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

抗癌药物治疗的失败在很大程度上是由于P-gp/BCRP药物外排系统在 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，在手术切除后 在原发肿瘤中，散布在大脑各处的残留肿瘤细胞仍然不受抗肿瘤药物的保护 抗癌药物。这构成了一个重大的临床问题，并代表了开发战略的迫切需要。 克服P-gp/BCRP的EGES。缺乏这样的战略可能会阻碍GBM治疗的改进。 APY。研究人员的长期目标是确定控制血脑屏障的分子机制。 并可靶向提高大脑对抗癌药物的摄取。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介导的抗癌药物外流 并延长GBM小鼠的存活时间。根据初步数据，中心假设是GBM诱导 P-gp/BCRP过表达和抑制PI3K/Akt将减少P-gp/BCRP过表达，这将 增加大脑对抗癌药物的摄取，从而缩小肿瘤体积，延长GBM小鼠的存活时间。 这项研究的基本原理是，它的成功完成预计将提供一个坚实的、有证据的 将我们的战略转化为临床的科学框架。基于强大的初步数据，这一假设 将通过追求三个具体目标来检验：1)确定GBM诱导的机制(S) P-gp/BCRP过表达；2)确定调节人血脑屏障P-gp/BCRP的途径； 以及3)开发一种治疗策略，以增加GBM小鼠对抗癌药物的脑摄取。在第一个下 目的：探讨GBM诱导P-gp/BCRP过度表达的机制步骤。 与原发肿瘤相对的半球内的淋巴管。阻断这些步骤对大脑摄取的影响 将测定携带GBM的小鼠中抗癌药物的含量。在第二个目标下，P-gp/BCRP通过 PTEN/PI3K/Akt/mTOR通路将在正常人和正常人的脑毛细血管中确定。 GBM患者。在第三个目标下，PI3K/Akt抑制剂与抗癌药物联合治疗的益处 降低P-gp/BCRP水平的药物，目的是提高大脑对抗癌药物的摄取并延长 将在三种不同的GBM模型中评估存活率。建议的研究具有创新性，在应用方面-- Cant的观点，因为它代表着通过转移焦点而与现状发生了新的实质性偏离 对GBM诱导的对侧大脑半球血脑屏障P-gp/BCRP过度表达及尿路感染的影响 应用基于分子开关的方法克服P-gp/BCRP介导的药物外排靶向肿瘤残留 远离原发肿瘤的MOR细胞。这项拟议的研究具有重要意义，因为预计 新的知识可能在治疗GBM患者中具有广泛的翻译重要性，并可能 其他脑瘤也是如此。

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.