May 7, 2003 HOUSTON – A research team led by The University of Texas M. D. Anderson Cancer Center has tested a novel "viral smart bomb" therapy that can completely eradicate brain tumors in mice, while leaving normal brain tissue alone.
The therapy, known as Delta-24-RGD, is thought to be the first treatment for malignant glioma, the deadliest form of brain cancer. It is a new-generation "replication-competent oncolytic" adenovirus therapy –– defined as a therapeutic virus that can spread, wavelike, throughout a tumor, infecting and killing cancer cells. There is no adequate treatment for these deadly brain cancers and, before this study, few experimental therapies tested in animals have shown much improvement.
The findings, published in the May 7 issue of the Journal of the National Cancer Institute, are considered so promising that the National Cancer Institute is providing financial support to produce, in its own labs, a drug-grade version of the therapy to test in humans, possibly by late next year. The researchers are also collaborating with the federal Food and Drug Administration on the treatment.
"We believe this therapy has a lot of potential, but one that needs much more study," says lead author Juan Fueyo, M.D., an assistant professor in M. D. Anderson's Department of Neuro-Oncology and the study's lead author. "We've never seen this kind of response before with any other treatment tested in either animals or humans."
Delta-24-RGD is designed in such a way that it can replicate only in cancer cells, not healthy tissue, in order to reproduce itself while killing the host cancer cell. It moves on to contaminate other tumor cells, and when no more cancer cells are left to infect, the virus itself dies.
"Biologic viral therapy like this may be just what we need to treat a complex disease like cancer," says Frederick Lang, M.D., an associate professor in the Department of Neurosurgery, a primary investigator of the study. "Cancer can be devious in that it does everything possible to evade destruction. But viruses are equally tricky in their quest to invade cells and propagate."
"In this experimental war between cancer and a viral therapy, the virus won," Lang says. "Of course, we hope to obtain similar results when patients are tested, but we cannot predict such success based on animal studies."
Fueyo, Lang and a team of researchers from M. D. Anderson, the University of Alabama at Birmingham and the Institut Catalá d'Oncologia in Barcelona, Spain, found in repeated experiments that more than half of mice that had human glioblastoma tumors implanted in their brains and treated with Delta-24-RGD survived for more than four months, whereas untreated mice lived for less than three weeks.
The mice were considered clinically cured of their brain tumors. Investigators found only empty cavities and scar tissue where the tumors had once been.
Recent advances in the understanding of brain tumor biology have led researchers to target molecular defects in brain tumors. At M. D. Anderson, researchers have focused on a gene and protein product that malfunctions in nearly all malignant gliomas as well as in many other solid tumors –– the retinoblastoma (Rb) protein. Found in all cells of the body, an Rb protein acts like a brake on cell division by preventing certain other regulatory proteins from triggering DNA replication. If the Rb protein is missing or non-functioning, a cell can replicate itself over and over, resulting in the development of a tumor.
In normal cells, the Rb protein also prevents a virus that enters a cell from replicating. Adenoviruses, however, counteract that defensive measure by expressing their own protein, known as E1A, which binds to Rb to stop it from functioning. That allows the common cold virus to "take hold" and spread in human cells until the immune system has a chance to destroy it.
The Delta-24-RGD therapy is designed to take advantage of the mutant Rb protein in cancer cells by introducing a virus with a non-functioning E1A protein, researchers say. Investigators created a new virus with a 24-base pair deletion in the adenovirus E1A gene so that the malfunctioning E1A protein cannot stop Rb from functioning, allowing the virus to infect and kill only cancer cells. A healthy cell with a normal Rb protein can successfully defend itself against the virus, say researchers.
The first version of the therapy (Delta-24) did not infect as many human glioma cells as hoped, so, working with researchers from the University of Alabama at Birmingham, investigators refined the therapy to add an "RGD-4C" binding region. This allowed it to dock to molecules known as integrins on the outside of the cancer cell.
The experiment reported in the Journal of the National Cancer Institute tested the hypothesis that Delta-24-RGD is more effective than Delta-24 in treating gliomas, but that it is equally selective for cancer cells.
Mice in each experiment were divided into three groups of six to 10 animals and all received injections directly into the brain tumors. The mean survival time for mice in the control group, which received a placebo was 19 days. Of 26 mice that were treated with Delta-24, four (15 percent) were considered cured because they survived for more than four months, or to the end of the experiment. But 15 of 25 (60 percent) of mice that received Delta-24-RGD were symptom-free, long-term survivors, says Fueyo. Although researchers don't know why some mice treated with Delta-24-RGD did not survive, they theorize that, due to natural variation, some animals may have needed a bigger dose of the therapy.
Because a glioma tumor does not metastasize, the virus only needs to travel through the tumor body to destroy the cancer. While the researchers say there may be a small zone around the tumor in which some normal cells could be affected from the battle between the virus and the cancer, they will not know if neurological deficits could result until a Phase I clinical trial is launched, which is expected to start in winter 2004.
The researchers also do not know if the human immune system will act against the virus. "We hope that an immune reaction will not inactivate the therapeutic virus," Lang says. "We want to get to the tumor before the virus can be inactivated."
Numerous other experiments have been conducted since this study and they replicate the paper's findings, Fueyo says. "In these new experiments, just as in this study, the majority of animals survived," he reports.
The study was supported by grants from the Pediatric Brain Tumor Foundation, M. D. Anderson, and the Anthony D. Bullock III Foundation. Co-authors include: M. D. Anderson researchers Candelaria Gomez-Manzano, M.D.; Gregory Fuller, M.D., Ph.D.; Charles Conrad, M.D.; Ta-Jen Liu, Ph.D.; Hong Jiang, Ph.D.; Asadullah Khan, M.D.; Michael Lemoine, Raymond Sawaya, M.D.; W. K. Alfred Yung, M.D., Ramon Alemany, Ph.D., from the Institut Catalá d'Oncologia in Barcelona, Spain; and Kaori Suzuki and David Curiel from the University of Alabama at Birmingham.
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