Development of Targeted Anticancer Drugs

描述(申请人提供)：该项目致力于开发一种新的药物开发范式，重点是利用动物的临床前研究来推导预测性药代动力学[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。该提案的一个独特特点是，药物在目标组织中的PK-PD特性，在这种情况下是脑和脑瘤，是药物开发计划的组成部分。拟议的药物开发战略将用于一系列表皮生长因子受体[EGFR]抑制剂，这是一种代表靶向抗癌药物的小分子化合物，是一种新兴的抗癌治疗策略。这种新药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，这些方法依赖于过多的药物疗效研究，这些研究缺乏对药物应该如何在人类身上使用的预测能力。此外，EGFR抑制剂代表了为癌症患者的靶向治疗确定最佳剂量的问题，因为这些类别的药物通常不具有容易识别的剂量限制毒物，这些毒物通常指导标准细胞毒物的使用。PK-PD驱动的方法将依赖于混合PK-PD模型的使用，该混合模型使目标组织[即脑瘤]能够以生理术语表示，这符合药物处置的机械性描述，并有助于模型放大到人类。药物开发计划将在只有EGFR状态不同的脑瘤模型中实施，一个是野生型，另一个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瘤模型中的更广泛适用性。具体目标的概要是：1)以盒式给药形式筛选新的EGFR抑制剂用于脑积聚；2)在体外确定与EGFR信号通路相关的PD终点；3)在小鼠身上建立混合PK-PD模型；以及4)基于PK-PD等量给药方案的使用，评估一系列脑瘤类型的药物疗效。拟议的药物开发方案依赖于药物的体内药理行为来筛选、选择并随后基于模型预测的PK-PD终点设计治疗方案。人们认为，这种方法为以合理和最佳的方式开发药物提供了最佳机会。公共卫生相关性：将新的抗癌药物的临床前药理信息翻译给患者并不提供直接渠道，以确保给予具有生物相关性和最佳药物剂量。目前的提案将试图通过实施一种基于药物在目标组织中的药代动力学和药效学特征的新药开发范例来纠正这些不足，对于本项目来说，靶组织是脑瘤。

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.