A novel strategy to overcome the P-gp/BCRP drug efflux system at the blood-brain barrier to improve brain uptake of CNS therapeutics

克服血脑屏障处的 P-gp/BCRP 药物流出系统以改善中枢神经系统治疗药物的大脑摄取的新策略

• 批准号: 10225435
• 负责人: Bjoern Bauer
• 金额: $ 38.25万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225435
• 关键词: ABCB1 gene; ABCG2 gene; AKT inhibition; Antineoplastic Agents; Blood - brain barrier anatomy; Blood capillaries; Brain; Brain Neoplasms; Cells; Cerebral hemisphere; Clinic; Clinical; Contralateral; Data; Development; Distant; Drug Efflux; Excision; FRAP1 gene; Failure; Glioblastoma; Goals; Human; Individual; Ipsilateral; Knowledge; Lateral; Lead; Mediating; Mission; Modeling; Molecular; Mus; National Institute of Neurological Disorders and Stroke; Natural regeneration; Outcome; PTEN gene; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Primary Neoplasm; Public Health; Regulation; Research; Research Personnel; Signal Transduction; Solid; System; TNF gene; TNFRSF1A gene; Testing; Therapeutic; Translating; Treatment outcome; United States National Institutes of Health; Work; base; blood-brain barrier function; cerebral capillary; effective therapy; evidence base; expectation; improved; in vivo; inhibitor/antagonist; innovation; lapatinib; neoplastic cell; nervous system disorder; novel; novel strategies; overexpression; prevent; therapeutically effective; treatment strategy; tumor; uptake

Failure of anticancer drug treatment is largely due to overexpression of the P-gp/BCRP drug efflux system at the blood-brain barrier. New evidence suggests that glioblastoma multiforme (GBM) induces P-gp/BCRP over- expression in capillaries of the brain hemisphere that is contralateral to the tumor. Thus, after surgical removal of the primary tumor, remnant tumor cells that are scattered throughout the brain remain shielded from anti- cancer drugs. This poses a significant clinical problem and represents an unmet critical need to develop strat- egies to overcome P-gp/BCRP. The absence of such strategies will likely prevent improvements in GBM ther- apy. The long-term goal of the investigator is to identify molecular mechanisms that control blood-brain barrier function and can be targeted to improve brain uptake of anticancer drugs. The overall objective of this applica- tion is to develop an effective therapeutic strategy to overcome P-gp/BCRP-mediated anticancer drug efflux and prolong survival in mice with GBM. Based on preliminary data the central hypothesis is that GBM induces P-gp/BCRP overexpression and that inhibiting PI3K/Akt will decrease P-gp/BCRP overexpression, which will increase brain uptake of anticancer drugs, thereby reducing tumor size and prolonging GBM mouse survival. The rationale for this research is that its successful completion is expected to provide a solid, evidence-based scientific framework for translating our strategy into the clinic. Based on strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Determine the mechanism(s) by which GBM induces P-gp/BCRP overexpression; 2) Identify pathways that regulate P-gp/BCRP at the human blood-brain barrier; and 3) Develop a therapeutic strategy to increase anticancer drug brain uptake in GBM mice. Under the first aim, mechanistic steps involved in GBM-induced overexpression of P-gp/BCRP will be assessed in brain capil- laries of the hemisphere contralateral to the primary tumor. The impact of blocking these steps on brain uptake of anticancer drugs in GBM-bearing mice will be determined. Under the second aim, P-gp/BCRP regulation by the PTEN/PI3K/Akt/mTOR pathway will be determined in brain capillaries from normal individuals and from GBM patients. Under the third aim, the therapeutic benefit of combining PI3K/Akt inhibitors with anticancer drugs to reduce P-gp/BCRP levels with the goal of improving brain uptake of anticancer drugs and prolonging survival will be assessed in three different GBM models. The proposed research is innovative, in the appli- cant's opinion, because it represents a new and substantive departure from the status quo by shifting the focus to GBM-induced overexpression of blood-brain barrier P-gp/BCRP in the contralateral hemisphere and by uti- lizing a molecular switch-based approach to overcome P-gp/BCRP-mediated drug efflux to target remnant tu- mor cells distant from the primary tumor. The proposed research is significant because it is expected that the new knowledge may have broad translational importance in the treatment of patients with GBM and potentially other brain tumors as well.

抗癌药物治疗的失败主要是由于p-gp/bcrp药物外排的过表达 血脑屏障。新的证据表明，多形胶质母细胞瘤（GBM）诱导P-gp/bcrp过度 脑半球毛细血管中的表达与肿瘤对侧。因此，手术切除后 在原发性肿瘤中，散布在整个大脑中的残留肿瘤细胞仍然避免 癌症药物。这构成了一个重大的临床问题，代表了发展阶层的未满足的重要需求 克服p-gp/bcrp的人。缺乏此类策略可能会阻止GBM治疗的改善 APY。研究者的长期目标是确定控制血脑屏障的分子机制 功能，可以针对改善抗癌药物的大脑摄取。该应用程序的总体目标 旨在制定有效的治疗策略来克服P-gp/BCRP介导的抗癌药物外排 并在GBM中延长小鼠的生存。基于初步数据，中心假设是GBM诱导 P-GP/BCRP过表达和抑制PI3K/AKT会降低P-gp/bcrp过表达，这将降低 增加抗癌药物的大脑摄取，从而减少肿瘤大小并延长GBM小鼠的存活。 这项研究的理由是，其成功的完成有望提供稳定的，循证的 将我们的策略转化为诊所的科学框架。基于强大的初步数据，该假设 将通过追求三个具体目标来测试：1）确定GBM诱导的机制 p-gp/bcrp过表达； 2）确定在人类血脑屏障上调节P-gp/bcrp的途径； 3）制定一种治疗策略，以增加GBM小鼠的抗癌药物脑摄取。在第一个 目的，将评估GBM诱导的P-gp/BCRP过表达的机械步骤将在脑capil-中评估 半球的laries与原发性肿瘤对侧。阻止这些步骤对大脑吸收的影响 将确定携带GBM小鼠中抗癌药物的抗癌药物。在第二个目标下，P-GP/BCRP调节 PTEN/PI3K/AKT/MTOR途径将在正常个体的脑毛细血管中确定 GBM患者。在第三个目标下，将PI3K/AKT抑制剂与抗癌相结合的治疗益处 降低p-gp/bcrp水平的药物，目的是改善抗癌药物的大脑摄取并延长 生存率将在三种不同的GBM模型中进行评估。拟议的研究具有创新性，在应用中 CAN的意见，因为它通过转移重点来代表与现状的新事物相去甚远 在对侧半球中，GBM引起的血脑屏障P-gp/bcrp的过表达以及 利用基于分子开关的方法来克服p-gp/bcrp介导的药物外排，以靶向残留的tu- MOR细胞远离原发性肿瘤。拟议的研究很重要，因为期望 新知识可能在治疗GBM患者和潜在的患者中具有广泛的翻译重要性 其他脑肿瘤也是如此。