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药物外排系统的过度表达， 血脑屏障新的证据表明，多形性胶质母细胞瘤（GBM）诱导P-gp/BCRP过度表达， 在肿瘤对侧的大脑半球的毛细血管中表达。因此，手术切除后， 在原发性肿瘤中，散布在整个大脑中的残余肿瘤细胞仍然受到抗- 抗癌药这提出了一个重大的临床问题，并代表了一个未满足的关键需要，发展战略， 克服P-gp/BCRP。缺乏这些策略可能会阻止GBM的改善， - 是的研究者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抗癌药物的脑摄取。本申请的总体目标是- 目的是开发一种有效的治疗策略来克服P-gp/BCRP介导的抗癌药物外排 并延长GBM小鼠的存活时间。基于初步数据，中心假设是GBM诱导 P-gp/BCRP过表达，抑制PI 3 K/Akt将减少P-gp/BCRP过表达，从而使P-gp/BCRP过表达 增加脑对抗癌药物的摄取，从而减小肿瘤大小并延长GBM小鼠存活。 这项研究的理由是，它的成功完成有望提供一个坚实的，以证据为基础的 将我们的战略转化为临床的科学框架。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过表达; 2）确定在人血脑屏障上调节P-gp/BCRP的途径; 和3）开发治疗策略以增加GBM小鼠中的抗癌药物脑摄取。根据第一项 目的是在脑毛细血管中评估GBM诱导的P-gp/BCRP过度表达的机制步骤， 原发肿瘤对侧半球的裂孔。阻断这些步骤对大脑摄取的影响 将测定荷GBM小鼠中抗癌药物的浓度。在第二个目标下，P-gp/BCRP的调节是通过 将在正常个体的脑毛细血管中测定PTEN/PI 3 K/Akt/mTOR途径， GBM患者。在第三个目的下，将PI 3 K/Akt抑制剂与抗癌药物组合的治疗益处是显著的。 降低P-gp/BCRP水平的药物，目的是改善抗癌药物的脑摄取， 将在三种不同的GBM模型中评估存活率。该研究具有一定的创新性和实用性。 cant的意见，因为它代表了一个新的和实质性的脱离现状的转移重点 GBM诱导的对侧半球血脑屏障P-gp/BCRP过度表达， 利用基于分子开关的方法克服P-gp/BCRP介导的药物外排靶向残余肿瘤， 莫尔的细胞远离原发肿瘤。拟议的研究意义重大，因为预计 新的知识可能在GBM患者的治疗中具有广泛的翻译重要性， 其他脑肿瘤也一样。