Virginia Commonwealth University Massey Cancer Center researchers have found that combining ionizing radiation with a secreted protein that selectively inhibits tumor cell growth and survival can target cancer cells and leave healthy cells alone, perhaps presenting a new approach for treating the deadliest type of brain tumor.
In a study published in the August 2004 issue of the journal Cancer Biology and Therapy, VCU Massey Cancer Center researchers report that exposing primary human glioma cells to radiation combined with the secreted protein, MDA-7 (IL24), activates the pathways in the cell that are associated with cell death. The study builds upon previous findings that demonstrated MDA-7 could sensitize rat brain tumor cells to the toxic effects of radiation both in vitro and in animals.
About 20,000 people in the United States are diagnosed each year with glioblastoma multiforme, the most common malignant brain tumor in adults and the most resistant to treatment. Typically, radiation therapy and chemotherapy are used in the management of gliomas, either following surgical removal or as primary therapy in patients who are not surgical candidates. But glioma is an invasive tumor and the cells are extremely migratory, so even if the bulk of a tumor mass is surgically removed, the cancer is likely to recur.
Lead investigator, Paul Dent, Ph.D., an associate professor in the department of radiation oncology, and his colleagues treated healthy brain-tissue cells and brain-cancer cells with either purified MDA-7 protein or with a genetically engineered adenovirus to make MDA-7 (Ad.mda-7). By itself, MDA-7 or Ad.mda-7, lowered the rate of growth and cell viability of brain cancer cells, but not of the healthy brain tissue cells. MDA-7 magnified the toxicity of radiation in the brain cancer cells – which did not occur in healthy brain tissue cells – suggesting that MDA-7 selectively targets tumor cells.
Researchers also found that MDA-7 made in healthy brain-tissue cells infected with Ad.mda-7 can be exported out of the normal cell and into the surrounding growth media. When a layer of soft agar containing glioma cells was spread over each plate of infected astrocytes, the growth of glioma cells was suppressed by the exported MDA-7. The exported MDA-7 also sensitized the glioma cells in the agar to the toxic effects of radiation. Thus, infected normal brain tissue cells produced MDA-7 which had a toxic “bystander effect” on the tumor cells – the healthy cell, via MDA-7, kills the bystander tumor cell.
“This data suggests that MDA-7 could have a significant bystander effect in the brain,” Dent said. “Normal astrocytes will make MDA-7 and can diffuse readily. MDA-7 would not only suppress the growth of the glioma cells, but it also would make the cells more radiosensitive.
“The findings of this research have implications for the design of a novel therapy for glioma,” he said. “Currently, with Ad.mda-7, there is Phase I data in other malignancies such as head and neck, breast, lung and melanoma,” he said. “The initial reports indicate that some patients are having significant responses with MDA-7 by itself.”
“Unfortunately, treatment strategies for glioma that combine chemotherapy and radiation have failed to produce the effects observed in other tumor cell types,” Dent said. “We believe that new strategies that enhance the effectiveness of standard radiotherapy protocols in glioma, such as Ad.mda-7, are needed.”
Also participating in the study were: Departments of Neurosurgery, Pathology and Urology, Columbia University Medical Center, College of Physicians and Surgeons, New York, N.Y.; Section of Medical Oncology, Department of Oncology, Mayo Clinic and Foundation, Rochester, Minn.; Department of Neurology, University of Pennsylvania, Philadelphia, Pa.; Gene Therapy Center, University of Alabama at Birmingham, Ala.