Making cancer precision medicine real: bottlenecks and opportunities

项目摘要 癌症精准医疗的概念很简单：患者治疗是由肿瘤的分子特征指导的。 他们的肿瘤。但实际上，情况要复杂得多。目前只有少数病人受益 从接近。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。这些挑战是本研究建议的重点。为 例如，我们现在知道，基因表达，而不是DNA水平的畸变，是最能预测药物作用的因素。 然而，整个临床基因组检测企业都专注于DNA。因此我们需要 开发适用于定量RNA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全面的地图， 考虑到肿瘤的分子特征，有可能预测药物敏感性（和遗传脆弱性）。这 需要扩大我们的细胞模型库（包括类器官、短期原代肿瘤培养物 以及结合肿瘤细胞和免疫细胞的联合收割机模型），开发出更复杂的药物读数 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。本提案旨在应对7年来的这些挑战。 通过开发新的方法和数据集，加速癌症精准医学研究， 在整个研究界。

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.