Influence of Anti-Angiogenic Therapy on Drug Delivery to Brain Tumors

描述（由申请方提供）：靶向血管内皮生长因子（VEGF）轴的抗血管生成治疗（AAT）是复发性胶质母细胞瘤（GBM）治疗的重要组成部分。在下一代GBM临床试验中，许多新的治疗策略正在与AAT联合开发。不幸的是，这些组合的开发没有理解AAT如何影响肿瘤核心中和周围的血脑屏障（BBB）的完整性以及随后新的化疗剂穿过BBB的递送。在胶质瘤发生期间，VEGF和其他促血管生成因子的表达促进未成熟肿瘤脉管系统的发展，伴有部分BBB破坏。AAT介导的VEGF信号传导的抑制可以恢复紧密连接的完整性并潜在地促进BBB药物外排转运蛋白的表达，即，“正常化” BBB脉管系统。在GBM临床试验中与AAT组合测试的许多药物具有有限的BBB渗透。本申请中的研究将测试核心假设，即AAT介导的BBB完整性恢复可能会矛盾地减少同时给药的药物向肿瘤的递送，导致疗效降低。该假设将在马约组的原发性GBM异种移植物和明尼苏达大学衍生的基因工程GBM模型（GEMM）中进行检验。目的之一是确定抗VEGF抗体Bev、VEGFR抑制剂西地尼布和新型PI 3 K/mTOR抑制剂GNE-317对原发性GBM异种移植物和GEMM中脑微血管功能（灌注、紧密连接和外排转运）的影响。目的二将检查Bev和GNE-317的抗血管生成作用如何改变具有不同BBB渗透性特征的相关药剂的药物递送（位点特异性药代动力学）（例如，替莫唑胺、厄洛替尼、GDC-0980和GNE-317）。我们假设，AAT将对递送和所产生的疗效产生可变的不利影响，这取决于联合治疗。目的三将测试两种不同的策略以提高组合疗法的功效：a）破坏BB B外排转运蛋白活性以增强AAT-转运蛋白底物组合的功效，和B）操纵化学结构以降低外排倾向并增加被动渗透性以增强AAT + PI 3 K/mTOR抑制剂组合的功效。许多与AAT联合开发的用于GBM的新型药物被BBB排除在外。因此，了解AAT对BBB完整性和药物递送的影响对于成功开发用于复发性GBM的AAT组合疗法至关重要。计划中的研究将确定影响AAT联合治疗方案疗效的关键参数，并在将来的联合收割机抗血管生成药物与其他新型治疗药物联合治疗的试验中使用这些信息改善患者结局。

DESCRIPTION (provided by applicant): Anti-angiogenic therapy (AAT) targeting the vascular endothelial growth factor (VEGF) axis is an important component of treatment for recurrent glioblastoma (GBM). Many novel therapeutic strategies are being developed in combination with AAT in the next generation of clinical trials for GBM. Unfortunately, these combinations have been developed without an understanding of how AAT influences the integrity of the blood-brain barrier (BBB) in and around the tumor core and the subsequent delivery of novel chemotherapeutic agents across the BBB. During gliomagenesis, expression of VEGF and other pro-angiogenic factors promotes development of an immature tumor vasculature with partial BBB disruption. AAT-mediated inhibition of VEGF signaling can restore tight junction integrity and potentially promote expression of BBB drug efflux transporters, i.e., "normalize" the BBB vasculature. Many drugs being tested in GBM clinical trials in combination with AAT have limited BBB penetration. Studies in this application will test the central hypothesis that AAT-mediated restoration of BBB integrity may paradoxically reduce delivery of concomitantly administered drugs to the tumor, leading to reduced efficacy. This hypothesis will be tested both in the Mayo panel of primary GBM xenografts and in University of Minnesota-derived genetically engineered GBM models (GEMMs). Aim one will determine the influence of the anti-VEGF antibody, Bev, the VEGFR inhibitor, cediranib, and a novel PI3K/mTOR inhibitor, GNE-317, on brain microvasculature function (perfusion, tight junctions and efflux transport) in primary GBM xenografts and GEMMs. Aim two will examine how anti-angiogenic effects of Bev and GNE-317 alter drug delivery (site-specific pharmacokinetics) for relevant agents that have different BBB permeability characteristics (e.g., temozolomide, erlotinib, GDC-0980 and GNE-317). We hypothesize that AAT will have a variable detrimental impact on delivery and resultant efficacy depending on the combination therapy. Aim three will test two distinct strategies to improve the efficacy of combination therapies: a) disruption of BBB efflux transporter activity to enhance the efficacy of AAT-transporter substrate combinations, and b) manipulation of chemical structure to reduce efflux liability and increase passive permeability to enhance efficacy of AAT + PI3K/mTOR inhibitor combinations. Many novel agents for GBM being developed in combination with AAT are excluded by the BBB. Thus, understanding the impact of AAT on BBB integrity and drug delivery is critical for successful development of AAT combination therapies for recurrent GBM. The planned studies will define critical parameters that influence the efficacy of AAT combination regimens and use that information to improve patient outcome in future trials that combine anti-angiogenic agents with other novel therapeutics.