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：
10620699
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/10620699
关键词：
5&apos -AMP-activated protein kinase Age Animal Model Antiepileptic Agents Antioxidants Biological Biological Assay Biological Availability Blood - brain barrier anatomy Brain Brain Neoplasms Brain region Cancer Biology Catabolism Cell Cycle Cell Death Cell Proliferation Cell Survival Cells Chemicals Chemoresistance Chemotherapy and/or radiation Child Circulation Development Diagnosis Drug Delivery Systems Drug resistance Effectiveness Enzymes Epigenetic Process Epilepsy Epithelium 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 Epithelial Cell Malignant Glioma Malignant Neoplasms Measures Mesenchymal Metabolic Metabolic Pathway Metabolism Molecular Mus Mutation Neoplasm Metastasis Nuclear Nucleotide Biosynthesis Oncogenes 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 Proliferating Proteins Public Health Radiation therapy Reporting Research Resistance Safety Signal Transduction Structure-Activity Relationship Survival Rate Tail Testing Therapeutic Tumor Suppressor Genes Tumor Tissue Xenograft Model Xenograft procedure analog anti-cancer cancer cell cancer pharmacology cancer therapy chemotherapy cytotoxicity dravet syndrome drug repurposing efficacy evaluation experimental study gamma-Aminobutyric Acid in vivo Model in vivo evaluation inhibitor insight lead candidate lipid metabolism metabolic abnormality assessment metabolomics mortality novel novel therapeutics overexpression pharmacologic pre-clinical preclinical efficacy protein expression scaffold screening standard of care synergism temozolomide therapeutic candidate timeline 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.

项目概要/摘要多形性胶质母细胞瘤 (GBM) 是最具侵袭性的原发性脑肿瘤，其 5 年生存率令人沮丧存活率（约 5%）。尽管进行放射治疗和化疗，中位生存时间仍然很糟糕，只有 15 岁。 GBM 治疗的主要挑战包括晚期诊断、转移、耐药性。因此，由于血脑屏障而导致化疗和药物输送问题。开发针对 GBM 的新药物疗法是非常有必要的。与癌基因和抑癌基因密切相关的代谢途径。代谢重编程赋予 GBM 在生存、增殖、转移、此外，癌症代谢领域的最新研究。揭示了一个重要的“乳酸穿梭”，它解释了乳酸从肿瘤微环境中的乳酸利用与大脑高度系统相关。我们的长期目标是通过药物靶向肿瘤代谢。为了实现这一目标，我们筛选了一些代谢物。 GBM 细胞抑制剂揭示了 FDA 批准的抗癫痫药物的有效性司替戊醇及其假定的目标乳酸脱氢酶本研究的目的是阐明。司替戊醇治疗 GBM 细胞和癌症生物学的分子机制和变化此外，我们将研究新型衍生物的结构-活性关系。从司替戊醇支架中鉴定出另外的制剂，以开发有效的抑制剂。司替戊醇和强效先导化合物将在肿瘤异种移植模型中开发和测试我们的研究将为 U87 异种移植物的机制药理学提供新的见解。司替戊醇，可以促进 GBM 治疗候选疗法的开发。