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Screening for DNA damage response modulators in glioblastoma stem cells

胶质母细胞瘤干细胞中 DNA 损伤反应调节剂的筛选

基本信息

批准号：
10038588
负责人：
Christian Elias Badr
金额：
$ 42万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10038588
关键词：
Acidosis Adjuvant Adjuvant Therapy Alkylating Agents Alternative Therapies Biological Assay Biological Process Blood Brain Neoplasms Cell Death Cell Survival Cells Cellular Stress Chemotherapy and/or radiation Conditioned Culture Media DNA DNA Damage DNA Double Strand Break DNA Repair DNA Sequence Analysis Dose Double Strand Break Repair Drug Screening Drug Targeting Environment Enzymes Event Excision Experimental Animal Model Fatty Acid Desaturases Genetic Glioblastoma Glioma Hypoxia Impairment Left Libraries Luciferases Malignant - descriptor Malignant Neoplasms Measures Mediating Molecular Profiling Monitor Nonhomologous DNA End Joining Normal Cell Nutrient Operative Surgical Procedures Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phase Population Primary Brain Neoplasms Proliferating Proteins Quality of life Rad51 recombinase Radiation therapy Recurrence Reporter Reporting Resistance Resistance development System Testing Therapeutic Time Treatment Efficacy analog base cancer stem cell chemoradiation conventional therapy design genotoxicity high throughput screening inhibitor/antagonist neoplastic cell novel outcome forecast oxidative DNA damage patient variability radioresistant repaired response screening small molecule stem cells stem-like cell temozolomide therapy resistant tumor virtual

项目摘要

Abstract There is presently no cure for high grade gliomas which are associated with a bleak prognosis and a poor quality of life. GBM patients typically undergo surgical resection followed by radiation therapy (RT) combined with the alkylating agent temozolomide (TMZ). However, virtually all GBM patients either fail to respond to this treatment, or ultimately develop resistance, underlining the urgency for effective adjuvant therapies. Both RT and TMZ can target tumor cells by causing lethal DNA double-strand breaks, which could be recognized and repaired by the intrinsic DNA damage response (DDR) thus protecting against DNA damage-induced cell death. Further, GBMs are enriched in a subset population of glioma cancer stem cells (GSCs), characterized by an upregulated DDR which contributes to their superior therapeutic resistance. Targeting DNA repair can increase/restore sensitivity of brain tumors to TMZ and RT, thus increasing therapeutic efficacy and minimizing tumor recurrence. We have designed a rapid, versatile and highly sensitive reporter that can detect and quantify minute amounts of DNA double-strand break repairs such as homology-directed repair as well as non-homologous end joining without disrupting cells. Here we propose to use this reporter in order to identify modulators of DNA damage repair in GSCs. In Aim 1 (R61 phase), we will develop and optimize a high-throughput screening assay to monitor DDR in GSCs. In Aim 2 (R33 phase), we will use this assay to screen for compounds which inhibit DNA damage repair. Upon completion of this project, this screen should identify novel compounds which effectively sensitize GSCs to chemoradiotherapy and increase the efficacy of genotoxic therapeutics.

摘要