Novel Drug Combination Inhibits Growth of MYC-driven Medulloblastoma
The growth of medulloblastoma was inhibited by a new drug in research conducted in cell cultures and mice. Medulloblastoma is a highly malignant childhood brain cancer, and this study targeted a particularly aggressive form of the disease driven by the oncogene MYC.1
The researchers conducted a high-throughput drug screen in a MYC-driven medulloblastoma mouse model. Histone deacetylase inhibitors (HDACIs) were among the most effective compounds at decreasing the viability of cancer cells in mice.
Researchers then discovered the likely mechanism that HDACIs use to decrease cancer growth. In a cell culture model of MYC-driven medulloblastoma, HDACI administration activated a tumor-suppressing gene, FOXO1.
Further cell culture results suggest that HDACIs work with phosphatidylinositol 3-kinase inhibitors (PI3KIs) to increase FOXO1 and decrease cancer cells more than either inhibitor compound separately. Additional mouse experiments confirmed that HDACIs and PI3KIs synergize to decrease cancerous growth without harming healthy cells.
"Our goal was to identify drugs with minimal toxicity that we can move quickly from the laboratory to the clinic, where new therapeutic options are desperately needed," said Robert Wechsler-Reya, PhD, director of the Tumor Initiation and Maintenance Program at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, and senior author of the study.
"Using high-throughput drug screening, we identified a compound that cooperates with a second drug to inhibit tumor growth in vitro and in vivo."
Medulloblastoma tumors grow rapidly and metastasize easily. Unlike other brain tumors, they can spread through the cerebrospinal fluid. Diagnosis of the MYC-driven medulloblastoma subtype comes with the worst prognosis. Only 40% of patients with the MYC-driven subtype become long-term survivors, compared with 80% for the other 3 medulloblastoma subtypes.
"This study highlights the value of high-throughput drug screening to identify therapies that are effective for specific types of disease," said Wechsler-Reya.
"It also demonstrates how combinations of drugs can be much more effective than single agents.”
1. Pei Y, Liu KW, Wang J, et al. HDAC and PI3K antagonists cooperate to inhibit growth of MYC-driven medulloblastoma. Cancer Cell. 2016;29(3):311-323. doi:10.1016/j.ccell.2016.02.011.