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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：
8900366
负责人：
William Elmquist
金额：
$ 49.36万
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 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8900366
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 targeted treatment 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）：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的临床试验中，许多新的治疗策略正在与AAT相结合。不幸的是，这些联合疗法的开发并不了解AAT如何影响肿瘤核心内部和周围血脑屏障（BBB）的完整性，以及随后新化疗药物如何通过血脑屏障传递。在胶质瘤形成过程中，VEGF和其他促血管生成因子的表达促进了未成熟肿瘤血管系统的发展，伴有部分血脑屏障的破坏。aat介导的VEGF信号抑制可以恢复紧密连接的完整性，并可能促进血脑屏障药物外排转运蛋白的表达，即使血脑屏障“正常化”