Research Frontiers: Combatting Cancer
The past 30 years have seen remarkable improvements in the treatment of childhood cancers. Children diagnosed with leukemia and other diseases once considered death sentences now typically survive at least five years. But brain cancer remains an ominous threat killing nearly 40% of children within five years of diagnosis, and leaving many survivors with permanent cognitive deficits as a result of surgeries and radiation therapies.
Kennedy Krieger researcher John Laterra, M.D., Ph.D., has dedicated his career to developing strategies to improve brain cancer treatment. Current therapies can carry tremendous side effects. "Radiation is a standard therapy for children with brain tumors," he says. "But doses we know can be effective have very severe side effects in terms of cognition and can be life-altering when it comes to educational and employment opportunities. What's more, the effects of radiation therapy are more pronounced the younger a child is, and the peak incidence of childhood brain tumors occurs during this period of increased vulnerability. Parents are forced to choose forfeiting cognitive capacity in favor of survival. They may decide to delay radiation therapy a year or two."
Dr. Laterra's work strives to eliminate tumors without resorting to such toxic levels of radiation. Earlier research determined that a chemical in the brain called hepacyte growth factor (HGF) makes gliomas, the most common primary brain tumors in children, resistant to radiation therapy. As a result, large amounts of radiation are needed to combat these tumors. Now, in a paper recently published in Clinical Cancer Research, Dr. Laterra explains how by using gene therapy to inhibit HGF and its cell surface receptor C-Met in animal models, it is possible to dramatically improve the efficacy of much lower, safer doses of radiation than are used in cancer therapies today.
"The difference in response was profound," says Dr. Laterra. "There were no long-term survivors in the group of rodents that received no therapy or a low dose of radiation therapy alone. In the group that received just gene therapy, 20% survived. In the group that received a combination of low-dose radiation and gene therapy, 80% survived."
Unfortunately, gene therapy can involve serious long-term side effects and is a relatively inefficient means of targeting the HGF/C-Met pathway. The key, says Dr. Laterra, is to develop therapies that are easier to translate into commercially available drugs. To reach this goal, Dr. Laterra and his colleagues at Kennedy Krieger have partnered with Galaxy Biotech, LLC of Mountain View, California to develop monoclonal antibodies that bind to HGF and prevent it from activating its receptor, C-Met. The team is working with animal models, but the strategy of using antibodies to target cancer-causing proteins is proving to be effective against other forms of cancer in humans.
"There are other antibody-based cancer drugs that are approved by the Food & Drug Administration," says Dr. Laterra. "One is Herceptin, which has dramatically improved breast cancer treatment. It's taken longer to reach this point with brain tumors because they occur relatively infrequently and it's been more difficult to understand the pathways that drive the tumors. But it is the most common cause of cancer-related death in children, so it has the most devastating impact. Now, we have a clearer pathway to the development of drugs that can make a profound difference in how this disease affects the lives of children diagnosed with it."