The Dana-Farber Cancer Institute Cancer Target Discovery and Development Center

描述(申请人提供)：大多数人类肿瘤，特别是那些来自上皮癌的肿瘤，表现出全球性的基因组变化，使其难以识别 突变对细胞转化和定义特定癌症的后果至关重要 相关突变。测序技术和绘制癌症相关扩增和缺失图谱的综合方法的最新进展现在使识别特定肿瘤所包含的所有基因变化成为可能，而应用这些技术的大规模努力，如TCGA，已经开始提供癌症基因组的全面视图。尽管有这些重要的进展，但将这些发现转化为将进入临床的治疗方法的一个关键瓶颈是作为潜在治疗靶点的基因的功能表征。具体地说，尽管识别出在很大一部分特定基因中发生突变的基因 癌症类型是关键的第一步，同时开发有效的方法来注释癌症相关基因的功能对于提炼有希望的候选基因是必要的 从这种癌症基因组的结构描述中寻找癌症靶点。因此，癌症基因的功能注释将识别其蛋白产物对肿瘤的启动或维持至关重要的基因，并将为这些癌症中调控异常的生化途径提供关键的见解。这些信息将加速新的分子靶向疗法的发展。在本申请中，我们建议将这些研究作为建立Dana-Farber癌症研究所癌症靶点发现和开发中心的基础。该中心将专注于使用高通量的遗传和生物信息学方法，在体外和体内识别和证明三种癌症(GBM、卵巢癌和结肠癌)的癌基因和相互依赖关系。我们将向科学界免费提供这些研究的成果(数据和方法)，并打算在这一项目的整个时间框架内参加反恐发展网络项目。我们预计，该中心将为癌症研究团体提供信息，有助于根据基因组和功能证据确定靶点的优先顺序，为下游机制和验证研究提供最合适的遗传背景，并促进将这些信息转化为治疗和诊断。

DESCRIPTION (provided by applicant): Most human tumors, particularly those derived from epithelial cancers, exhibit global genomic alterations that make it difficult to identify mutations critical for cell transformation and to define the consequences of specific cancer associated mutations. Recent advances in sequencing technologies and comprehensive methods to map cancer-associated amplicons and deletions now make it possible to identify all of the genetic alterations harbored by a particular tumor, and large-scale efforts such as TCGA to apply these technologies have already begun to provide comprehensive views of cancer genomes. Despite these important advances, a critical bottleneck in translating these discoveries into therapies that will enter the clinic remais the functional characterization of genes as potential therapeutic targets. Specifically, although the identification of genes that are mutated in a substantial fraction of particular cancer types is an essential first step, the parallel development of efficient methods to annotate the function of cancer-associated genes is necessary to distill promising candidate cancer targets from this structural description of cancer genomes. Thus, functional annotation of cancer genes will identify those genes whose protein products are essential for tumor initiation or maintenance and will provide critical insights into the biochemical pathways that ar dysregulated in these same cancers. This information will accelerate the development of new molecularly targeted therapeutics. In this application, we propose use these studies as a foundation to establish the Dana- Farber Cancer Institute Cancer Target Discovery and Development Center. This Center will focus on the use of high throughput genetic and bioinformatic approaches to identify and credential oncogenes and co-dependencies in three cancers (GBM, ovarian, and colon) in vitro and in vivo. We will make the outputs of these studies (data and methodologies) freely available to the scientific community and intend to participate in CTDD Network projects throughout the time frame of this project. We anticipate that this Center will provide the cancer research community with information tht will facilitate the prioritization of targets based on both genomic and functional evidence, inform the most appropriate genetic context for downstream mechanistic and validation studies and facilitate the translation of this information into therapeutics and diagnostis.