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).
Glioblastoma multiforme (GBM) is the most prominent and malignant primary brain tumor confers a dismal median survival of about one year. In this proposal we will test the hypothesis that our identified compound that specifically affect GBM's mutation will serve as a new therapeutic strategy against GBM. We will use pharmacological and molecular approaches in GBM cell culture and in GBM animal tumor models.
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