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

肌醇磷脂平衡平衡是细胞内稳态和肌醇磷脂失衡的关键 可能对快速生长的细胞有害。多形性胶质母细胞瘤(GBM)，最具侵袭性的脑肿瘤 中位生存期14.6个月，将恶性PI(3，4，5)P3提高到超生理水平 成长。然而，PI(3，4，5)P3的药理减少在临床试验中显示出有限的成功，部分 由于它的毒性。在这里，我们提出了一种相反的方法-人工合成致命结合 在GBM中PI(3，4，5)P3。在初步研究中，我们发现了两个化合物-缩写GBM-Blast1和 GBM-Blast2-不成比例的磷脂酰肌醇并导致灾难性的空泡化 PI(3，4，5)P3依赖的方式和GBM的细胞死亡，但在原代胶质细胞中不存在。我们的生化分析显示 GBM-Blast1和GBM-Blast2具有一种新的抗肌醇磷脂酶活性。治疗 GBM-Blast1和GBM-Blast2与GBM细胞的磷脂酰肌醇平衡发生显著变化。有趣的是， GBM-Blast1和GBM-Blast2治疗可降低AKT的激活并诱导灾难性的空泡化和 GBM细胞以PI(3，4，5)P3依赖的方式死亡。重要的是，GBM-Blast1和GBM-Blast2不影响 在初级神经胶质细胞中。我们的PD/PK(药效学/药代动力学)分析表明，GBM-Blast1具有 对血脑屏障的超强穿透，提高了GBM-Blast1和GBM-Blast2对GBM的治疗潜力 治疗性应用。基于这些观察，我们假设GBM-Blast1和GBM-Blast2将 是一种新颖、选择性和安全的方法，可以在对正常组织影响最小的情况下抑制GBM的进展。至 为了验证这一假设，我们将使用GBM细胞株和 临床相关的GBM小鼠模型(Aim1)。我们将学习药物化学和构效关系 试验以开发更有效的化合物(AIM2)。

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).