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: 10657403
• 负责人: AMANDA G PAULOVICH
• 金额: $ 69.28万
• 依托单位: FRED HUTCHINSON CANCER 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10657403
• 关键词: Analytical Chemistry; Antibodies; Antibody Specificity; Biological Assay; Biomedical Engineering; Blood Cells; Calibration; 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; Heterogeneity; Human; Immunoassay; Immunohistochemistry; Industrialization; Industry; Laboratories; Leadership; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Measurement; Methods; Modernization; National Cancer Institute; Pathologist; Pathology; Pathway interactions; Patient Selection; Performance; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Phosphotransferases; Process; Protein Biochemistry; Proteins; Proteome; Proteomics; Protocols documentation; Reagent; Research Personnel; Sampling; Schedule; Shipping; Signal Transduction; Site; Standardization; Technology; Testing; Tissues; Translating; Translations; Tumor Suppressor Proteins; Validation; Variant; Western Blotting; Work; 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; response; small molecule; statistics; targeted cancer therapy; targeted treatment; tissue fixing; 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/).

项目概要/摘要 由于技术限制，目前还没有有效的方法来量化大多数人类蛋白质 临床生物样本，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 癌症疗法作用于蛋白质，我们无法量化蛋白质，这阻碍了靶向治疗的转化 疗法。此外，蛋白质充当互连的“网络”，因此我们必须能够量化面板 癌症中的蛋白质，以评估决定治疗反应的途径和网络的活性。我们的 该项目旨在转化（用于临床试验环境）用于量化肿瘤的多重蛋白质测定 响应 DNA 损伤的抑制蛋白和细胞信号网络 - 一个关键网络 当前的药物发现工作。该测定基于用于量化蛋白质组合用途的 NextGen 平台 靶向多反应监测质谱 (MRM-MS)，补充了现有的蛋白质检测 技术并克服了许多技术限制，包括实现多重检测 单个网络中的许多蛋白质。 MRM 已在临床前领域得到广泛验证，但尚未得到验证 已适应临床试验。我们的多学科团队汇集了具有不同背景的学术合作伙伴 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）与在药物开发和生产方面拥有丰富经验的工业合作伙伴（阿斯利康） 临床试验。这种基于 MRM 的检测小组成功适应临床试验环境将为我们提供一条道路 地图和标准操作方案 (SOP)，用于翻译其他基于 MRM 的检测面板（>1,500 检测结果已在 https://assays.cancer.gov/ 上公开提供。

项目成果

Phase I/II results of ceralasertib as monotherapy or in combination with acalabrutinib in high-risk relapsed/refractory chronic lymphocytic leukemia.

• DOI: 10.1177/20406207231173489
• 发表时间: 2023
• 期刊: THERAPEUTIC ADVANCES IN HEMATOLOGY
• 影响因子: 3.4
• 作者: Jurczak, Wojciech;Elmusharaf, Nagah;Fox, Christopher P.;Townsend, William;Paulovich, Amanda G.;Whiteaker, Jeffrey R.;Krantz, Fanny;Wun, Chuan-Chuan;Parr, Graeme;Sharma, Shringi;Munugalavadla, Veerendra;Manwani, Richa;Dean, Emma;Munir, Talha
• 通讯作者: Munir, Talha