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: 9227435
• 负责人: Atsuo Sasaki
• 金额: $ 25.11万
• 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 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9227435
• 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; Drug Kinetics; Enzymes; Epigenetic Process; Equilibrium; FDA approved; Glioblastoma; Goals; Growth; Homeostasis; In Vitro; Intracellular Membranes; Lead; Lupus Erythematosus; Malignant - descriptor; Membrane Protein Traffic; Modality; Modeling; Molecular; Multiple Sclerosis; Mutation; Neuroglia; Normal tissue morphology; PTEN gene; Pathway interactions; Patients; Penetration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; 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; Ulcerative Colitis; 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; 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).

磷脂酰肌醇平衡的平衡对于细胞内环境的稳定和磷脂酰肌醇的失衡至关重要 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 中位生存期为14.6个月，PI（3，4，5）P3升高至超生理水平， 增长然而，PI（3，4，5）P3的药理学还原在临床试验中显示出有限的成功，部分地 因为它的毒性。在这里，我们提出了一种相反的方法-合成致命的组合与提高 GBM中的PI（3，4，5）P3。在初步研究中，我们发现了两种化合物-缩写GBM-Blast 1和 GBM-Blast 2-通过使磷酸肌醇不成比例，导致灾难性空泡化， PI（3，4，5）P3依赖的方式和细胞死亡的GBM，但不是在初级胶质细胞。我们的生化分析显示 GBM-Blast 1和GBM-Blast 2具有抗磷酸肌醇激酶的新活性。治疗 GBM细胞的GBM-Blast 1和GBM-Blast 2显著改变磷酸肌醇平衡。有趣的是， GBM-Blast 1和GBM-Blast 2的处理减少了AKT活化并诱导灾难性空泡化， GBM细胞以PI（3，4，5）P3依赖的方式死亡。重要的是，GBM-Blast 1和GBM-Blast 2不影响 在初级胶质细胞中。我们的PD/PK（药效学/药代动力学）分析显示，GBM-Blast 1具有显著的 对血脑屏障的上级渗透，提高了GBM的GBM-Blast 1和GBM-Blast 2的潜力 治疗应用。基于这些观察结果，我们假设GBM-Blast 1和GBM-Blast 2 是抑制GBM进展的新的、选择性的和安全的方法，对正常组织的影响最小。到 为了验证这一假设，我们将使用GBM细胞系确定GBM-Blast 1和GBM-Blast 2的抗肿瘤作用， 临床相关GBM小鼠模型（Aim 1）。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（Aim 2）。