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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