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

项目摘要/摘要：在给定分子特征的情况下预测漏洞的能力 患者的肿瘤是癌症精准医学手术的核心。而患者肿瘤的测序是 越来越普遍的是，研究人员、临床医生和药物开发人员目前缺乏识别哪种 肉体改变的基因和变异体是肿瘤存活所必需的，和/或赋予其他 基因(合成致命性)。“癌症依赖地图(DepMap)”项目直接解决了这一问题 挑战。这项工作继续按季度生成和发布出版前数据 不受限制，目前包括1,000多个带有基因组注释的癌细胞株和有机化合物 模型，超过750个全基因组CRISPR/Cas9活性筛查，以及大规模药物再用途筛查 总计超过100万个数据点。此外，我们还创建了广泛的计算算法来 发现依赖关系并从分子特征中推断它们。 为了确保科学界能够轻松地利用这些数据和工具进行科学发现，我们 2018年4月，Depmap.org启动试点。该试点旨在了解如何最好地支持分析 以及世界各地的研究人员对这些数据的可视化(无论是在布罗德研究所还是在其他地方创建的)。 试点被证明是成功的：目前，desmap.org拥有62,000名用户，有&gt；800 Unique访问 每天有来自200个实验室的研究人员。 在这里，我们建议对desmap.org进行高级开发，以满足不同用户不断涌现的需求 社区： 癌症生物学家：使用desmap.org来发现基因和变异的功能，以及这些 引发导致漏洞的网络更改(用户编程经验有限，我们将 强调用户体验，支持上传研究人员自己的数据并与 其他实验研究工具)； 转化型癌症研究人员：使用desmap.org从CRISPR数据和 现有药物在特定肿瘤类型背景下促进药物发现的作用机制 (用户编程经验有限，我们会强调用户体验和肿瘤型 功能、与生物门户网站和患者数据的连接)； 计算学家：目标是开发新的预测建模应用程序和数据分析工具 这些内容可以很容易地与desmap.org社区分享(用户有丰富的编程经验 经验，我们将重点创建应用程序编程接口(API)协议和支持 与desmap.org分享新的计算工具) 我们的修订提案侧重于三个相辅相成的具体目标： 在目标1中，我们将开发新的功能来支持预定义的癌症科学查询 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 综合分析药物和CRISPR活性数据，(B)创建工具，将患者肿瘤与细胞模型联系起来， (C)制定作用机制、功能和(D)支持针对肿瘤和特定基因的查询。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分析工具 研究人员以及为高级计算专家提供的API。这将包括由多个 机构以及与用户上传的数据和API的互操作性的新功能，以导出协调 用于外部分析的数据。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外展方案以及实时通信渠道 以获得用户反馈和支持。 ITCR的这项提议将使我们走上一条让大多数癌症患者常规使用Depmap.org的道路 世界各地的研究人员。如果得到资助，这项提议将是支持的唯一专门资金来源。 这个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上 如果没有专门的资金。因此，它将对基础癌症和转化性癌症产生重大影响 研究并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.