Genetic determinants of Chemo-Radiation Combination

描述(申请人提供)：放化疗组合是治疗范围广泛的实体肿瘤的主要药物。放射线与DNA烷化类药物之间具有很强的协同效应，从而提高了放化疗联合治疗的临床疗效。到目前为止，调节协同效应的机制(S)仍然不清楚。细胞对化疗放射治疗的敏感性/抵抗力的遗传决定因素仍未确定。这项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疗-放射组合的抵抗中发挥关键作用的基因，以及放射和化疗之间协同作用的分子基础。为了以公正的方式识别这些基因，我们已经建立了用于全基因组RNAi筛选的高通量平台。初步的试验筛选已经验证了技术平台，并获得了原理结果的证明。R21应用程序的直接目标反映在两个具体目标上：1.对对细胞生存至关重要的候选基因进行多个全基因组范围的初步筛选；2.针对化疗放射治疗 在二次筛选中提炼一次命中，以从功能上验证作为协同因子的基因和细胞中普遍存在的对化疗放射治疗耐药的基因。解开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。我们希望这个高风险/高回报的项目能够产生临床上相关的和机械上有信息的候选者，这可能会导致进一步的深入研究，以改进化疗-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.