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

KRP203/芬戈莫德与 PI3K 信号传导的合成致死组合可导致多形性胶质母细胞瘤灾难性空泡化死亡

• 批准号: 9335996
• 负责人: Atsuo Sasaki
• 金额: $ 19.71万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9335996
• 关键词: 1-Phosphatidylinositol 4-Kinase; Affect; Animals; Biochemical; Biological Assay; Blood - brain barrier anatomy; Brain Neoplasms; Cell Culture Techniques; Cell Death; Cell Line; Cell Survival; Cells; Cessation of life; Chemicals; Clinical Trials; Development; Enzymes; Epigenetic Process; Equilibrium; FDA approved; Glioblastoma; Goals; Growth; Homeostasis; In Vitro; Intracellular Membranes; Lead; Lupus Erythematosus; Malignant - descriptor; Membrane; Modality; Modeling; Molecular; Multiple Sclerosis; Mutation; Neuroglia; Normal tissue morphology; PIK3CG gene; PTEN gene; Pathway interactions; Patients; Penetration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Phase II Clinical Trials; Phosphatidylinositols; Physiological; Primary Brain Neoplasms; Principal Investigator; Production; Protein Isoforms; Proto-Oncogene Proteins c-akt; Signal Transduction; Sphingosine-1-Phosphate Receptor; Structure; System; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Tumorigenicity; Ulcerative Colitis; Vacuole; acronyms; analog; antitumor effect; base; clinically relevant; high throughput screening; in vivo; innovation; mouse model; multidisciplinary; novel; novel therapeutic intervention; overexpression; phosphoinositide-3,4,5-triphosphate; programs; success; tool; trafficking; tumor; tumorigenic

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).

磷酸肌醇平衡的平衡对于细胞稳态和磷酸肌醇的失衡至关重要 可以将其删除为快速生长的细胞。胶质母细胞瘤多形（GBM），最具侵略性的脑肿瘤 其中位生存期为14.6个月，将PI（3,4,5）P3升高到超生理水平的恶性肿瘤 生长。但是，PI的药物减少（3,4,5）P3在临床试验中的成功有限，部分是 由于其毒性。在这里，我们提出了一种反向方法 - 与升高的合成致命组合 GBM中的Pi（3,4,5）P3。在初步研究中，我们发现了两种化合物 - 歧义gbm-blast1和 GBM-blast2-磷酸肌醇不成比例，并通过 PI（3,4,5）P3依赖性时尚和GBM中的细胞死亡，但在原发性胶质细胞中却没有。我们的生化分析揭示了 GBM-Blast1和GBM-Blast2具有针对磷酸肌醇激酶的新活性。处理 具有GBM细胞的GBM-Blast1和GBM-blast2在磷酸肌醇平衡中发生了巨大变化。有趣的是， GBM-Blast1和GBM-Blast2的治疗减少了Akt的激活并诱导灾难性的真空化和 GBM细胞在PI中的细胞死亡（3,4,5）P3依赖性方式。重要的是GBM-Blast1和GBM-Blast2不影响 在原发性神经胶质中。我们的PD/PK（药效学/药代动力学）分析表明，GBM-Blast1具有 GBM的GBM-BLAST1和GBM-Blast2的潜力升高到血脑屏障中 治疗应用。基于这些观察结果，我们假设GBM-Blast1和GBM-Blast2将 要新颖，选择性和安全的方法来抑制GBM进展，对正常组织的影响最小。到 检验假设，我们将使用GBM细胞系以及 临床相关的GBM小鼠模型（AIM1）。我们将进行医学化学和结构活性关系 分析以开发更多的潜在化合物（AIM2）。