Genetic determinants of Chemo-Radiation Combination

描述（由申请人提供）：放射化疗联合治疗是治疗广泛实体瘤的主要药物。放化疗与DNA烷基化药物的协同作用增强了放化疗联合治疗的临床疗效。迄今为止，介导协同效应的机制仍然难以捉摸。细胞对化学放射治疗的敏感性/耐药性的遗传决定因素仍不明确。本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细胞抵抗放化疗组合中起关键作用的基因以及放化疗协同作用的分子基础。为了以公正的方式鉴定这些基因，我们建立了全基因组RNAi筛选的高通量平台。初步中试筛验证了技术平台，取得了原理结果的验证。这个R21应用程序的直接目标反映在两个具体目标上：1。开展多个全基因组筛选，筛选对化疗-放疗细胞存活至关重要的候选基因；2. 来

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.