The American Brain Tumor Association has provided funding assistance through its Discovery Grant program toward the development of a new investigational drug for glioblastomas, the most malignant of all primary brain cancers. The Methodist Hospital in Houston and Dallas-based Remeditex Ventures LLC have entered into an exclusive agreement to develop the drug. Current treatments only prolong survival for an average of five months.
The drug MP-MUS was developed by David S. Baskin, M.D., and Martyn A. Sharpe, Ph.D., Department of Neurosurgery researchers at the Methodist Neurological Institute and The Methodist Hospital Research Institute. This novel substance has been shown in recent studies to kill human glioblastoma cells in cell culture and in an animal model. The drug works by selectively targeting mitochondria in glioblastoma cells and destroying mitochondrial activity. Methodist's sponsored research agreement with Remeditex could help move the drug toward human clinical trials.
“In glioblastomas, expression of the enzyme monoamine oxidase B is typically elevated by more than five-fold on the surface of the mitochondria, relative to normal, healthy cells," said Baskin, a Professor of Neurosurgery and the project's principal investigator. "Dr. Sharpe and I designed a drug that binds to this enzyme and is changed to a positively charged toxic compound. This compound is rapidly drawn across the mitochondrial membrane and ends up inside, after which it breaks mitochondrial DNA and kills the cell. We are hopeful the selective delivery of a chemotherapy drug into the mitochondria of glioblastoma cells will one day change how physicians treat this deadly form of brain cancer."
Approximately 10,000 people are diagnosed with a glioma in the United States each year. Treatment usually involves surgery and chemotherapy but the survival rate is poor, with only one patient in five surviving two years.
Mitochondria, often called the "powerhouses of the cell," have their own DNA. Once inside the mitochondria, the drug MP-MUS causes breaks in mitochondrial DNA, which is not repaired. As the mitochondria degrade, reactive molecules are released that further damage the cancer cells, killing them. Since MP-MUS is much more likely to be imported by glioma mitochondria, the mitochondria in normal cells are spared.
Baskin and Sharpe’s research suggests MP-MUS's toxicity in mouse and chimera models is nil at therapeutically relevant doses of the drug. The drug is the first known example of targeted chemotherapy that selectively attacks the mitochondria.
“Drs. Baskin and Sharpe and the Methodist team are using clever chemistry that allows MP-MUS to target just cancer cells without damaging nearby healthy tissue,” said Claire Aldridge, Ph.D., vice president of venture development at Remeditex. “The next step in determining the potential for this technology as a therapeutic will be implanting glioblastoma cells from patients into the brain in an animal model to test whether the promise of this therapy in the tissue culture dish and initial animal studies translates into an appropriate in vivo model using the brain microenvironment.”
If animal testing is successful, Remeditex has an exclusive option to license and commercialize MP-MUS to bring a much needed new treatment to glioma patients.
MP-MUS was developed with funding assistance from the American Brain Tumor Association, The Taub Foundation, and The Methodist Hospital Foundation.