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: 9761586
• 负责人: Bjoern Bauer
• 金额: $ 38.64万
• 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/9761586
• 关键词: 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; P-Glycoprotein; 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 Efficacy; Treatment outcome; United States National Institutes of Health; Work; base; cerebral capillary; effective therapy; evidence base; expectation; improved; in vivo; inhibitor/antagonist; innovation; lapatinib; neoplastic cell; nervous system disorder; novel; novel strategies; overexpression; prevent; 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.

抗癌药物治疗失败很大程度上是由于P-gp/BCRP药物外排系统在 血脑屏障。新证据表明多形性胶质母细胞瘤 (GBM) 诱导 P-gp/BCRP 过度 在肿瘤对侧的大脑半球毛细血管中表达。因此，手术切除后 在原发性肿瘤中，分散在整个大脑中的残余肿瘤细胞仍然免受抗- 癌症药物。这提出了一个重大的临床问题，并代表了制定战略的未满足的关键需求。 例如克服 P-gp/BCRP。缺乏此类策略可能会阻碍 GBM 治疗的改进 阿比。研究人员的长期目标是确定控制血脑屏障的分子机制 功能并可以有针对性地提高大脑对抗癌药物的吸收。本申请的总体目标 的目标是开发一种有效的治疗策略来克服 P-gp/BCRP 介导的抗癌药物外流 并延长患有 GBM 的小鼠的生存期。根据初步数据，中心假设是 GBM 诱导 P-gp/BCRP 过表达，抑制 PI3K/Akt 将减少 P-gp/BCRP 过表达，从而 增加大脑对抗癌药物的吸收，从而减小肿瘤大小并延长 GBM 小鼠的生存期。 这项研究的基本原理是，其成功完成预计将提供坚实的、基于证据的 将我们的策略转化为临床的科学框架。该假设基于强有力的初步数据 将通过追求三个具体目标进行测试： 1) 确定 GBM 诱导的机制 P-gp/BCRP 过度表达； 2）确定在人血脑屏障上调节P-gp/BCRP的途径； 3) 制定治疗策略以增加 GBM 小鼠大脑对抗癌药物的摄取。在第一个下 目的，将在脑容量中评估 GBM 诱导的 P-gp/BCRP 过度表达所涉及的机制步骤。 原发肿瘤对侧半球的巢穴。阻止这些步骤对大脑摄取的影响 将确定携带 GBM 的小鼠中的抗癌药物的作用。根据第二个目标，P-gp/BCRP 监管 PTEN/PI3K/Akt/mTOR 通路将在正常个体和来自 GBM 患者。第三个目标是 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，目的是改善大脑对抗癌药物的吸收并延长寿命 将在三种不同的 GBM 模型中评估生存率。所提出的研究具有创新性，在应用 不能的观点，因为它代表着通过转移焦点对现状的新的实质性偏离 GBM 诱导的对侧半球血脑屏障 P-gp/BCRP 过度表达，并通过使用 正在开发一种基于分子开关的方法来克服 P-gp/BCRP 介导的药物外流，以靶向残留的 tu- mor 细胞远离原发肿瘤。拟议的研究意义重大，因为预计 新知识在 GBM 患者的治疗中可能具有广泛的转化重要性，并且有可能 其他脑肿瘤也是如此。