Genetic determinants of Chemo-Radiation Combination

化学放射组合的遗传决定因素

基本信息

批准号：
8567515
负责人：
LEI LI
金额：
$ 20.88万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8567515
关键词：
Address Affect Area Bioinformatics Biological Biological Markers Candidate Disease Gene Cell Survival Cell model Cells Cisplatin Clinic Clinical Combination Drug Therapy Combined Modality Therapy DNA DNA Adducts Data Dose Double-Stranded RNA Drosophila genus Drug Targeting Fluorouracil Genes Genetic Genetic Determinism Genetic Screening Genome Goals Human Investigation Knowledge Laboratory Study Lead Libraries Mediating Modality Molecular Outcome Pathway interactions Patients Pharmaceutical Preparations Play RNA Interference Radiation Radiation therapy Rationalization Reagent Regimen Resistance Role Solid Neoplasm Steel Therapeutic Validation base cancer therapy chemotherapeutic agent chemotherapy clinical efficacy clinically relevant combinatorial design genome wide association study genome-wide high reward high risk improved novel novel therapeutics nucleoside analog outcome forecast public health relevance radiation effect response statistics success synergism

项目摘要

DESCRIPTION (provided by applicant): Radiation chemotherapy combination is a major remedy in treating a broad spectrum of solid tumors. The clinical efficacy of chemo-radiation combination is enhanced by a strong synergy effect between radiation and DNA alkylating drugs. To date, the mechanism(s) mediating the synergistic effect remains elusive. The genetic determinants of cellular sensitivity/resistance against chemo-radiation treatment remain undefined. This application is aimed at addressing these important questions via genetic approaches. Our long term objective is to reveal genes that play a crucial role in cellular resistance against chemo-radiation combination and the molecular basis of synergy between radiation and chemotherapy. To identify these genes in an unbiased manner, we have established high throughput platforms for genome-wide RNAi screen. An initial pilot screen has validated technical platform and acquired proof of principle results. The immediate goals of this R21 application are reflected by two Specific Aims, 1. To conduct multiple genome-wide primary screens for candidate genes critical for cellular survival against chemo-radiation treatment; 2. To refine the primary hits in a secondary screen to functionally validate genes acting as synergy factors and genes prevalent in cellular resistant to chemo-radiation treatment. Unraveling genetic determinants of chemo-radiation response provides potential biomarkers for prognosis and treatment rationalization. Elucidating the biological underlining for synergy helps to derive novel therapeutic combinations. We expect this high risk/high reward project to yield clinically relevant as well as mechanistically informative candidates that could lead to further in- depth investigations to improve the chemo-radiation therapeutic regimen.

描述（由申请人提供）：放射化疗组合是治疗广泛的实体瘤的主要补救措施。化学辐射组合的临床疗效通过辐射和DNA烷基化药物之间的强大协同作用增强。迄今为止，介导协同作用的机制仍然难以捉摸。对化学放射治疗的细胞敏感性/耐药性的遗传决定因素仍然不确定。该应用程序旨在通过遗传方法解决这些重要问题。我们的长期目标是揭示在对化学辐射组合的细胞耐药性和放射疗法和化学疗法之间协同作用的基础上起着至关重要的基因。为了以公正的方式识别这些基因，我们为全基因组RNAi筛选建立了高吞吐量平台。初始的试点屏幕已验证了技术平台，并获得了原理结果证明。该R21应用的直接目标反映了两个特定的目标，即进行多个基因组的主要筛选，以实现对化学辐射治疗至关重要的细胞存活至关重要的候选基因； 2 在次级筛选中完善主要命中，以在功能上验证起作用的基因和基因在耐化学辐射治疗的耐药性中普遍存在。化学放射反应的遗传决定因素为预后和治疗合理化提供了潜在的生物标志物。阐明生物下划线的协同作用有助于得出新颖的治疗组合。我们期望这个高风险/高奖励项目能够产生临床上相关的以及机械信息丰富的候选者，这可能会导致进一步的深度研究以改善化学放射治疗方案。