Phenotype Arrays--An approach to Novel Anticancer Target

描述：（申请人提供） 癌症研究界面临的一个重大挑战是 鉴定提供治疗机会的蛋白质， 特异性消除癌细胞。该应用程序提供了一个合理的 发现新的抗癌靶点的方法是基于 合成致死性的遗传学原理目标是识别突变 它们本身是可以容忍的，但与改变不相容， 在癌基因和肿瘤抑制基因中， 在癌细胞中改变。这样的搜索至少在技术上是令人生畏的 在哺乳动物中。然而，简单的遗传工具的可用性和充分 测序的基因组使模式生物成为一种有吸引力的替代品。公 建立了果蝇是一个方便的模型，在其中检查癌基因 和肿瘤抑制途径。我们最近证明了RNA 干扰可用于消除培养果蝇中的基因表达 细胞在这个探索性的应用程序中，我们建议利用 果蝇unigene设置创建一个阵列的细胞株，其中每个基因 在一组中被单独破坏。含有每一种的细胞的活力 将在不存在和存在以下任何一种情况下对中断进行评估 激活ras或Rb丢失。细胞株仅在细胞中显示凋亡， 癌症突变的存在将确定合成致死性 交互.这项技术的发展不仅可以让 寻找抗癌靶点，但无疑也将应用于 广泛的生物学问题。

DESCRIPTION: (provided by applicant) A significant challenge facing the cancer research community is the identification of proteins that present therapeutic opportunities for the specific elimination of cancer cells. This application presents a rational approach to the discovery of novel anti-cancer targets that is based upon the genetic principle of synthetic lethality. The goal is to identify mutations which are tolerated on their own but which are incompatible with alterations in oncogenes and tumor suppressors that are commonly if not universally altered in cancer cells. Such a search is, at a minimum, technically daunting in mammals. However, the availability of facile genetic tools and fully sequenced genomes make model organisms an attractive alterative. It is well established that Drosophila is a convenient model in which to examine oncogene and tumor suppressor pathways. We have recently demonstrated that RNA interference can be used to ablate gene expression in cultured Drosophila cells. In this exploratory application, we propose to take advantage of the Drosophila unigene set to create an array of cell strains in which each gene in the set is disrupted individually. The viability of cells containing each disruption will be evaluated in the absence and in the presence of either activated ras or Rb-loss. Cell strains that show apoptosis only in the presence of the cancer mutation will identify synthetically lethal interactions. The development of this technology will allow not only allow a search for anti-cancer targets but will also undoubtedly find application to a broad range of biological problems.