Development of Targeted Anticancer Drugs

描述（由申请人提供）：该项目涉及开发一种新的药物开发范式，该范式侧重于使用动物临床前研究来获得预测性药代动力学[PK] -药效学[PD]模型，该模型可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药物在靶组织（在这种情况下是大脑和脑肿瘤）中的PK-PD特性是药物开发计划不可或缺的一部分。提出的药物开发策略将被证明为一系列表皮生长因子受体（EGFR）抑制剂，一类小分子量化合物，是靶向抗癌药物的代表，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，这种方法依赖于过多的药物功效研究，缺乏对药物应如何用于人类的预测能力。此外，EGFR抑制剂是确定癌症患者靶向治疗最佳剂量的问题的代表，因为这类药物通常不具有易于确定的剂量限制毒性，通常指导标准细胞毒素的使用。PK-PD驱动的方法将依赖于混合PK-PD模型的使用，该模型使目标组织（即脑肿瘤）能够以生理术语表示，从而适应药物处置的机制描述，并促进模型扩展到人类。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在其他已知分子特征的脑肿瘤模型中的更广泛适用性。具体目的的概要是：1)筛选新的EGFR抑制剂，以盒式给药形式用于大脑积聚；2)确定与EGFR信号通路相关的体外PD终点；3)建立小鼠PK-PD杂交模型；4)基于使用PK-PD等效给药方案评估药物在一系列脑肿瘤类型中的疗效。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、选择和随后设计基于模型预测的PK-PD终点的治疗方案。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：将新的抗癌药物的临床前药理信息传递给患者，并不能提供一个直接的渠道来确保生物学相关和最佳药物剂量的施用。目前的提案将试图通过实施一种基于药物在靶组织中的药代动力学和药效学特征的新药物开发范式来纠正这些缺陷，该项目的靶组织是脑肿瘤。

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.