SPECIFIC SPHINGOSINE KINASE 1 INHIBITORS FOR MALIGNANT GLIOMA TREATMENT

Gliomas account for 28% of all primary brain and central nervous system tumors, and 80% of gliomas are malignant. Among the sphingolipid metabolic enzymes, sphingosine kinase 1 (SK1) is a key regulator of the sphingolipid metabolism and is up-regulated in malignant glioma, glioblastoma multiforme (GBM). Elevated expression of SK1 correlates with poor survival in GBM patients. We hypothesize that SK1-selective inhibitors can be a therapeutic option for malignant brain tumors. We determined the cytotoxicity and cell death mechanisms of two SK1 selective inhibitors (SKI) on the human brain tumor cells in in vitro. We also evaluated whether SKI have anti-tumor effects in orthotopic nude mouse brain tumor models. The two SK1 inhibitors (SKI-178, SKI-349) are selective SK1 inhibitors. In the in-vitro SK1 activity assay, SKI-349 (IC50 ≈2μM) is more potent towards SK1 than SKI-178 (IC50 ≈35 μM). SKI-349 showed almost 10 fold lower LC50 (50% cell growth inhibition concentration) to the GBM cell lines and GBM stem cells than SKI-178 (4-74 nM vs 272-506 nM). There are combination effect of SKI and Temozolomide on GBM and GBM stem cells. SKI-349 dose dependently induced apoptosis and an accumulation of cells in mitosis in GBM stem cells. These results suggest that SKI could potentially be efficacious in mouse models of GBM. However, SKI-349 did not significantly affect the average survival time for tumor-bearing mice relative to the vehicle treated control group. The lack of therapeutic efficacy suggests that SKI-349 is not able to cross the blood-brain-barrier (BBB) given the efficacy of SKI-349 in xenograft models of other cancer types. Together, these studies suggest that SKI-349 would not be an effective therapy for GBM in its current state. Future studies will be to overcome the BBB permeability of SKI-349 by conjugation of SKI-349 to carrier molecules capable of crossing the BBB.