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

丹娜—法伯癌症研究所癌症靶标发现和开发中心

• 批准号: 9362809
• 负责人: William C. Hahn
• 金额: $ 102.74万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9362809
• 关键词: Bioinformatics; Biological; CRISPR/Cas technology; CRKL gene; Cancer Model; Cancer cell line; Carcinoma; Clinical; Clinical Trials; Colon Carcinoma; Combined Modality Therapy; Communities; Credentialing; Dana-Farber Cancer Institute; Data; Dependency; Development; Diagnostic; FRS2 gene; Foundations; Future; GAB2 gene; Gene Combinations; Gene Targeting; Genes; Genetic; Genetic Screening; Genomic Instability; Genomics; Goals; Human; Immune; Immune Evasion; Immune Response Genes; Immune system; Immunotherapeutic agent; Immunotherapy; In Vitro; International; Investigator-Initiated Research; Investments; Knowledge; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mammalian Cell; Maps; Methodology; Methods; Modeling; Mus; Mutation; Oncogenes; Oncogenic; Open Reading Frames; Output; Pathway interactions; Patients; RNA Interference; Research Infrastructure; Resistance; SMARCA2 gene; Suppressor Genes; System; TBK1 gene; Techniques; Technology; Testing; Therapeutic; Translations; Tumor Suppressor Genes; anticancer research; base; cancer cell; cancer classification; cancer genome; cancer heterogeneity; drug discovery; effective therapy; experimental study; gain of function; gene discovery; genetic technology; genome-wide; immune checkpoint blockade; improved; in vivo; insight; loss of function; member; molecular targeted therapies; neoplastic cell; novel; novel therapeutic intervention; pressure; programs; response; success; therapeutic candidate; therapeutic target; tool; translational study; tumor; tumor heterogeneity

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.

抽象的 现在，国际癌症基因组的努力为我们提供了突变和 人类癌症发生的拷贝数变化。这些努力扩大了我们对已知的知识 致癌途径，并确定了新的癌基因和肿瘤抑制基因。但是，它 现在也清楚地表明，大多数上皮癌的遗传改变是由于 基因组不稳定性，这使识别肿瘤维持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既赋予肿瘤细胞 能够逃避免疫系统。检查点封锁的新兴临床成功是由 观察到大多数患者对免疫疗法没有反应。需要新的免疫疗法目标 改善肿瘤反应并指导有理组合免疫疗法以克服抗药性。识别 对于肿瘤生存和免疫逃避必不可少的基因将加速新的发展 分子靶向疗法。 在过去的几年中，我们开发并部署了高吞吐量遗传和 生物信息学方法以识别和凭证癌症靶标。具体来说，我们已经进行了基因组 功能的尺度丧失和功能屏幕的增益在大量人类癌细胞系和患者衍生下 模型并确定了新的癌基因和合成致命相互作用。这些实验的规模 使我们能够克服癌症的固有异质性，并分类癌症的依赖性和 他们的背景，这对于启动药物发现工作至关重要。 在此应用程序中，我们建议将这些研究用作新的Dana-Farber癌的基础 研究所CTD2中心。该中心将着重于识别和凭证癌症目标， 开发合理定义组合疗法的手段，以及调节基因的识别 通过使用新型体外和体内HT遗传和 生物信息学方法。我们将继续使这些研究的产出很容易获得 科学界并参加CTD2网络活动。我们预计这个中心将提供 癌症研究界的信息将促进基于两者的目标的优先级 基因组和功能证据，为下游机械的最合适的遗传环境提供信息 研究并促进将这些信息转化为治疗剂和诊断。