Clinical translation of a NexGen platform for quantifying protein networks in human biospecimens

用于量化人类生物样本中蛋白质网络的 NexGen 平台的临床转化

• 批准号: 10190852
• 负责人: AMANDA G PAULOVICH
• 金额: --
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190852
• 关键词: Analytical Chemistry; Antibodies; Antibody Specificity; Biological Assay; Biomedical Engineering; Blood Cells; Clinical; Clinical Chemistry; Clinical Trials; Collaborations; Communities; Complement; Conduct Clinical Trials; DNA Damage; Data; Development; Dose; Ensure; Environment; Enzyme-Linked Immunosorbent Assay; Formalin; Freezing; Genomics; Goals; Guidelines; Human; Immunoassay; Immunohistochemistry; Industrialization; Industry; Laboratories; Leadership; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Measurement; Methods; Modernization; National Cancer Institute; Pathologist; Pathology; Pathway interactions; Patients; Performance; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Phosphotransferases; Process; Protein Biochemistry; Proteins; Proteome; Proteomics; Protocols documentation; Research Personnel; Sampling; Schedule; Shipping; Signal Transduction; Site; Specimen; Standardization; Technology; Testing; Tissues; Translating; Translations; Tumor Suppressor Proteins; Validation; Variant; Western Blotting; Work; base; cancer therapy; clinical translation; driver mutation; drug candidate; drug development; drug discovery; early phase clinical trial; early phase trial; experience; improved; innovation; multidisciplinary; multiple reaction monitoring; multiplex assay; next generation; novel; novel anticancer drug; novel therapeutics; open source; pre-clinical; precision oncology; reagent standard; response; small molecule; statistics; targeted cancer therapy; targeted treatment; treatment response; tumor

Project Summary/Abstract Due to technological limitations, there are no validated assays for quantifying the majority of human proteins in clinical biospecimens, and thus most of the human proteome is clinically inaccessible. Because most modern cancer therapies act on proteins, our inability to quantify proteins is an impediment to the translation of targeted therapies. Furthermore, proteins act as interconnected “networks,” and thus we must be able to quantify panels of proteins in cancers to assess the activity of pathways and networks that determine treatment responses. Our project aims to translate (for use in clinical trial settings) a multiplex protein assay for quantifying tumor suppressor proteins and cell signaling networks that response to DNA damage- a critical network targeted by current drug discovery efforts. The assay is based on a NextGen platform for quantifying protein panels uses targeted, multiple reaction monitoring mass spectrometry (MRM-MS), which complements existing protein assay technologies and overcomes many of the technological limitations, including enabling multiplexing of assays for many proteins in a single network. MRM has been extensively validated in the preclinical space but has not yet been adapted for clinical trials. Our multidisciplinary team brings together academic partners with diverse expertise (MRM-MS, analytical chemistry, clinical chemistry, pathology, statistics, bioengineering, protein biochemistry) with an industrial partner (AstraZeneca) that has extensive experience in drug development and clinical trials. Successful adaptation of this MRM-based assay panel to the clinical trial setting will provide a road map and standard operating protocols (SOPs) for translation of additional MRM-based assay panels (>1,500 assays are already publicly available at https://assays.cancer.gov/).

项目摘要/摘要 由于技术的限制，目前还没有经过验证的方法来定量测定人体中的大多数蛋白质。 临床生物标本，因此大多数人类蛋白质组在临床上是无法获得的。因为最现代的 癌症治疗作用于蛋白质，我们无法量化蛋白质是靶向翻译的障碍 治疗。此外，蛋白质充当相互连接的“网络”，因此我们必须能够量化面板 以评估决定治疗反应的通路和网络的活性。我们的 该项目旨在转化(用于临床试验环境)一种用于量化肿瘤的多重蛋白质分析方法 抑制蛋白和对DNA损伤做出反应的细胞信号网络--一个关键的网络 目前的药物发现工作。该分析基于NextGen平台，用于量化蛋白质面板的使用 靶向多反应监测质谱学(MRM-MS)是对现有蛋白质分析的补充 技术，并克服了许多技术限制，包括实现分析的多路传输 在一个单一的网络中有许多蛋白质。MRM已经在临床前领域得到了广泛的验证，但还没有 已被改编用于临床试验。我们的多学科团队将不同学科的学术合作伙伴聚集在一起 专业知识(MRM-MS、分析化学、临床化学、病理学、统计学、生物工程、蛋白质 生物化学)与阿斯利康(AstraZeneca)合作，阿斯利康在药物开发和 临床试验。这一基于MRM的分析小组成功地适应临床试验环境将提供一条道路 MAP和标准操作规程(SOP)，用于翻译其他基于MRM的分析小组(&gt；1,500 化验方法已经在https://assays.cancer.gov/).上公开提供