Sep. 17, 1998 Despite advances in neuroimaging and surgery, no major developments in the treatment of malignant brain tumors have been introduced in the past two decades. Right now, surgeons rely on radiation therapy after removal of the tumor to mop up microscopic cancerous cells that could lead to regrowth. Brain tumors, however, are extremely resistant to radiation treatment. Researchers at the University of Pennsylvania Medical Center have now found a way to make brain cancer cells more receptive to radiation treatment --by 60-fold in some cases.
"The goal of our research is to extend the survival of terminally ill patients and give them a better quality of life during that time," says Donald M. O'Rourke, MD, assistant professor of neurosurgery. "Following a diagnosis of brain cancer, median survival of patients is only 12 months with treatment." More than 17,000 new cases of brain cancer are reported each year, according to O'Rourke, and this diagnosis is nearly always fatal.
In a biochemical one-two punch to brain cancer cells, O'Rourke and colleagues inactivated a common cell-surface receptor called the Epidermal Growth Factor Receptor (or erbB for short) to arrest cell growth in human cell lines, which further sensitized the cells to radiation. This approach works in a similar way to Herceptin, the new breast-cancer-fighting drug awaiting FDA approval. Herceptin, a monoclonal antibody therapy, is based on the basic research performed by the laboratory of Mark I. Greene, MD, PhD, at Penn. Both strategies target mutated or overexpressed erbB receptor proteins that allow cancer cells to grow unchecked.
"Depending on which type of cell we used, we achieved between 20 and 60 percent cell death in cancer cells where the erbB receptor was first deactivated, versus zero to 5 percent in radiation-alone controls," reports O'Rourke. These findings were published in a September issue of the Proceedings of the National Academy of Sciences.
ErbB receptors are a family of four proteins and are widely expressed in many tumors; but, when mutated or overexpressed at very high levels, lead to abnormal enzyme activity and deregulated cell growth. "The mutated or overexpressed receptors tend to be associated with cancers of the brain, breast, ovary, prostate, and pancreas," explains lead author O'Rourke. "There are either more receptors on the cell than normal or the ones that are there are more active."
The researchers are aiming for a more targeted approach than radiation and chemotherapy to kill cancer cells that remain after surgery. "ErbBs are a natural target to block," says O'Rourke. "There's more of a biological likelihood that we may impact this disease and minimize side effects using this strategy."
The group is currently working on several ways to inactivate erbB receptor proteins. One is a form of gene therapy to make cancer cells express a non-active receptor. "The second form of inhibition, which is even more promising, will be the use of smaller compounds called peptide mimetics," says O'Rourke. "These compounds are less complicated and work directly on the cell surface, eliminating the need to get to the cell's nucleus, as with gene therapy." The team is currently designing human clinical trials, notes O'Rourke, but they're still about six to twelve months away from starting trials.
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