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

摘要 国际上对癌症基因组特征的研究现在为我们提供了突变的初步看法， 发生在人类癌症中的拷贝数改变。这些努力扩大了我们对已知的 致癌途径，并确定了新的致癌基因和肿瘤抑制基因的类别。但 现在也很清楚，大多数上皮癌都有数百种遗传变异， 基因组不稳定性，这使得识别对肿瘤维持和驱动至关重要的突变的努力变得复杂。 肿瘤异质性此外，尚不清楚这些改变中的哪一个赋予肿瘤细胞以免疫抑制作用。 逃避免疫系统的能力。检查点阻断的临床成功受到以下因素的影响： 观察到大多数患者对免疫疗法没有反应。需要新的免疫治疗靶点， 提高肿瘤应答，指导合理联合免疫治疗克服耐药性。识别 对于肿瘤生存和免疫逃避至关重要的基因将加速新的肿瘤细胞的发展。 分子靶向治疗 在过去的几年里，我们已经开发和部署了高通量遗传和 生物信息学方法来识别和认证癌症靶点。具体来说，我们已经进行了基因组 在大量的人癌细胞系和患者来源的肿瘤细胞系中进行功能丧失和功能获得筛选 模型，并确定了新的致癌基因和合成致命的相互作用。这些实验的规模 使我们能够克服癌症固有的异质性，并对癌症依赖性进行分类， 他们的背景，这是至关重要的药物发现工作的启动。 在本申请中，我们建议使用这些研究作为一个新的丹娜-法伯癌症的基础 CTD 2中心。该中心将专注于癌症靶点的识别和认证， 开发合理定义联合治疗的方法，并鉴定调节 对免疫治疗剂的反应，所有这些都是通过使用新的体外和体内HT遗传和 生物信息学方法我们会继续把这些研究的结果， 科学界和参加CTD 2网络的活动。我们预计，该中心将提供 癌症研究界的信息，将有助于优先考虑的基础上， 基因组和功能证据，为下游机制提供最合适的遗传背景 研究，并促进这些信息转化为治疗和诊断。

Abstract International efforts to characterize cancer genomes now provide us with an initial view of the mutations and copy number alterations that occur in human cancers. These efforts have expanded our knowledge of known oncogenic pathways and have identified new classes of oncogenes and tumor suppressor genes. However, it is now also clear that most epithelial cancers harbor hundreds of genetic alterations as a consequence of genomic instability, which complicates efforts to identify mutations critical for tumor maintenance and drives tumor heterogeneity. Moreover, it remains unclear which of these alterations confers on the tumor cell the ability to evade the immune system. The emerging clinical success of checkpoint blockade is tempered by the observation that most patients do not respond to immunotherapy. New immunotherapy targets are needed to improve tumor responses and guide rational combination immunotherapy to overcome resistance. Identifying genes that are essential for tumor survival and immune evasion will accelerate the development of new molecularly targeted therapeutics. Over the past several years, we have developed and deployed high throughput genetic and bioinformatics approaches to identify and credential cancer targets. Specifically, we have performed genome scale loss of function and gain of function screens in large sets of human cancer cell lines and patient-derived models and have identified new oncogenes and synthetic lethal interactions. The scale of these experiments has allowed us to overcome the inherent heterogeneity of cancers and to classify cancer dependencies and their context, which is essential for the initiation of drug discovery efforts. In this application, we propose to use these studies as a foundation for a new Dana-Farber Cancer Institute CTD2 Center. This Center will focus on the identification of and credentialing cancer targets, developing the means to rationally define combination therapies, and the identification of genes that modulate the response to immunotherapeutics, all through the use of novel in vitro and in vivo HT genetic and bioinformatic approaches. We will continue to make the outputs of these studies readily available to the scientific community and to participate in CTD2 Network activities. We anticipate that this Center will provide the cancer research community with information that will facilitate the prioritization of targets based on both genomic and functional evidence, inform the most appropriate genetic context for downstream mechanistic studies and facilitate the translation of this information into therapeutics and diagnostics.