AI-27 * BKM-120: AN ANTI-INVASIVE CANDIDATE FOR THE TREATMENT OF GLIOBLASTOMA

Abstract

BKM-120 is a selective pan-class I phosphatidyl-inositol-3 kinase (PI3K) inhibitor. BKM-120 can penetrate the blood-brain barrier and it is currently in clinical trials for a several types of solid tumor, including glioblastoma. The PI3K pathway is one of the most commonly deregulated in glioblastoma and therefore represents an important therapeutic target. Several studies have examined the cytotoxic effects of BKM-120 and other PI3K inhibitors in glioblastoma, however, surprisingly little attention has been paid to the potential role of PI3K in cell migration; this is a key feature of glioblastoma, and no drugs are currently available that have been shown to effectively prevent migration in patients. We found that BKM-120 is a potent anti-invasive molecule in different glioblastoma cell lines (including patient-derived GSCs) analyzed in a range of in vitro cell migration assays. This effect is clearly distinguishable from cytostatic and cytotoxic effects which occur at higher drug concentrations and longer incubation times. The blockade of migration was reversible and accompanied by morphological changes, and pronounced alterations in both cell/cell and cell/substrate adhesion. We previously showed upregulation of pSTAT3 in glioblastoma cell migration. This was blocked by BKM-120, and may be at least one of the mechanisms involved. In vivo, BKM-120 led to marked alterations in tumor spread in an orthotopic xenograft. Thus, BKM-120 is a candidate blood-brain barrier penetrant drug, that may be useful as an anti-invasive therapeutic for the treatment of highly invasive tumors such as glioblastoma.