Genetic determinants of Chemo-Radiation Combination

描述（由申请人提供）：放疗和化疗联合是治疗广谱实体瘤的主要药物。化疗-放疗组合的临床疗效通过放疗和DNA烷基化药物之间的强协同作用而增强。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/抗性的遗传决定因素仍然不确定。本申请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对化学-放射组合的抗性中起关键作用的基因以及放射和化学疗法之间协同作用的分子基础。为了以公正的方式鉴定这些基因，我们建立了高通量的全基因组RNAi筛选平台。初步试验筛选验证了技术平台，并获得了原理验证结果。这一R21应用的直接目标体现在两个具体目标中，1。进行多个全基因组的初步筛选，以寻找对细胞抵抗化疗-放射治疗的存活至关重要的候选基因; 2.到 在第二次筛选中改进初级命中，以功能性地验证作为协同因子的基因和在对化学-辐射处理具有抗性的细胞中普遍存在的基因。阐明放化疗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。阐明协同作用的生物学基础有助于获得新的治疗组合。我们期望这个高风险/高回报的项目产生临床相关的以及机械信息的候选人，可以导致进一步的深入研究，以改善化学-放射治疗方案。

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.