CSHL Molecular Target Discovery and Development Center

描述(由申请人提供)：在这份申请中，我们描述了我们创建分子靶标发现和开发中心(MTDDC)的计划，该中心将作为癌症基因组图谱(TCGA)项目的下游组成部分。我们的前提是，癌症基因组改变的复杂性直接导致癌症行为和结果的异质性，而要将丰富的癌症基因组特征转化为临床实用，需要对潜在驱动基因进行功能鉴定和验证。驱动基因识别将导致对癌症基因类型的更深入了解，创造一套重要的新生物标记物和治疗靶点，并与全基因组RNAi筛查相结合，导致识别将作为新一代治疗靶点的关键遗传脆弱性。我们计划的中心是冷泉港实验室(CSHL)长期合作项目的自然扩展，并结合了我们已经开发并将继续在本申请中概述的几种强大的方法。这些方法包括：以基因操纵的祖细胞移植到受体小鼠适当组织的灵活小鼠模型；获取复杂癌症基因组数据集并精确定位候选驱动基因和显著改变的通路的新型生物信息学；用于操控候选靶基因在体外和体内表达的新的RNAi技术；以及全基因组RNAi筛选以发现癌细胞的遗传脆弱性。CSHL MTDDC将使用这些创新工具，将癌症基因组项目确定的复杂的基因组改变阵列置于生物学背景中。在老鼠模型中的高通量筛选将被用来确定候选基因是司机还是乘客。此外，通过识别肿瘤维持所需的驱动基因，以及通过全基因组RNAi筛查来发现主要癌症基因型的可药物脆弱性，我们将发现并验证新一代癌症药物靶点。由此产生的数据、试剂和新验证的生物标记物和靶点将在TCGA网络和更广泛的癌症研究社区之间公开共享，就像我们对RNAi Codex所做的那样，RNAi Codex是CSHL用于短发夹状RNA(ShRNA)基因沉默构建的开放访问门户/数据库。 与公共卫生相关：分子靶标发现和发展中心有两个关键目标，以帮助开发癌症的新疗法。第一个目标必须是验证哪种基因突变是癌症进展的驱动因素。这些标记物可能会导致治疗靶点，但这对大多数基因来说是不太可能的。然而，驱动基因在诊断、预后和将治疗与癌症亚型联系起来方面具有巨大的潜力。然而，发现基因依赖性也是必要的，这些基因是特定基因构成或组织类型癌症的有效靶点。这种依赖性有可能成为治疗靶点，选择性地针对癌细胞而不是正常细胞。

DESCRIPTION (provided by applicant): In this application we describe our plans to create a Molecular Target Discovery and Development Center (MTDDC) that will act as downstream component of The Cancer Genome Atlas (TCGA) project. Our premise is that the complexity of cancer genome alterations leads directly to the heterogeneity of cancer behavior and outcome, and that to translate the wealth of cancer genome characterization into clinical utility requires the functional identification and validation of the underlying driver genes. Driver gene identification will lead to a deeper understanding of cancer genotypes, create an important new set of biomarkers and therapeutic targets, and when combined with genome-wide RNAi screens, lead to the identification of key genetic vulnerabilities that will serve as a new generation of therapeutic targets. Our planned center is a natural expansion of long- standing collaborative projects at Cold Spring Harbor Laboratory (CSHL) and combines several powerful methods that we have developed and will continue to build upon as outlined in this application. These methods include flexible mouse models based on the transplantation of genetically-manipulated progenitor cells into the appropriate tissues of recipient mice; novel bioinformatics that take complex cancer genome datasets and pinpoint candidate driver genes and considerably altered pathways; new RNAi technology to manipulate the expression of candidate target genes in vitro and in vivo; and genome-wide RNAi screens to find genetic vulnerabilities of cancer cells. The CSHL MTDDC will use these innovative tools to place the complex array of genomic alterations identified by cancer genome projects into biologic context. High-throughput screening in mouse models will be used to determine whether candidate genes are drivers or passengers. Additionally, through the identification of those driver genes that are required for tumor maintenance and by genome-wide RNAi screens to find the druggable vulnerabilities of major cancer genotypes, we will discover and validate a new generation of cancer drug targets. The resultant data, reagents, and newly validated biomarkers and targets will be openly shared among the TCGA network and broader cancer research communities, as we have done with RNAi Codex, CSHL's open-access portal/database for short-hairpin RNA (shRNA) gene-silencing constructs. PUBLIC HEALTH RELEVANCE: There are two critical goals for Molecular Target Discovery and Development Centers to make towards helping develop new treatments for cancer. The first goal must be to validate which of the gene mutations is a driver for cancer progression. These markers may lead to therapeutic targets, but this is unlikely for most genes. However the driver genes have great potential for diagnosis, prognosis and linking therapies to cancer subtypes. It is also necessary, however, to discover gene dependencies, the genes that are validated targets for cancers of specific genetic make up or tissue type. Such dependencies have the potential to become therapeutic targets that will selective target cancer cells versus normal cells.