Development of Targeted Anticancer Drugs

靶向抗癌药物的开发

基本信息

批准号：
7800475
负责人：
James M. Gallo
金额：
$ 35.17万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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/7800475
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 Clinical Clinical Trials Coupled Data Set Development Development Plans Dose Dose-Limiting Drug Efflux Drug Kinetics Drug or chemical Tissue Distribution 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 Regimen Reliance Route Schedule Scheme Screening procedure Series Signal Pathway Site Testing Therapeutic Time Tissues Translations Tumor Cell Line Tumor-Derived Tyrosine Kinase Inhibitor anti-cancer therapeutic base cytotoxic cytotoxicity design drug candidate drug development drug discovery drug efficacy drug sensitivity efflux pump epidermal growth factor receptor VIII in vitro activity in vivo mutant novel pre-clinical preclinical study progesterone 11-hemisuccinate-(2-iodohistamine)programs public health relevance 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）：该项目涉及一种新的药物开发范式的发展，该范式侧重于在动物中使用临床前研究来得出预测性药代动力学[PK] - 药效[PD]模型，可以帮助合理地选择药物候选者，并用于预测人类PK -PD特征。该提案的一个独特特征是该药物在靶组织中的PK-PD特性（在这种情况下为脑肿瘤）是药物开发计划不可或缺的。拟议的药物开发策略将用于一系列表皮生长因子受体[EGFR]抑制剂，这是一类代表靶向抗癌药物的小分子量化合物，这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，这些方法依赖于许多药物疗效研究，这些研究缺乏有关如何在人类中使用药物的预测能力。此外，EGFR抑制剂代表了定义癌症患者靶向疗法最佳剂量的问题，因为这些类型的药物通常不容易鉴定出通常指导使用标准细胞毒素的剂量限制性毒性毒性。 PK-PD驱动的方法将依赖于构成目标组织的混合PK-PD模型[即[脑肿瘤]可以用生理术语表示，该术语可容纳药物处置的机理描述，并促进了对人类的模型扩展。该药物开发方案将在仅在EGFR状态上不同的脑肿瘤模型中实施，一个是野生型，另一个是VIII突变体，这与药物敏感性有关，这将使我们能够检验该方法对其他分子特性的其他脑肿瘤模型的更广泛适用性。特定目的的提要是1）筛选新的EGFR抑制剂，以磁带剂量格式脑积累； 2）确定与EGFR信号通路相关的体外PD端点； 3）在小鼠中开发混合PK-PD模型； 4）根据使用PK-PD等效给药方案，评估一系列脑肿瘤类型的药物疗效。提出的药物开发软件包依靠药物的体内药理行为来筛查，选择并随后根据模型预测的PK-PD端点设计治疗方案。人们认为，这种方法为以合理和最佳的方式提供了最好的机会来开发药物。公共卫生相关性：新抗癌药物向患者的临床前药理信息的翻译不提供直接管道，以确保给予生物学相关和最佳药物剂量。当前的建议将尝试通过基于药物的药代动力学和药物动力学特征在靶组织中实施新的药物开发范式来纠正这些缺陷，这对此项目是脑肿瘤。