Making cancer precision medicine real: bottlenecks and opportunities

让癌症精准医疗成为现实：瓶颈与机遇

• 批准号: 10473781
• 负责人: TODD R. GOLUB
• 金额: $ 100.38万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10473781
• 关键词: Address; Cell Survival; Cell model; Cells; Clinical; Communities; Complex; DNA; Data Set; Diagnostic; Drug resistance; Gene Expression; Genetic Predisposition to Disease; Genomics; Immune; Maps; Mediating; Methods; Minority; Modeling; Molecular; Organoids; Patients; Pre-Clinical Model; Primary Neoplasm; RNA; Research; Research Proposals; Testing; base; drug action; drug response prediction; drug sensitivity; in situ sequencing; insight; neoplastic cell; precision oncology; public health relevance; tumor; tumor microenvironment

PROJECT SUMMARY The concept of cancer precision medicine is simple: patient treatments are guided by the molecular features of their tumor. In practice, however, the situation is more complex. Only a minority of patients at present benefit from the approach. A number of scientific challenges must be overcome before cancer precision medicine can become a reality for all patients. These challenges are the focus on the present research proposal. For example, we now know that gene expression, not DNA-level aberrations, are the most predictive of drug response, and yet the entire clinical genomic testing enterprise is focused on DNA. We therefore need to develop methods suitable for quantitative RNA-based diagnostics, likely using emerging single cell and in situ sequencing methods. In addition, we must develop comprehensive maps using preclinical models that make it possible to predict drug sensitivity (and genetic vulnerabilities) given the molecular features of the tumor. This will require expanding our repertoire of cell models (to include organoids, short-term primary tumor cultures and models that combine tumor cells and immune cells), developing more sophisticated read-outs of drug action beyond viability, and also developing new insights into the influence of the tumor microenvironment on mediating cell survival and drug resistance. The present proposal aims to address these challenges over the 7 years ahead by developing new methods and datasets that will accelerate cancer precision medicine research throughout the research community.

项目概要 癌症精准医学的概念很简单：患者的治疗以癌症的分子特征为指导。 他们的肿瘤。然而，在实践中，情况更为复杂。目前只有少数患者受益 从方法。在癌症精准医学能够实现之前，必须克服许多科学挑战 成为所有患者的现实。这些挑战是本研究提案的重点。为了 例如，我们现在知道基因表达，而不是 DNA 水平的畸变，是最能预测药物的 反应，但整个临床基因组测试企业都专注于 DNA。因此我们需要 开发适合基于 RNA 的定量诊断的方法，可能使用新兴的单细胞和原位 测序方法。此外，我们必须使用临床前模型开发综合图谱，使其成为可能 鉴于肿瘤的分子特征，可以预测药物敏感性（和遗传脆弱性）。这 将需要扩大我们的细胞模型库（包括类器官、短期原发性肿瘤培养物 以及结合肿瘤细胞和免疫细胞的模型），开发更复杂的药物读数 超越生存能力的行动，并对肿瘤微环境的影响提出新的见解 介导细胞存活和耐药性。本提案旨在解决 7 年内的这些挑战 通过开发新方法和数据集来加速癌症精准医学研究，未来几年 整个研究界。