Preclinical evaluation of novel therapeutics for CNS tumor therapy

目前，我们有几个由动物护理和使用委员会批准的积极方案，用于新药物的临床前药代动力学分析，与POB的药理学和实验治疗学部门保持着持续的合作关系，并与NCI的分子药理学部门(Doug Figg)建立了新的合作关系，以合作进行新药物的药理学研究。我们已经成功地从壁内和壁外来源获得了新的药物进行评估，并正在开发临床前环境中的生物标记物。一般来说，抗肿瘤药物要发挥作用，你需要：a)一种活性物质，b)对肿瘤的输送，c)它必须以其活性形式存在于肿瘤部位，d)有效浓度，e)足够长的时间(即有效暴露)和f)达到上述要求所需剂量的耐受性。对于靶向治疗，我们需要知道靶点是否存在。我们正在开发进一步研究目前处于临床试验中的药物的作用机制的方法，并研究药物活性和肿瘤反应的生物标记物或替代标记物。我们开发了一种新的脑微透析动物模型，以确定脑脊液渗透是否是中枢神经系统组织渗透的合适替代品。我们还在评估常见的同步用药，如类固醇对化疗药物药代动力学的影响。由于PI的离开，这个项目停止了。

We currently have several active protocols approved by the Animal Care and Use Committee for preclinical pharmacokinetic analysis of new agents,a continued collaborative relationship with the Pharmacology and Experimental Therapeutics Section of the POB, and a new collaborative relationship with the Molecular Pharmacology Section (Doug Figg) of NCI to partner in pharmacologic investigations of new agents. We have successfully obtained new agents from intramural and extramural sources to evaluate, and are developing biomarkers in the preclinical setting. In general, for an antitumor agent to have an effect, you need: a) an active agent, b) Delivery to tumor c) it must be present at tumor site in its active form, d) Effective concentrations, e) Long enough period of time (i.e.e effective exposure) and f) Tolerability at doses necessary to achieve above. For targeted therapy, we need to know if the target is present. We are developing methods to further investigate the mechanisms of action of agents currently in clinical trials, and investigate biomarkers or surrogate markers of drug activity and tumor response. We have developed a new animal model for brain microdialysis in an effort to determine if cerebrospinal fluid penetration is an appropriate surrogate for CNS tissue penetration. We are also evaluating effects of common concurrent medications such as steroids on the pharmacokinetics of chemotherapeutic agents. This project halted due to the PI departure.