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

癌症依赖性地图门户网站 (DepMap.org) 的高级开发

• 批准号: 10058960
• 负责人: Aviad Tsherniak
• 金额: $ 79.11万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-03 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10058960
• 关键词: Academia; Address; Advanced Development; Back; Biological; CRISPR/Cas technology; Cancer cell line; Cell Line; Cell model; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Communication; Communities; Complement; Computational algorithm; Data; Data Analyses; Data Set; Dependence; Development; Education and Outreach; Educational workshop; Ensure; Environment; Feedback; Fostering; Funding; Funding Agency; Future; Genes; Genomics; Genotype; Goals; Human; Industry; Institutes; Institution; Intuition; Investments; Laboratories; Laboratory Research; Learning; Maintenance; Malignant Neoplasms; Maps; Methods; Modeling; Molecular; Organoids; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Philosophy; Protocols documentation; Public Health; Publications; RNA Interference; Research; Research Personnel; Resources; Scientific Inquiry; Survival Rate; Testing; Therapeutic; Time; Training; Training Programs; Variant; Visit; Visualization; Visualization software; Work; anticancer research; application programming interface; base; cBioPortal; cancer genomics; cancer type; computerized tools; data access; data harmonization; data interoperability; data portal; data tools; drug discovery; drug sensitivity; experience; experimental study; gene function; genetic variant; genome-wide; interest; interoperability; member; outreach program; precision medicine; precision oncology; predictive modeling; programs; success; tool; translational cancer research; translational scientist; tumor; user-friendly; webinar

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.

项目摘要/摘要：根据分子特征预测漏洞的能力 患者的肿瘤对于实施癌症精准医学至关重要。虽然对患者肿瘤进行测序 越来越常见的是，研究人员、临床医生和药物开发商目前缺乏识别哪些疾病的能力 体细胞改变的基因和变体是肿瘤生存所必需的和/或赋予其他 基因（合成致死率）。 “癌症依赖图（DepMap）”项目直接解决了这个问题 挑战。这项工作将继续每季度生成和发布预发布数据 无限制，目前涵盖超过 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 活力筛选以及大规模药物再利用筛选 总计超过 1,000,000 个数据点。此外，我们还创建了多种计算算法来 发现依赖性并从分子特征推断它们。 为了确保科学界能够轻松地使用这些数据和工具来做出科学发现，我们 于 2018 年 4 月启动了 depmap.org 试点。该试点旨在了解如何最好地支持分析 各地研究人员对此类数据（无论是在布罗德研究所还是其他地方创建）进行可视化。 试点取得了成功：目前，depmap.org 拥有 62,000 名用户，超过 800 名独立用户访问 每天来自超过 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兴需求 社区： ● 癌症生物学家：使用 depmap.org 发现基因和变异的功能以及它们如何发挥作用 诱发网络变化导致漏洞（用户编程经验有限，我们将 强调用户体验，实现研究人员自己的数据上传以及与 其他实验研究工具）； ● 转化癌症研究人员：使用 depmap.org 对 CRISPR 数据中的新靶标进行优先排序，并 现有药物在特定肿瘤类型背景下的作用机制，以推进药物发现 （用户编程经验有限，我们会强调用户体验和肿瘤类型 功能、与 cBioPortal 的连接和患者数据）； ● 计算学家：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） 我们修订后的提案侧重于三个互补的具体目标： 在目标 1 中，我们将开发新功能来支持预先定义的癌症科学调查 生物学家和转化研究人员。在这里，我们将 (a) 使用户能够通过以下方式优先考虑癌症目标： 药物和 CRISPR 活力数据的综合分析，(b) 创建将患者肿瘤与细胞模型连接起来的工具， (c) 开发作用功能机制；(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转化学家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专家的 API。这将包括多个生成的数据 机构以及与用户上传的数据和 API 进行互操作的新功能，以导出协调一致的数据 供外部分析的数据。在目标 3 中，我们将开发一套资源来培训和吸引多元化的用户 社区。这项工作将包括主要的培训和外展计划以及实时沟通渠道 以获得用户反馈和支持。 这项 ITCR 提案将使我们走上大多数癌症患者常规使用 depmap.org 的道路 全世界的研究人员。如果获得资助，该提案将成为支持的唯一专用资金来源 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 没有专门的资金。因此，它将对基础癌症和转化癌症产生重大影响 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。