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

抗血管生成治疗对脑肿瘤药物输送的影响

基本信息

批准号：
8702251
负责人：
William Elmquist
金额：
$ 48.88万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8702251
关键词：
Angiogenesis Inhibitors Angiogenic Factor Antibodies Blood - brain barrier anatomy Blood Circulation Blood Vessels Blood capillaries Brain Brain Neoplasms Capillary Endothelial Cell Characteristics Chemical Structure Clinical Trials Combined Modality Therapy Development Distant Drug Combinations Drug Delivery Systems Drug Efflux Drug Kinetics Effectiveness Endothelial Cells Endothelium Erlotinib FDA approved Future Genetic Engineering Genetically Engineered Mouse Glioblastoma Gliomagenesis Growth Ligands Malignant neoplasm of brain Mediating Methods Minnesota Modeling Monoclonal Antibodies North America Outcome Patients Penetration Perfusion Permeability Pharmaceutical Preparations Phosphotransferases Physiology Progression-Free Survivals Recurrence Regimen Role Side Signal Transduction Site Systemic Therapy Testing Therapeutic Therapeutic Agents Tight Junctions Tumor Burden Universities Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors Vascular blood supply Work Xenograft procedure base bevacizumab capillary chemotherapeutic agent chemotherapy effective therapy efflux pump human FRAP1 protein improved inhibitor/antagonist mTOR Inhibitor mouse model neoplastic cell next generation novel novel therapeutics prevent restoration temozolomide tumor

项目摘要

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.

描述（由申请人提供）：针对血管内皮生长因子（VEGF）轴的抗血管生成治疗（AAT）是治疗复发性胶质母细胞瘤（GBM）的重要组成部分。在 GBM 的下一代临床试验中，许多新的治疗策略正在与 AAT 结合开发。不幸的是，这些组合的开发并没有了解 AAT 如何影响肿瘤核心内部和周围血脑屏障 (BBB) 的完整性，以及随后跨 BBB 输送新型化疗药物。在神经胶质瘤发生过程中，VEGF 和其他促血管生成因子的表达促进了部分 BBB 破坏的未成熟肿瘤血管系统的发育。 AAT 介导的 VEGF 信号传导抑制可以恢复紧密连接的完整性，并可能促进 BBB 药物外排转运蛋白的表达，即“正常化” BBB 脉管系统。 GBM 临床试验中与 AAT 联合使用的许多药物都限制了 BBB 渗透。本申请中的研究将检验一个中心假设，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输送，从而导致疗效降低。这一假设将在梅奥原发性 GBM 异种移植组和明尼苏达大学衍生的基因工程 GBM 模型 (GEMM) 中得到检验。目标一将确定抗 VEGF 抗体 Bev、VEGFR 抑制剂西地尼布和新型 PI3K/mTOR 抑制剂 GNE-317 对原发性 GBM 异种移植物中脑微血管功能（灌注、紧密连接和外排转运）的影响和 GEMM。目标二将研究 Bev 和 GNE-317 的抗血管生成作用如何改变具有不同 BBB 通透性特征的相关药物（例如替莫唑胺、厄洛替尼、GDC-0980 和 GNE-317）的药物递送（位点特异性药代动力学）。我们假设 AAT 将对分娩和最终疗效产生不同的不利影响，具体取决于联合疗法。目标三将测试两种不同的策略来提高联合疗法的功效：a）破坏BBB外排转运蛋白活性以增强AAT-转运蛋白底物组合的功效，b）操纵化学结构以减少外排倾向并增加对AAT-转运蛋白底物组合的被动渗透性增强 AAT + PI3K/mTOR 抑制剂组合的功效。许多与 AAT 联合开发的 GBM 新型药物均被 BBB 排除在外。因此，了解 AAT 对 BBB 完整性和药物输送的影响对于成功开发针对复发性 GBM 的 AAT 联合疗法至关重要。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，并利用该信息在未来将抗血管生成药物与其他新型疗法相结合的试验中改善患者的治疗结果。