Pharmacology Core

药理学核心

• 批准号: 10305364
• 负责人: William Elmquist
• 金额: $ 20.9万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10305364
• 关键词: Address; Agar; Biochemical; Biological; Biological Assay; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Cells; Clinical Trials; Collaborations; DNA Damage; Data; Development; Double Minutes; Drug Exposure; Drug Kinetics; Engineering; Evaluation; Funding; Heterogeneity; Human; Image; Imaging technology; Immunofluorescence Immunologic; Institutes; Laboratories; Lead; Liquid Chromatography; Mass Spectrum Analysis; 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; Time; 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/antagonist; innovation; mid-career faculty; neurosurgery; novel therapeutics; pharmacodynamic biomarker; pharmacokinetics and pharmacodynamics; phosphoproteomics; physical science; professor; programs; response; specific biomarkers; tandem mass spectrometry; therapeutically effective; transcriptomics; tumor

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价核心密切合作， 为所有拟定研究提供全面的药理学支持。药理学支持的研究 核心将解决关键的药理学问题，并将告知新药开发中的关键“去-不去”决定 GBM的发展，包括围绕血脑屏障（BBB）的问题。了解药物的能力 通过血脑屏障分布到肿瘤组织和周围被GBM细胞浸润的“正常”脑中是至关重要的 对于开发有效的治疗方法，特别是那些可能导致长期死亡的治疗方法， 生存拟议的中心项目的重点是开发利用DNA损伤的组合方案 靶向共济失调毛细血管扩张突变（ATM）和ATM和Rad 3相关（ATR）的DDR反应（DDR）抑制剂 信号通路（项目1）或p53/鼠双微体2（MDM 2）通路（项目2）。这些的功效 联合策略依赖于在整个肿瘤体积的最佳时间的充分药物暴露， 包括渗透区域。此外，这两个项目都将使用严格的药代动力学空间评价 (PK)这些药物在正常脑内和整个脑组织中的作用过程和产生的药效学（PD）效应 脑肿瘤组织来设计和实施最有效的组合方案。The Pharmacology 核心由William Elmquist博士领导，他是明尼苏达大学的药剂学教授， 药物通过血脑屏障（BBB）进入正常大脑和大脑的PK方面的世界专家 肿瘤的他的主要合作研究者包括来自马萨诸塞州理工学院的Forest白色博士和来自麻省理工学院的Dr. 来自哈佛大学的Nathalie Agar这三个研究小组有着广泛的合作历史， 许多计划中的战略已经通过跨部门的密切合作得到了严格的验证， 三个实验室该药理学核心的具体功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CNS分布分析 具体目标2：支持药效学生物标志物的开发 具体目标3：支持人类0/1期临床试验开发