

"This drug delivery system is attracted to cancer cells no matter what form they are in or where they are," says Andreeff. He is planning to apply for federal permission to test the concept in patients with melanoma."We will need to optimize the genes that are delivered, and are building a program around that, but the most important discovery here is that these cells are capable of migrating from the bone marrow or blood circulation into tumors," says Andreeff.

"It is exciting because it is an entirely new approach that looks like it can be developed into a potent therapy," he says. "It's not just a twist of an old idea."