Development of Targeted Anticancer Drugs

靶向抗癌药物的开发

基本信息

批准号：
7522199
负责人：
James M. Gallo
金额：
$ 31.13万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7522199
关键词：
Animals Antineoplastic Agents Area Under Curve Behavior Biological Assay Blood - brain barrier anatomy Brain Brain Neoplasms Bypass Cancer Patient Cell Line Cells Characteristics Class Clinical Clinical Trials Coupled Data Set Development Dose Dose-Limiting Drug Efflux Drug Kinetics Drug or chemical Tissue Distribution End Point Ensure Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib Failure Gefitinib Glioma Goals Human Hybrids In Vitro Individual Inhibitory Concentration 50 Investigation Lead Letters Link Measurement Measures Modeling Molecular Molecular Weight Motivation Mus Oral Pathway interactions Patients Penetration Pharmaceutical Preparations Pharmacodynamics Pharmacogenetics Phase Physiological Plasma Procedures Property Protocols documentation Public Health Range Reliance Route Schedule Scheme Screening procedure Series Signal Pathway Site Standards of Weights and Measures Testing Therapeutic Time Tissues Translations Treatment Protocols Tumor-Derived Tyrosine Kinase Inhibitor anti-cancer therapeutic base cytotoxic cytotoxicity design desire drug development drug discovery drug efficacy drug sensitivity efflux pump epidermal growth factor receptor VIII in vivo mutant neoplastic cell novel pre-clinical preclinical study progesterone 11-hemisuccinate-(2-iodohistamine)programs scale up therapeutic target tool tumor uptake

项目摘要

DESCRIPTION (provided by applicant): This project is concerned with the development of a new drug development paradigm that focuses on the use of preclinical studies in animals to derive predictive pharmacokinetic [PK] - pharmacodynamic [PD] models that can aid in the rational selection of drug candidates, and be used to predict human PK-PD characteristics. A unique feature of the proposal is that the drug's PK-PD properties in target tissues, in this case brain and brain tumors, are integral to the drug development plan. The proposed drug development strategy will be demonstrated for a series of epidermal growth factor receptor [EGFR] inhibitors, a class of small molecular weight compounds that are represenative of targeted anticancer drugs, an emerging anticancer therapeutic strategy. The motivation for this new drug development approach is based on limitations of current semi-empirical anticancer drug development approaches, which rely on a plethora of drug efficacy studies that lack predictive capability on how drugs should be used in humans. Moreover, EGFR inhibitors are representative of the problems of defining optimal doses for targeted therapies in cancer patients, since these classes of drugs often do not possess readily identified dose-limiting toxicites that typically guide the use of standard cytotoxics. The PK-PD driven approach will rely on the use of hybrid PK-PD models that enables a target tissue [i.e. brain tumors] to be represented in physiological terms, which accomodates a mechanistic depiction of drug disposition, and facilitates model scale-up to humans. The drug development scheme will be implemented in brain tumor models that differ only in EGFR status, one being wild-type and the other the vIII mutant, which is associated with drug sensitivity, which will allow us to test the broader applicability of the approach to other brain tumor models whose molecular characteristics are known. A synopsis of the Specific Aims are 1) screen new EGFR inhibitors for brain accumulation in a cassette dosing format; 2) determine in vitro PD endpoints associated with EGFR signaling pathways; 3) develop hybrid PK-PD models in mice; and 4) evaluate drug efficacy in a range of brain tumor types based on the use of PK-PD equivalent dosing regimens. The proposed drug development package relies on a drug's in vivo pharmacological behavior to screen, select, and subsequently design therapeutic regimens based on model-predicted PK-PD endpoints. It is believed that this approach offers the best opportunity to develop drugs in a rational and optimal manner. PUBLIC HEALTH RELEVANCE: The translation of preclinical pharmacological information of new anticancer drugs to patients does not offer a direct conduit to ensure biologically relevant and optimal drug doses are administered. The current proposal will attempt to rectify these deficiencies through the implementation of a new drug development paradigm based on a drug's pharmacokinetic and pharmacodynamic characteristics in the target tissue, which for this project is brain tumors.

描述（由申请人提供）：该项目涉及新药物开发范例的开发，该范例侧重于使用动物临床前研究来导出预测药代动力学 [PK] - 药效学 [PD] 模型，以帮助合理选择候选药物，并用于预测人类 PK-PD 特征。该提案的一个独特之处在于，该药物在靶组织（在本例中为脑和脑肿瘤）中的 PK-PD 特性是药物开发计划不可或缺的一部分。拟议的药物开发策略将针对一系列表皮生长因子受体[EGFR]抑制剂进行论证，这是一类代表靶向抗癌药物的小分子量化合物，是一种新兴的抗癌治疗策略。这种新药物开发方法的动机是基于当前半经验抗癌药物开发方法的局限性，这些方法依赖于大量的药物疗效研究，而这些研究缺乏对药物应如何在人类中使用的预测能力。此外，EGFR抑制剂代表了确定癌症患者靶向治疗最佳剂量的问题，因为这类药物通常不具有容易识别的剂量限制毒性，而这些毒性通常指导标准细胞毒素的使用。 PK-PD 驱动方法将依赖于混合 PK-PD 模型的使用，该模型能够实现目标组织 [即脑肿瘤]以生理学术语表示，它可以对药物分布进行机械描述，并有助于将模型扩大到人类。该药物开发方案将在仅 EGFR 状态不同的脑肿瘤模型中实施，一种是野生型，另一种是与药物敏感性相关的 vIII 突变体，这将使我们能够测试该方法更广泛的适用性其他分子特征已知的脑肿瘤模型。具体目标的概要是 1) 筛选新的 EGFR 抑制剂，以盒式给药形式进行脑蓄积； 2）确定与EGFR信号通路相关的体外PD终点； 3）开发小鼠混合PK-PD模型； 4) 基于 PK-PD 等效剂量方案的使用，评估多种脑肿瘤类型的药物疗效。拟议的药物开发方案依赖于药物的体内药理学行为来筛选、选择，并随后根据模型预测的 PK-PD 终点设计治疗方案。人们相信这种方法提供了以合理和最佳方式开发药物的最佳机会。公共卫生相关性：将新抗癌药物的临床前药理学信息翻译给患者并不能提供直接的渠道来确保施用生物学相关的最佳药物剂量。目前的提案将尝试通过实施新的药物开发范例来纠正这些缺陷，该范例基于药物在目标组织中的药代动力学和药效学特征，对于该项目来说，目标组织是脑肿瘤。