Polyamine Catabolism and Therapeutic Resistance in Glioblastoma Multiforme

多形性胶质母细胞瘤的多胺分解代谢和治疗耐药

基本信息

批准号：
9122361
负责人：
Scott Michael Welford
金额：
$ 36.11万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-07 至 2017-07-03
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9122361
关键词：
Acetyl Coenzyme A Acetylation Adjuvant Affect BRCA1 Protein BRCA1 gene Back Binding Biological Assay Brain Brain Neoplasms Camptothecin Cell Line Cell physiology Cells Charge Chromatin Clinical DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Gene Data Databases Diagnosis Disease Enzymes Epigenetic Process Excision Gene Expression Gene Expression Profile Gene Expression Regulation Genes Genetic Determinism Genetic Screening Genetic Transcription Glioblastoma Goals HDAC1 gene Health Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Histone H3 Human Immunoprecipitation Injection of therapeutic agent Ionizing radiation Libraries Link Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Mass Spectrum Analysis Mediator of activation protein Metabolic Metabolism Mitosis Modality Mus National Institute of Neurological Disorders and Stroke Nucleic Acids Outcome Pathway interactions Patient-Focused Outcomes Pharmaceutical Preparations Physical condensation Poison Polyamine Catabolism Polyamines Proteins Publishing Radiation Radiation Induced DNA Damage Radiation therapy Radioresistance Radiosensitization Regulation Regulator Genes Relaxation Repair Complex Reporter Research Resistance Role S Phase Scheme Site Small Interfering RNA Source Specificity Spermidine Spermidine/Spermine N1-Acetyltransferase Spermine System Testing Therapeutic Therapeutic Intervention Time United States National Institutes of Health Xenograft procedure anticancer research cancer therapy chromatin immunoprecipitation chromatin remodeling epigenetic regulation gene repression homologous recombination improved inhibitor/antagonist knock-down macromolecule mutant novel novel therapeutics overexpression promoter protein complex recombinational repair repaired resistance gene resistance mechanism small hairpin RNA small molecule standard of care subcutaneous temozolomide therapy resistant transcriptome sequencing tumor tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Mediators of DNA damage, such as ionizing radiation, are frequently used for cancer therapy. Glioblastoma multiforme is the most common and severe form of brain tumor that is unfortunately resistant to most DNA damaging modalities, though they remain the standard of care. Here, in an attempt to define genetic determinants of therapeutic resistance in brain tumors, we have identified a novel mechanism of resistance to DNA damage that tumors employ that depends on the overexpression of a metabolic enzyme that we hypothesize is involved in regulating DNA and chromatin dynamics. The enzyme, spermidine/spermine-N1- acetyltrasferase 1 (SAT1), is a rate-limiting regulator of the catabolism of polyamines, ubiquitous positively charged small molecules that have been found to promote condensation of chromatin. By overexpressing SAT1, tumors are better prepared to repair deleterious double strand DNA breaks which require opening of chromatin to perform repair. In this application, we propose to 1) determine the mechanism of regulation of DNA repair by SAT1, 2) investigate the role of SAT1 as an epigenetic regulator of DNA repair related gene expression, and 3) determine the therapeutic benefit of inhibiting SAT1 expression in human tumors xenografted in mice. The overall goal is to determine if the polyamine pathway provides a novel target for therapeutic intervention in glioblastoma, while simultaneously revealing a previously unappreciated aspect of DNA repair regulation that depends on polyamine metabolism and chromatin remodeling.

描述（由申请人提供）：DNA 损伤介质（例如电离辐射）经常用于癌症治疗，多形性胶质母细胞瘤是最常见和最严重的脑肿瘤，不幸的是，尽管它们仍然是最常见和最严重的脑肿瘤，但它们对大多数 DNA 损伤方式具有抵抗力。在这里，为了定义脑肿瘤治疗耐药性的遗传决定因素，我们发现了肿瘤所采用的一种新的抵抗 DNA 损伤的机制，该机制取决于我们捕获的代谢酶的过度表达。亚精胺/精胺-N1-乙酰转移酶 1 (SAT1) 是调节 DNA 和染色质动力学的酶，是多胺分解代谢的限速调节剂，多胺是普遍存在的带正电荷的小分子，被发现可以促进染色质的缩合。过度表达 SAT1，肿瘤可以更好地修复有害的双链 DNA 断裂，而双链 DNA 断裂需要打开染色质才能进行修复。应用中，我们建议1）确定SAT1调节DNA修复的机制，2）研究SAT1作为DNA修复相关基因表达的表观遗传调节剂的作用，以及3）确定抑制SAT1表达在人类肿瘤中的治疗益处总体目标是确定多胺途径是否为胶质母细胞瘤的治疗干预提供了新的靶点，同时揭示了依赖于多胺代谢和DNA修复调节的先前未被认识到的方面。染色质重塑。