Advanced development of the Cancer Dependency Map portal (DepMap.org)

项目总结/摘要：根据一种病毒的分子特征预测漏洞的能力。 患者的肿瘤是实施癌症精准医疗的核心。虽然患者肿瘤的测序是 越来越普遍，研究人员，临床医生和药物开发人员目前缺乏识别哪种药物的能力。 体细胞改变的基因和变体是肿瘤存活所需的和/或赋予其他生物学特性的需要。 基因（合成致死性）。“癌症依赖地图（DepMap）”项目直接解决了这一问题 挑战.这项工作继续每季度生成和发布出版前数据 目前包括超过1，000种基因组注释的癌细胞系和类器官， 模型，超过750个全基因组CRISPR/Cas9活性筛选，以及大规模药物再利用筛选 总计超过一百万个数据点此外，我们还创建了各种计算算法， 发现依赖性并从分子特征中推断它们。 为了确保科学界能够轻松地使用这些数据和工具来进行科学发现，我们 于2018年4月推出depmap.org试点。该试点旨在了解如何最好地支持分析 以及各地研究人员对这些数据（无论是在布罗德研究所还是其他地方创建的）的可视化。 该试点证明是成功的：目前，depmap.org有62，000名用户，访问量超过800个独特的 每天有超过200个实验室的研究人员。 在这里，我们建议对depmap.org进行高级开发，以满足不同用户的新需求 社群： ●癌症生物学家：使用depmap.org来发现基因和变体的功能，以及这些基因和变体如何在癌症中发挥作用。 导致网络变化，从而导致漏洞（用户的编程经验有限，我们将 强调用户体验，使研究人员自己的数据上传和互操作性， 其他实验研究工具）; ●转化癌症研究人员：使用depmap.org从CRISPR数据中优先考虑新靶点， 现有药物在特定肿瘤类型背景下的作用机制，以促进药物发现 （用户编程经验有限，我们会强调用户体验和瘤型 功能、与cBioPortal和患者数据的连接）; ●计算专家：旨在开发新的预测建模应用程序和数据分析工具 可以很容易地与depmap.org社区共享（用户有广泛的编程 经验，我们将强调创建应用程序编程接口（API）协议和支持 与depmap.org共享新的计算工具） 我们的修订提案侧重于三个互补的具体目标： 在目标1中，我们将开发新的功能，以支持预定义的癌症科学调查 生物学家和翻译研究人员。在这里，我们将（a）使用户能够通过 药物和CRISPR生存力数据的综合分析，（B）创建将患者肿瘤与细胞模型连接的工具， (c)开发作用机制功能和（d）支持肿瘤和基因型特异性查询。在目标2中， 我们将为癌症生物学家和翻译人员开发新的可视化和交互式分析工具， 研究人员以及高级计算人员的API。这将包括由多个 机构以及与用户上传的数据和API进行互操作的新功能， 外部分析的数据。在目标3中，我们将开发一套资源来培训和吸引不同的用户 社区这项工作将包括一个主要的培训和推广计划和实时沟通渠道 用户反馈和支持。 ITCR的提案将使我们走上一条大多数癌症患者常规使用depmap.org的道路。 全世界的研究人员。如果得到资助，这一提议将是支持这一项目的唯一专用资金来源。 这个广受欢迎的门户网站的维护和扩展根本无法维持在所需的水平 没有专门的资金。因此，它将对基础和转化癌症产生重大影响 研究，使计算学家和生物学家能够继续做出关键的癌症发现。

PROJECT SUMMARY/ABSTRACT: The ability to predict vulnerabilities given the molecular features of a patient’s tumor is central to operationalizing cancer precision medicine. While sequencing of patient tumors is increasingly common, researchers, clinicians, and drug developers currently lack the ability to identify which somatically altered genes and variants are required for tumor survival and/or confer a requirement for other genes (synthetic lethality). The “Cancer Dependency Map (DepMap)” project directly addresses this challenge. This effort, which continues to generate and release pre-publication data on a quarterly basis without restriction, currently encompasses over 1,000 genomically annotated cancer cell lines and organoid models, over 750 genome-wide CRISPR/Cas9 viability screens, and large scale drug repurposing screens totaling over 1,000,000 data points. In addition, we have created a wide range of computational algorithms to discover dependencies and to infer them from molecular features. To ensure that the scientific community can easily use these data and tools to make scientific discoveries, we launched the pilot of depmap.org on April 2018. This pilot aimed to learn how best to support the analysis and visualization of such data (whether created at the Broad Institute or elsewhere) by researchers everywhere. The pilot proved to be a success: currently, depmap.org has 62,000 users and is visited by >800 unique researchers from >200 laboratories daily. Here, we propose the advanced development of depmap.org to address the emerging needs of distinct user communities: ● cancer biologists: use depmap.org to discover the function of genes and variants and how these induce network changes that result in vulnerabilities (users have limited programming experience, we will emphasize user experience, enabling the upload of researchers’ own data and the interoperability with other experimental research tools); ● translational cancer researchers: use depmap.org to prioritize new targets from CRISPR data and mechanism of action of existing drugs within specific tumor type contexts to advance drug discovery (users have limited programming experience, we will emphasize user experience and tumor-type functionality, connectivity with cBioPortal and patient data); ● computationalists: aim to develop new predictive modeling applications and data analysis tools that can be readily shared back with the depmap.org community (users have extensive programing experience, we will emphasize creating application programming interface (API) protocols and support sharing of new computational tools back with depmap.org) Our revised proposal focuses on three complementary Specific Aims: In Aim 1, we will develop new functionalities to support pre-defined scientific inquiries of cancer biologists and translational researchers. Here, we will (a) enable users to prioritize cancer targets via the integrated analysis of drug and CRISPR viability data, (b) create tools to connect patient tumors with cell models, (c) develop mechanism of action functionality and (d) support tumor- and genotype-specific inquiries. In Aim 2, we will develop new visualization and interactive analysis tools for cancer biologists and translational researchers as well as APIs for advanced computationalists. This will include data generated by multiple institutions as well as new functionality for interoperability with user uploaded data and APIs to export harmonized data for outside analysis. In Aim 3, we will develop a set of resources to train and engage a diverse user community. This work will include a major training and outreach program and real-time communication channels for user feedback and support. This ITCR proposal will put us on a path towards the routine use of depmap.org by a majority of cancer researchers worldwide. If funded, this proposal would represent the only dedicated source of funds to support the maintenance and expansion of this popular portal which simply cannot be sustained at the needed level without dedicated funding. As such, it will have a significant impact on both basic and translational cancer research and enable computationalists and biologists to continue to make key cancer discoveries.