A researcher at Sylvester Comprehensive Cancer Center of the University of Miami Miller School of Medicine has identified a potential target for halting the unchecked cell division in medulloblastoma, the most common pediatric brain tumor. However, laboratory studies indicate that inhibiting cellular division must be done carefully during a relatively narrow window of time to avoid damage to a child’s still-developing brain.
“Our work has significantly advanced understanding of neurogenesis, the cellular process that results in the creation of new neurons in the cerebellum, the last part of a child’s brain to develop,” said Nagi G. Ayad, Ph.D., a Sylvester member and associate professor of psychiatry and behavioral sciences.
Dr. Ayad is the lead author of a collaborative study, “Time Series Modeling of Cell Cycle Exit Identifies Brd4 Dependent Regulation of Cerebellar Neurogenesis,” published recently in Nature Communications. The study included researchers with Sylvester Comprehensive Cancer Center, the Miami Project to Cure Paralysis, and the Departments of Surgery and Neurosurgery, as well as Florida International University, Rockefeller University, University of Texas Southwestern Medical Center, and the University of Nebraska. Funding for this study was provided by the National Institute of Neurological Disorders and Stroke, Sylvester, and the Miami Project to Cure Paralysis.
Miller School co-authors were Clara Penas, Ph.D., Marie E. Maloof, Vasileios Stathias, Ph.D., Jun Long, Ph.D., Sze Kiat Tan, Jose Mier, Jezabel Rodriguez-Blanco, Ph.D., Cheng-Ming Chiang, Ph.D., David J. Robbins, Ph.D., Daniel J. Liebl, Ph.D., and Jae K. Lee, Ph.D..
In the study, the researchers focused on the role of the Brd4 protein in regulating how cerebellar granule cell progenitors (GCPs) divide a certain number of times before differentiating into neurons. “Dysfunction of this process underlies many neurological diseases, including medulloblastoma and ataxia, a degenerative disease of the nervous system,” said Dr. Ayad. “We developed a statistical model identifying the pathways controlling cell cycle exit in GCPs.”
While Brd4 is present during the cellular division process, it is deactivated as the GCPs become neurons, said Dr. Ayad. “By inhibiting Brd4 at the right time, it may be possible to halt the proliferation of brain cells in medulloblastomas,” he added. “However, any potential treatment strategy needs to be done with caution, because children’s brains are still growing and adding new neurons.”
The researchers found that inhibiting or deleting the Brd4 protein in the brains of young laboratory mice resulted in ataxia. But there were no equivalent side effects in mice that were older than the human equivalent of 5-7 years old.
“Our work suggests another potential approach to treating brain cancers in children along with surgery, radiation, and chemotherapy,” said Dr. Ayad. “We also plan to do more biochemical studies to understand why this protein is so essential to cerebellar neurogenesis, since we have deleted other genes in the cerebellum without any consequence.”