Synthetic Lethal Combination of KRP203/Fingolimod with PI3K signaling for glioblastoma multiforme death by catastrophic vacuolization

University Of Cincinnati, Cincinnati OH

Investigators

Linked publications, trials & patents

Abstract

Equilibrium of phosphoinositides balance is critical for cellular homeostasis and imbalance of phosphoinositides could be deleterious to rapidly growing cells. Glioblastoma multiforme (GBM), the most aggressive brain tumor with a median survival of 14.6 months, elevate PI(3,4,5)P3 to supra-physiological levels for their malignant growth. However, pharmacological reduction of PI(3,4,5)P3 have shown a limited success in clinical trials, partly due to its toxicity. Here, we propose a reverse approach?synthetic lethal combination with the elevated PI(3,4,5)P3 in GBM. In the preliminary study, we discovered two compounds?acronyms GBM-Blast1 and GBM-Blast2?that disproportionate phosphoinositides and led to catastrophic vacuolization via PI(3,4,5)P3-dependent fashion and cell death in GBM, but not in primary glia. Our biochemical analysis reveals that GBM-Blast1 and GBM-Blast2 possess a novel activity against phosphoinositide kinases. Treatment of GBM-Blast1 and GBM-Blast2 with GBM cells dramatically changes in phosphoinositide balance. Interestingly, treatment of GBM-Blast1 and GBM-Blast2 diminished AKT activation and induce catastrophic vacuolization and cell death of GBM cells in PI(3,4,5)P3 dependent fashion. Importantly GBM-Blast1 and GBM-Blast2 did not affect in primary glia. Our PD/PK (Pharmacodynamics/Pharmacokinetics) analysis showed that GBM-Blast1 has a superior penetration to blood-brain-barrier, raising a potential of GBM-Blast1 and GBM-Blast2 for GBM therapeutic application. Based on these observations, we hypothesize that GBM-Blast1 and GBM-Blast2 would be novel, selective and safe approach to inhibit GBM progression with minimum impact on normal tissues. To test the hypothesis, we will define the anti-tumor effect of GBM-Blast1 and GBM-Blast2 using GBM cell lines and clinically relevant GBM mice models (Aim1). We will take medicinal chemistry and structure-activity relations assay to develop more potent compound (Aim2).