Pharmacology Core

药理学核心

基本信息

批准号：
10704629
负责人：
William Elmquist
金额：
$ 37.28万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10704629
关键词：
Address Agar Biochemical Biological Assay Biomedical Engineering Blood - brain barrier anatomy Brain Brain Neoplasms Cells Clinical Trials Collaborations DNA Damage Data Development Double Minutes Drug Exposure Drug Kinetics Evaluation Funding Heterogeneity Human Imaging technology Immunofluorescence Immunologic Infiltration Laboratories Liquid Chromatography Massachusetts Measures Minnesota Modeling Mus Normal tissue morphology Pathway interactions Periodicity Pharmaceutical Preparations Pharmacodynamics Pharmacology Pharmacy (field)Phase 0/1 Clinical Trial Process Proteomics Radiology Specialty Recording of previous events Regimen Research Research Personnel Sampling Schedule Signal Pathway Spatial Distribution Systems Analysis TP53 gene Technology Therapeutic Therapeutic Agents Therapy Evaluation Tissue Sample Tissue imaging Tissues Tumor Tissue Tumor Volume Universities Validation Work ataxia telangiectasia mutated protein combinatorial design drug development drug distribution drug efficacy effective therapy forest inhibitor innovation mass spectrometric imaging mid-career faculty neurosurgery novel therapeutics pharmacodynamic biomarker pharmacokinetics and pharmacodynamics pharmacologic phosphoproteomics physical science professor programs response tandem mass spectrometry therapeutically effective transcriptomics tumor

项目摘要

PROJECT DESCRIPTION/ABSTRACT – PHARMACOLOGY CORE The Pharmacology Core will work closely with the project teams and the Therapy Evaluation Core to provide comprehensive pharmacology support for all proposed studies. The studies supported by the Pharmacology Core will address key pharmacologic issues and will inform crucial “go-no go” decisions in novel drug development for GBM, including issues surrounding blood-brain barrier (BBB). Understanding the ability of drugs to distribute across the BBB into tumor tissue and surrounding ‘normal’ brain infiltrated by GBM cells is critically important for the development of effective therapies, especially those treatments that could lead to long-term survival. The proposed Center projects are focused on developing combinatorial regimens using DNA damage response (DDR) inhibitors targeting the ataxia telangiectasia mutated (ATM) and ATM and Rad3-related (ATR) signaling pathways (Project 1) or the p53/murine-double minute 2 (MDM2) pathway (Project 2). Efficacy of these combination strategies is dependent on adequate drug exposure at optimal times throughout the tumor volume, including the infiltrative regions. Further, both projects will use a rigorous spatial evaluation of pharmacokinetic (PK) processes and resulting pharmacodynamic (PD) effects of these drugs within normal brain and throughout brain tumor tissues to design and implement the most efficacious combination regimens. The Pharmacology Core is led by Dr. William Elmquist, who is a Professor of Pharmaceutics at the University of Minnesota and a world expert in the PK of drug distribution across the blood-brain barrier (BBB) into normal brain and brain tumors. His key co-investigators include Dr. Forest White from Massachusetts Institute of Technology and Dr. Nathalie Agar from Harvard University. These three research groups have an extensive collaborative history, and many of the strategies planned have been rigorously validated through this close collaboration across the three laboratories. The specific functions of this Pharmacology Core can be divided into three specific Aims: Specific Aim 1: Pharmacokinetic and CNS distribution analyses of novel therapeutic agents Specific Aim 2: Support the development of pharmacodynamic biomarkers Specific Aim 3: Support human Phase 0/1 clinical trial development

项目描述/摘要——药理学核心药理学核心将与项目团队和治疗评估核心密切合作，提供所有拟议研究的全面药理学支持这些研究得到药理学支持。核心将解决关键的药理学问题，并将为新药的关键“继续”决策提供信息 GBM 的发展，包括有关血脑屏障 (BBB) 的问题了解药物的能力。穿过 BBB 分布到肿瘤组织和周围被 GBM 细胞浸润的“正常”大脑至关重要对于开发有效疗法非常重要，尤其是那些可能导致长期疗效的疗法拟议的中心项目侧重于开发利用 DNA 损伤的组合疗法。针对共济失调毛细血管扩张突变 (ATM) 以及 ATM 和 Rad3 相关 (ATR) 的反应 (DDR) 抑制剂信号通路（项目 1）或 p53/鼠双分钟 2 (MDM2) 通路（项目 2）。联合策略取决于在整个肿瘤体积的最佳时间充足的药物暴露，此外，这两个项目都将使用严格的药代动力学空间评估。这些药物在正常大脑和整个大脑中的（PK）过程和由此产生的药效（PD）效应脑肿瘤组织设计和实施最有效的组合方案。 Core 由 William Elmquist 博士领导，他是明尼苏达大学药剂学教授和跨血脑屏障（BBB）药物分布进入正常大脑和大脑的PK世界专家他的主要合作研究人员包括麻省理工学院的 Forest White 博士和哈佛大学的娜塔莉·琼脂（Nathalie Agar）这三个研究小组有着广泛的合作历史，通过整个组织的密切合作，许多计划的战略都得到了严格的验证。三个实验室。该药理学核心的具体职能可分为三个具体目标：具体目标 1：新型治疗药物的药代动力学和中枢神经系统分布分析具体目标 2：支持药效生物标志物的开发具体目标 3：支持人类 0/1 期临床试验开发