Pharmacology Core

项目说明/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，以提供 为所有拟议的研究提供全面的药理学支持。药理学支持的研究 CORE将解决关键的药理学问题，并将为新药的关键决定提供信息 GBM的发展，包括围绕血脑屏障(BBB)的问题。对药物能力的理解 通过血脑屏障分布到肿瘤组织和周围被GBM细胞渗透的正常脑组织是至关重要的 对于开发有效的治疗方法很重要，特别是那些可能导致长期 生死存亡。拟议的中心项目重点是开发使用DNA损伤的组合方案 针对共济失调毛细血管扩张突变(ATM)和ATM及Rad3相关(ATR)的反应(DDR)抑制剂 信号通路(方案1)或P53/小鼠双分钟2(MDM2)通路(方案2)。这些药物的功效 联合策略依赖于在整个肿瘤体积的最佳时间内充分暴露药物， 包括浸润性区域。此外，这两个项目都将使用严格的药代动力学空间评估。 这些药物在正常脑内和全身的(PK)过程和由此产生的药效学(PD)效应 设计并实施脑肿瘤组织最有效的联合治疗方案。药理学 CORE由威廉·埃尔姆奎斯特博士领导，他是明尼苏达大学的药剂学教授，也是 通过血脑屏障(BBB)将药物分布到正常脑和脑内的PK方面的世界专家 肿瘤。他的主要合作调查员包括麻省理工学院的福里斯特·怀特博士和 哈佛大学的娜塔莉·琼脂。这三个研究小组有着广泛的合作历史， 计划中的许多战略都已通过这种跨 三个实验室。这一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中枢神经系统分布分析 具体目标2：支持药效生物标记物的开发 具体目标3：支持人类0/1期临床试验开发

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