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（由申请人提供）：针对血管内皮生长因子（VEGF）轴的抗血管生成疗法（AAT）是复发性胶质母细胞瘤（GBM）治疗的重要组成部分。在GBM的下一代临床试验中，正在开发许多新型的治疗策略。不幸的是，这些组合已经开发出来，而没有了解AAT如何影响肿瘤核心及其周围血脑屏障（BBB）的完整性以及随后在BBB中的新型化学治疗剂的递送。在神经胶质作用期间，VEGF和其他促血管生成因子的表达促进了未成熟的肿瘤脉管系统的发展，并部分BBB破坏。 AAT介导的VEGF信号的抑制可以恢复紧密的连接完整性，并有可能促进BBB药物外排转运蛋白的表达，即“正常化” BBB脉管系统。在GBM临床试验中与AAT结合使用的许多药物在BBB渗透中有限。在本应用中的研究将检验一个中心假设：AAT介导的BBB完整性的恢复可能会矛盾地减少同时给药的药物向肿瘤的递送，从而降低疗效。该假设将在原发性GBM异种移植物的Mayo面板和明尼苏达大学衍生的基因工程GBM模型（GEMMS）中进行检验。 AIM ONE将确定抗VEGF抗体，BEV，VEGFR抑制剂，Cediranib和新型的PI3K/MTOR抑制剂GNE-317对主要GBM Xenografts和Gemms中的脑微血管功能（灌注，紧密连接和外排运输）的影响。目标两个将研究BEV和GNE-317的抗血管生成作用如何对具有不同BBB渗透率特征不同的相关药物（例如，Temozolomide，Erlotinib，GDC-0980和GNE-317）的相关药物进行抗血管生成作用。我们假设AAT会根据联合疗法的不同，对递送的有害影响和最终功效。 AIM三将测试两种不同的策略来提高组合疗法的功效：a）BBB外排运输蛋白活性的破坏，以增强AAT-转运蛋白底物组合的功效，b）化学结构以减少外排责任的操纵并降低AAT + PI3K/mmmtor的无源渗透性并提高释放性的功效。 BBB排除了许多与AAT结合使用的GBM的新型GBM的新药。因此，了解AAT对BBB完整性和药物递送的影响对于成功开发AAT组合疗法的复发性GBM至关重要。计划的研究将定义关键参数，以影响AAT组合方案的功效，并在将抗血管生成剂与其他新型治疗剂结合使用的未来试验中使用该信息来改善患者结果。