New research from the University of Alabama at Birmingham identifies a key regulator of brain-tumor growth that holds potential for targeted therapy and can be an independent predictor in patient outcomes.
In a study that was published online in Clinical Cancer Research, a journal of the American Association for Cancer Research, on May 22, 2012, Christopher D. Willey, M.D., Ph.D., assistant professor in the UAB Department of Radiation Oncology and associate scientist in the experimental therapeutics program at the UAB Comprehensive Cancer Center, has examined a protein called Myristoylated Alanine Rich C-Kinase Substrate, or MARCKS, in the context of glioblastoma multiforme, the most common and deadly cancer originating in the brain.
Until now, very little was known about what MARCKS does in brain tumors. Based on studies in glioblastoma cell cultures and in human glioblastoma tumors implanted in mice, the research team led by John Jarboe, graduate student in the UAB Medical Scientist Training Program, found that when MARCKS levels are low, glioblastoma behave very aggressively, but when MARCKS levels are high, glioblastoma are much less aggressive, suggesting that MARCKS may behave like a tumor suppressor.
“When we reduced MARCKS levels in the cancer cells, the tumor cells grew more rapidly and became resistant to the standard treatment of GBM — radiation therapy,” says Willey. “Conversely, when we overexpressed MARCKS in aggressive GBM cells with low basal levels of MARCKS, we were able substantially to slow their growth and make them enter a dormant state known as senescence.”
These findings were not limited to cell culture and animal models. The research team also investigated The Cancer Genome Atlas, a database that catalogs genetic and clinical information about various cancer patients, including patients with glioblastoma multiforme. They discovered that patients with higher levels of MARCKS expression lived longer than patients with lower levels. The researchers also found that a particular subgroup of patients especially benefitted from high levels of MARCKS expression.
During the past several years, investigators have used information within resources such as the Cancer Genome Atlas to identify subclasses of glioblastoma multiforme that are related at the molecular level. “We found that high MARCKS expression was protective to younger patients even when they had other poor prognostic markers. We also found that some patients had vastly improved survival when MARCKS expression was high — going from a median survival of less than 11 months up to an astounding 65-month median survival,” says Willey.
The results from this study suggest that MARCKS may be a biomarker for prognosis and could serve as a potential target for therapy in glioblastoma multiforme. “We feel that MARCKS-targeted agents have the potential to modify the natural history of GBM, particularly because we see that patients with high levels of MARCKS live considerably longer,” says Willey.
The research was funded by the American Society for Radiation Oncology, the National Institutes of Health, the UAB Brain Specialized Program of Research Excellence grant, and the University of Alabama Health Services Foundation.