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

摘要 国际上为确定癌症基因组的特征所做的努力现在为我们提供了对突变和 人类癌症中发生的拷贝数改变。这些努力扩大了我们对已知知识的了解 并发现了新的致癌基因和抑癌基因。然而，它 现在也很清楚，大多数上皮性癌症都有数百种基因改变，其结果是 基因组不稳定，使识别对肿瘤维持和驱动至关重要的突变的努力复杂化 肿瘤异质性。此外，目前还不清楚这些变化中的哪一种使肿瘤细胞 逃避免疫系统的能力。检查点封锁的新临床成功受到了 观察到大多数患者对免疫治疗没有反应。需要新的免疫治疗靶点来 提高肿瘤反应，指导合理联合免疫治疗，克服耐药性。识别 对肿瘤存活和免疫逃避至关重要的基因将加速新的 分子靶向疗法。 在过去的几年里，我们已经开发和部署了高通量的遗传和 识别和证明癌症靶点的生物信息学方法。具体地说，我们已经进行了基因组 大组人类癌细胞系和患者来源的功能筛选的比例损失和功能筛选的获得 模型，并确定了新的致癌基因和合成致死相互作用。这些实验的规模 使我们能够克服癌症固有的异质性，并对癌症的相关性和 他们的背景，这是启动药物发现努力的关键。 在本申请中，我们建议使用这些研究作为新的Dana-Farber癌症的基础 研究所CTD2中心。该中心将专注于癌症靶点的识别和认证， 开发合理定义联合疗法的方法，并识别调节基因 对免疫疗法的反应，都是通过使用新的体外和体内HT基因和 生物信息学方法。我们会继续把这些研究的结果提供给 科学界并参加CTD2网络活动。我们预计该中心将提供 癌症研究社区提供的信息将有助于根据这两个因素确定目标的优先顺序 基因组和功能证据，为下游机制提供最合适的遗传背景 研究并促进将这些信息转化为治疗学和诊断学。

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.