Pharmacological and Chemical Approaches to Repurpose an Antiepileptic for Glioblastoma Treatment

重新利用抗癫痫药治疗胶质母细胞瘤的药理学和化学方法

基本信息

批准号：
10412617
负责人：
Vikas Vasudeo Dukhande
金额：
$ 16.4万
依托单位：
ST. JOHN'S UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-11 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10412617
关键词：
5&apos -AMP-activated protein kinase Age Animal Model Antiepileptic Agents Antioxidants Biological Biological Assay Biological Availability Blood - brain barrier anatomy Blood Circulation Brain Brain Neoplasms Brain region Cancer Biology Catabolism Cell Cycle Cell Death Cell Proliferation Cell Survival Cells Chemicals Chemoresistance Child Development Diagnosis Drug Delivery Systems Drug resistance Effectiveness Enzymes Epigenetic Process Epilepsy Epithelial Excision FDA approved Formulation Gene Expression Genus Hippocampus Glioblastoma Glioma Glycogen Glycogen Phosphorylase Glycolysis Goals Grant Healthcare Hydrogen Bonding Hydrophobicity Immune Immune Evasion Immunohistochemistry In Vitro Investigation Lactate Dehydrogenase Lead Link Malignant Glioma Measures Mesenchymal Metabolic Metabolic Pathway Metabolism Molecular Mus Mutation Neoplasm Metastasis Nuclear Nucleotide Biosynthesis Operative Surgical Procedures Pathway interactions Pentosephosphate Pathway Permeability Persons Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacology Study Pharmacotherapy Phosphotransferases Physiological Preclinical Testing Prevalence Primary Brain Neoplasms Primary carcinoma of the liver cells Prognosis Proteins Public Health Radiation Radiation therapy Reporting Research Resistance Safety Signal Transduction Structure-Activity Relationship Survival Rate Tail Testing TimeLine Transitional Cell Tumor Suppressor Genes Tumor Tissue Xenograft Model Xenograft procedure analog anti-cancer base cancer cell cancer pharmacology cancer therapy chemotherapy cytotoxicity dravet syndrome drug repurposing experimental study gamma-Aminobutyric Acid in vivo Model in vivo evaluation inhibitor insight lactate dehydrogenase A lead candidate lipid metabolism metabolic abnormality assessment metabolomics mortality novel novel therapeutics overexpression pre-clinical preclinical efficacy protein expression scaffold screening standard of care synergism temozolomide therapeutic candidate transcriptome sequencing treatment strategy tumor tumor metabolism tumor microenvironment tumor xenograft

项目摘要

PROJECT SUMMARY / ABSTRACT Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with a dismal 5-year survival rate (~ 5 %). GBM metastasizes to different brain regions which makes surgical resection difficult. Despite radiation therapy and chemotherapy, the median survival timeline is dire at 15 months. The major challenges in GBM therapy include late diagnosis, metastasis, resistance to chemotherapeutics, and drug delivery issues due to blood-brain barrier. Thus, efforts towards developing novel pharmacotherapies for GBM are highly warranted. Cancer cells rewire their metabolic pathways that are intimately linked to oncogenes and tumor suppressor genes. The metabolic reprogramming confers GBM several advantages in survival, proliferation, metastasis, drug resistance, and immune evasion. In addition, recent research in the cancer metabolism field has revealed an important ‘lactate shuttle’ that explains the key role of lactate transfer from systemic circulation into tumor microenvironment. Lactate utilization is highly relevant for brain tumors such as GBM. Our long-term goal is to pharmacologically target tumor metabolic reprogramming for cancer therapy. Towards that goal, we screened a number of metabolic inhibitors in GBM cells that uncovered effectiveness of an FDA-approved antiepileptic drug stiripentol with its putative target lactate dehydrogenase. The objective of this study is to elucidate molecular mechanism and changes in cancer biology by stiripentol treatment in GBM cells and GBM in vivo models. In addition, we will study structure-activity relationships of novel derivatives identified from stiripentol scaffold to develop potent inhibitors. Additionally, formulations of stiripentol and potent lead compounds will be developed and tested in the tumor xenograft model of U87 xenografts. Our research will offer novel insights in the mechanistic pharmacology of stiripentol and can lead to the development of candidate therapeutics for GBM treatment.

项目摘要 /摘要胶质母细胞瘤多形（GBM）是最具侵略性的原发性脑肿瘤，五年存活率（〜5％）。 GBM向不同的大脑区域转移了手术切除难的。尽管放射疗法和化学疗法，但中位生存时间表在15 月份。 GBM治疗的主要挑战包括晚期诊断，转移，抵抗力化学治疗药和由于血脑屏障引起的药物输送问题。那，努力高度保证为GBM开发新型的药物治疗。癌细胞重新连接与肿瘤基因和肿瘤抑制基因密切相关的代谢途径。这代谢重编程承认GBM生存，增殖，转移，耐药性和免疫进化。此外，癌症代谢领域的最新研究揭示了一个重要的“赛车班车”，解释了乳酸转移的关键作用全身循环到肿瘤微环境中。乳酸利用率与大脑高度相关肿瘤，例如GBM。我们的长期目标是用药物靶向肿瘤代谢重新编程进行癌症治疗。为了实现这一目标，我们筛选了许多代谢 GBM细胞中抑制剂发现了FDA批准的抗癫痫药的有效性搅动蛋白醇及其推定的靶标为脱氢酶。这项研究的目的是阐明通过搅拌GBM细胞和 GBM体内模型。此外，我们将研究新型衍生物的结构活性关系从锡立替托支架中鉴定出来开发潜在的抑制剂。另外，公式在肿瘤特征模型中将开发和测试搅拌蛋白醇和潜在的铅化合物 U87 Xenographing。我们的研究将提供有关机械药理学的新见解搅动蛋白酚，并可能导致候选治疗的GBM治疗。