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

• 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
• 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

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(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)是治疗复发胶质母细胞瘤(GBM)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结合开发。不幸的是，这些组合的开发并不了解AAT如何影响肿瘤核心内和周围的血脑屏障(BBB)的完整性，以及随后新的化疗药物通过BBB的输送。在胶质瘤形成过程中，血管内皮生长因子和其他促血管生成因子的表达促进了部分血脑屏障破坏的未成熟肿瘤血管的发展。AAT介导的抑制血管内皮生长因子信号可以恢复紧密连接的完整性，并潜在地促进BBB药物外流转运体的表达，即使 血脑屏障血管系统。许多在GBM临床试验中与AAT联合测试的药物的血脑屏障渗透率有限。这项应用中的研究将检验一个中心假设，即AAT介导的血脑屏障完整性的恢复可能会矛盾地减少同时给药到肿瘤的药物输送，导致疗效降低。这一假设将在原始GBM异种移植的Mayo小组和明尼苏达大学衍生的基因工程GBM模型(GEMM)中进行验证。目的研究抗血管内皮生长因子抗体BEV、VEGFR抑制剂头孢拉尼和新型PI3K/mTOR抑制剂GNOE-317对原代GBM异种移植和GEMM微血管功能(灌流、紧密连接和外流转运)的影响。目的研究Bev和GNE-317对血脑屏障通透性不同的相关药物(如替莫唑胺、厄洛替尼、GDC-0980和GNE-317)的抗血管生成作用。我们假设，根据联合治疗的不同，AAT将对分娩和由此产生的疗效产生可变的有害影响。目的三将测试两种不同的策略来提高联合治疗的疗效：a)阻断血脑屏障外排转运体活性以增强AAT-转运体底物组合的疗效，以及b)操纵化学结构以减少外排倾向并增加被动通透性以增强AAT+PI3K/mTOR抑制剂组合的疗效。许多与AAT联合开发的GBM新药被BBB排除在外。因此，了解AAT对血脑屏障完整性和药物传递的影响对于成功开发AAT联合疗法治疗复发性GBM至关重要。计划中的研究将确定影响AAT联合疗法疗效的关键参数，并利用这些信息在未来将抗血管生成剂与其他新疗法相结合的试验中改善患者结果。