Pharmacologic and Genomic Imaging Core

药理学和基因组成像核心

• 批准号: 10491826
• 负责人: Mario Luca Suva
• 金额: $ 22.96万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491826
• 关键词: Adult Glioblastoma; Agar; Animal Model; Blood - brain barrier anatomy; Blood Vessels; Brain Neoplasms; Cell Nucleus; Cells; Clinic; Clinical; Clinical Research; Clinical Trials; Complex; Consent; Dana-Farber Cancer Institute; Data; Development; Disease; Drug Targeting; Drug or chemical Tissue Distribution; Ensure; Epigenetic Process; Equipment; Experimental Models; Freezing; Gene Expression; Genetic; Genomics; Glioblastoma; Glioma; Goals; Heterogeneity; Histopathology; Hospitals; Human Resources; Image; Immune; Infrastructure; Knowledge; Maps; Mass Spectrum Analysis; Measurement; Metabolic Pathway; Methods; Modeling; Multi-Institutional Clinical Trial; Multiplexed Ion Beam Imaging; Mus; Neuroglia; Neurons; Organ; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacotherapy; Pre-Clinical Model; Procedures; Proteins; Quality Control; Reagent; Reproducibility; Resistance; Resolution; Resources; Sampling; Services; Signal Transduction; Site; Slide; Specimen; Standardization; Technical Expertise; Techniques; Technology; Testing; Therapeutic; Therapeutic Effect; Tissues; brain tissue; cancer cell; cancer heterogeneity; data sharing; design; digital imaging; drug candidate; drug distribution; effective therapy; fluorescence imaging; genome-wide; imaging system; improved; in vivo imaging; innovation; liquid crystal polymer; mass spectrometric imaging; metabolomics; mouse model; neoplastic cell; neuropathology; new therapeutic target; novel; patient derived xenograft model; patient oriented; pharmacodynamic model; programs; response; single cell technology; success; targeted therapy trials; transcriptome sequencing; transcriptomics; treatment response; tumor; tumor heterogeneity; tumor microenvironment

Summary: Glioblastoma represents a complex disease in which heterogeneity in both tumor composition and drug distribution needs to be considered for understanding treatment response. Genetic, epigenetic and developmental programs that differ between malignant cells influence the response to any drug candidates (DC). Additionally, pathophysiological barriers of the microenvironment and vasculature, such as the blood- brain barrier (BBB), produce heterogeneous distribution of DC, de facto exposing heterogeneous malignant cells and their microenvironment to variable drug concentrations. Assessing these variable parameters is paramount to precisely dissect the response of glioblastoma to any DC. Many targeted therapy trials have failed to incorporate such measurements, hampering our ability to interpret results. The Pharmacological and Genomic Imaging Core (PGIC) of the Harvard/Stanford U19 Program will provide state-of-art technical expertise and resources for characterizing drug concentration and glioblastoma response in patient tumor samples and in comprehensively characterized orthotopic mouse patient-derived xenografts (PDX) glioma models. PGIC brings together multiscale technologies from microscale analysis to macroscale organ in vivo imaging with micro- and macro-scale registration. PGIC provides an integrated platform to fuse detailed histopathology, drug distribution, metabolomics, and single-cell transcriptomics with registration to in vivo imaging when available. Specifically, PGIC will: (Aim1) perform spatially-resolved measurements of DC and metabolic pathways in brain tissue specimens sampled from both clinical trials and experimental models; (Aim 2) perform single-nucleus RNA-sequencing analysis of glioma and microenvironmental cells from frozen clinical samples and pre-clinical models of glioblastoma; (Aim 3) perform spatial analysis of dynamic therapeutic effects in glioblastoma patient samples and models using spatial transcriptomics and multiplex digital imaging. We have developed innovative and efficient clinical pipelines and multi-site clinical trials infrastructure to obtain samples for PGIC analysis and put in place systematic workflows in the hospital setting. Our analyses will be performed on frozen samples, facilitating the flow of acquired specimen across multiple sites in the Harvard/Stanford GTN. PGIC will provide consistent workflows, standardize the acquisition of samples and data, provide expert personnel, facilitate the sharing of knowledge within the program, and maintain the sophisticated equipment necessary to generate data for all Projects which is critical for data reproducibility and data sharing across projects. PGIC will be led Dr. Mario Suvà, Dr Nathalie Agar and Dr. Keith Ligon who will contribute their expertise in single-cell technologies, mass spectrometry imaging and neuropathology.

总结： 胶质母细胞瘤代表了一种复杂的疾病，其中肿瘤成分和药物的异质性 为了理解治疗反应，需要考虑分布。遗传的、表观遗传的和 恶性细胞之间不同的发育程序会影响对任何候选药物的反应 （DC）。此外，微环境和脉管系统的病理生理屏障，如血液- 脑屏障（BBB），产生异质性分布的DC，事实上暴露异质性恶性 细胞及其微环境对不同药物浓度的影响。评估这些可变参数是 这对于精确分析胶质母细胞瘤对任何DC的反应至关重要。许多靶向治疗试验 未能纳入这些测量，妨碍了我们解释结果的能力。药理学和 哈佛/斯坦福大学U19项目的基因组成像核心（PGIC）将提供最先进的技术， 用于表征患者肿瘤中药物浓度和胶质母细胞瘤反应的专业知识和资源 样品和全面表征的原位小鼠患者来源的异种移植物（PDX）胶质瘤 模型PGIC汇集了从微观分析到宏观器官的多尺度技术 通过微观和宏观尺度配准进行成像。PGIC提供了一个集成平台， 组织病理学、药物分布、代谢组学和单细胞转录组学与体内登记 成像时可用。具体而言，PGIC将：（目标1）对DC进行空间分辨测量， 从临床试验和实验模型中取样的脑组织标本中的代谢途径;（目的 2)对冷冻的胶质瘤和微环境细胞进行单核RNA测序分析， 胶质母细胞瘤的临床样本和临床前模型;（目标3）进行动态空间分析 使用空间转录组学和多路复用技术在胶质母细胞瘤患者样品和模型中的治疗效果 数字成像我们开发了创新和高效的临床管道和多中心临床试验 我们需要建立基础设施，以获取PGIC分析所需的样本，并在医院环境中实施系统化的工作流程。 我们的分析将在冷冻样本上进行，便于采集的标本在多个 在哈佛/斯坦福大学GTN的网站。PGIC将提供一致的工作流程，标准化采购， 样本和数据，提供专家人员，促进计划内的知识共享，以及 维护为所有项目生成数据所需的精密设备，这对数据至关重要 可重复性和跨项目的数据共享。PGIC将由Mario Suvà博士、Nathalie Agar博士和 基思利贡谁将贡献他们的专业知识，在单细胞技术，质谱成像和 神经病理学