BKM120, a Novel PI3K Inhibitor, Promotes Medulloblastoma Cell Death Through the Prevention of Akt Phosphorylation and Activation of Apoptotic Pathways.
Voydanoff, Austin P.
MetadataShow full item record
Medulloblastoma is the most common malignant pediatric brain tumor, and is fatal in 30% of cases. Traditional treatment of medulloblastoma consists of surgical resection followed by chemotherapy and radiation. However, for many young patients radiotherapy is not a viable treatment option because it causes damage to the developing brain. Due to the limited therapeutic options for young patients and the relatively high mortality rate associated with the disease, new and improved treatments are necessary for medulloblastoma. The targeted-therapy approach to treating cancer involves identifying the molecular cause of the disease and treating patients with a regimen of drugs specific to their tumor. One cellular pathway commonly deregulated in medulloblastoma is the PI3K pathway, which is involved in cell proliferation and apoptosis. Thus, in order to improve the available medulloblastoma therapeutic options, the present study investigated the efficacy of BKM120, a novel PI3 kinase inhibitor, on three medulloblastoma cell lines in vitro. BKM120 induced cell death in all three cell lines, as demonstrated through calcein AM assays, and western blot analysis suggests the activation of caspase 3-mediated apoptosis. PIK3CD and PIK3AP1 were identified as potential genetic biomarkers for BKM120 sensitivity through RNA expression analysis. Lastly, preliminary isobologram data suggested a potential synergistic relationship between BKM120 and etoposide or doxorubicin to be further investigated. These initial in vitro results justify further evaluation of BKM120 treatment of medulloblastoma in vivo, however careful investigation of the effects of the drug on the immune system are necessary prior to clinical use.